Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 1 of 148 PageID: 1

Charles M. Lizza William C. Baton SAUL EWING ARNSTEIN & LEHR LLP One Riverfront Plaza, Suite 1520 Newark, New Jersey 07102-5426 (973) 286-6700 [email protected]

Attorneys for Plaintiff Celgene Corporation

UNITED STATES DISTRICT COURT DISTRICT OF NEW JERSEY

CELGENE CORPORATION, Civil Action No. ______Plaintiff, COMPLAINT FOR v. PATENT INFRINGEMENT

DR. REDDY’S LABORATORIES, LTD. (Filed Electronically) and DR. REDDY’S LABORATORIES, INC.,

Defendants.

Plaintiff Celgene Corporation (“Celgene”), by its undersigned attorneys, for its

Complaint against defendants Dr. Reddy’s Laboratories, Ltd. (“DRL Ltd.”) and Dr. Reddy’s

Laboratories, Inc. (“DRL Inc.,” together with DRL Ltd., “DRL” or “Defendants”), alleges as

follows:

Nature of the Action

1. This is an action for patent infringement under the patent laws of the United

States, 35 U.S.C. §100, et seq., arising from the filing of Abbreviated New Drug Application

(“ANDA”) No. 213234 (“DRL’s ANDA”) with the United States Food and Drug Administration

® (“FDA”) seeking approval to commercially market generic versions of Celgene’s POMALYST

drug products prior to the expiration of United States Patent Nos. 8,198,262 (the “’262 patent”), Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 2 of 148 PageID: 2

8,673,939 (the “’939 patent”), 8,735,428 (the “’428 patent”), 8,828,427 (the “’427 patent”), and

9,993,467 (the “’467 patent”), all owned by Celgene (collectively, “the patents-in-suit”).

The Parties

2. Plaintiff Celgene is a biopharmaceutical company committed to improving the

lives of patients worldwide. Celgene focuses on, and invests heavily in, the discovery and

development of products for the treatment of severe and life-threatening conditions. Celgene is a world leader in the treatment of many such diseases, including cancer. Celgene is a corporation organized and existing under the laws of the State of Delaware, having a principal place of business at 86 Morris Avenue, Summit, New Jersey 07901.

3. On information and belief, Defendant DRL Ltd. is a public limited liability

company organized and existing under the laws of India, having a principal place of business at

8-2-337, Road No. 3, Banjara Hills, Hyderabad, Telangana, India 500 034.

4. On information and belief, Defendant DRL Inc. is a corporation organized and

existing under the laws of New Jersey, having a principal place of business at 107 College

Road East, Princeton, NJ 08540.

5. On information and belief, DRL Inc. is a wholly owned subsidiary of DRL Ltd.

6. On information and belief, DRL Inc. is the authorized U.S. agent for DRL Ltd.

The Patents-in-Suit

7. On June 12, 2012, the United States Patent and Trademark Office (“USPTO”)

duly and lawfully issued the ’262 patent, entitled, “Methods for treating multiple myeloma using

4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione,” to Celgene as assignee of the inventor Jerome B. Zeldis. A copy of the ’262 patent is attached hereto as Exhibit A.

8. On March 18, 2014, the USPTO duly and lawfully issued the ’939 patent,

entitled, “Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-

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isoindoline-1,3-dione,” to Celgene as assignee of the inventor Jerome B. Zeldis. A copy of the

’939 patent is attached hereto as Exhibit B.

9. On May 27, 2014, the USPTO duly and lawfully issued the ’428 patent, entitled,

“Methods for treating multiple myeloma with 4-(amino)-2-(2,6-dioxo(3-piperidyl))-

isoindoline-1,3-dione,” to Celgene as assignee of the inventor Jerome B. Zeldis. A copy of the

’428 patent is attached hereto as Exhibit C.

10. On September 9, 2014, the USPTO duly and lawfully issued the ’427 patent,

entitled, “Formulations of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione,” to

Celgene as assignee of the inventors Anthony Tutino and Michael T. Kelly. A copy of the

’427 patent is attached hereto as Exhibit D.

11. On June 12, 2018, the USPTO duly and lawfully issued the ’467 patent, entitled,

“Formulations of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione,” to Celgene as

assignee of the inventors Anthony J. Tutino and Michael T. Kelly. A copy of the ’467 patent is

attached hereto as Exhibit E.

® The POMALYST Drug Product

12. Celgene holds an approved New Drug Application (“NDA”) under Section

505(a) of the Federal Food Drug and Cosmetic Act (“FFDCA”), 21 U.S.C. § 355(a), for

® pomalidomide capsules (NDA No. 204026), which it sells under the trade name POMALYST .

® POMALYST is an FDA-approved medication used for the treatment of multiple myeloma.

13. The claims of the patents-in-suit cover, inter alia, methods of use and administration of pomalidomide or pharmaceutical compositions containing pomalidomide.

14. Pursuant to 21 U.S.C. § 355(b)(1) and attendant FDA regulations, the patents- in-suit are listed in the FDA publication, “Approved Drug Products with Therapeutic

® Equivalence Evaluations” (the “Orange Book”), with respect to POMALYST .

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® 15. The labeling for POMALYST instructs and encourages physicians, pharmacists,

® and other healthcare workers and patients to administer POMALYST according to one or more of

the methods claimed in the patents-in-suit.

Jurisdiction and Venue

16. This Court has jurisdiction over the subject matter of this action pursuant to 28

U.S.C. §§ 1331, 1338(a), 2201, and 2202.

17. The Court has personal jurisdiction over DRL by virtue of, inter alia, its

continuous and systematic contacts with the State of New Jersey. On information and belief,

DRL Inc.’s principal place of business is in Princeton, New Jersey. On information and belief,

DRL Inc. is registered with the State of New Jersey’s Division of Revenue and Enterprise

Services as a business operating in New Jersey under Business I.D. No. 0100518911. On

information and belief, DRL Inc. is registered with the State of New Jersey’s Department of

Health as a drug manufacturer and wholesaler, under Registration No. 5002312. On information

and belief, DRL Inc. purposefully has conducted and continues to conduct business in this

Judicial District. On information and belief, DRL Inc. is a corporation organized and existing

under the laws of the State of New Jersey. By virtue of its incorporation in New Jersey, this

Court has personal jurisdiction over DRL Inc.

18. On information and belief, DRL is in the business of, among other things,

manufacturing, marketing, importing, offering for sale, and selling pharmaceutical products,

including generic drug products, throughout the United States, including in this Judicial District.

This Judicial District is a likely destination for the generic drug product described in DRL’s

ANDA. On information and belief, DRL also prepares and/or aids in the preparation and

submission of ANDAs to the FDA.

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19. This Court has personal jurisdiction over DRL because, inter alia, it has committed an act of patent infringement under 35 U.S.C. § 271(e)(2), and has sent notice of that infringement to Celgene in the State of New Jersey. On information and belief, DRL intends a future course of conduct that includes acts of patent infringement in New Jersey. These acts have led and will continue to lead to foreseeable harm and injury to Celgene in New Jersey and in this Judicial District.

20. In DRL’s Notice Letter, DRL stated that the name and address of its agent in the

United States authorized to accept service of process for purposes of an infringement action based upon DRL’s Notice Letter is Anjum Swaroop, Ph.D., Esq., Vice President, Intellectual

Property, Dr. Reddy’s Laboratories, Inc., 107 College Road East, Princeton, New Jersey 08540.

By naming Dr. Swaroop in Princeton as its agent in connection with this action, DRL has consented to jurisdiction in New Jersey.

21. On information and belief, DRL has previously been sued in this Judicial

District and has not challenged personal jurisdiction. See, e.g., Celgene Corporation v.

Dr. Reddy’s Labs., Ltd., et al., Civil Action No. 18-6378 (LDW)(SDW); Celgene Corporation v.

Dr. Reddy’s Labs., Ltd., et al., Civil Action No. 17-5314 (LDW)(SDW); BioMarin Pharm. Inc. v. Dr. Reddy’s Labs., Inc. and Dr. Reddy’s Labs., Ltd., Civil Action No. 17-774 (MAS)(TJB);

Celgene Corporation v. Dr. Reddy’s Labs., Ltd., et al., Civil Action No. 16-7704 (LDW)(SDW);

Dexcel Pharma Techs Ltd., et al. v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc., Civil

Action No. 15-8042 (SDW)(LDW); AstraZeneca AB, et al. v. Dr. Reddy’s Labs, Inc. and

Dr. Reddy’s Labs., Ltd., Civil Action Nos. 11-2317 (MLC)(DEA) and 13-91 (MLC)(DEA);

Wyeth LLC v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc., Civil Action No. 10-4551

(FLW)(DEA); Albany Molecular Research, Inc. v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s

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Labs., Inc., Civil Action No. 09-4638 (SRC)(CLW); Sepracor, Inc. v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc., Civil Action No. 09-1302 (SDW)(MF); Hoffman-La Roche Inc. v.

Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc., Civil Action No. 08-4055 (SRC)(MAS); and AstraZeneca AB, et al. v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc., Civil Action

No. 08-328 (MLC)(TJB).

22. DRL has also admitted that it is subject to personal jurisdiction in this Judicial

District. See, e.g., BioMarin Pharm. Inc. v. Dr. Reddy’s Labs., Inc. and Dr. Reddy’s Labs., Ltd.,

Civil Action No. 17-774 (MAS)(TJB), Answer to Complaint , ¶¶ 9, 10; BioMarin Pharm. Inc. v.

Dr. Reddy’s Labs., Inc. and Dr. Reddy’s Labs., Ltd., Civil Action No. 17-774 (MAS)(TJB),

Answer to Amended Complaint, ¶¶ 20, 21; Dexcel Pharma Techs Ltd., et al. v. Dr. Reddy’s

Labs., Ltd. and Dr. Reddy’s Labs., Inc., Civil Action No. 15-8041 (SDW)(LDW), Answer to

Complaint, ¶ 18; AstraZeneca AB et al. v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc.,

Civil Action No. 11-2317 (MLC)(DEA), Answer to Second Amended Complaint, ¶ 29; and

AstraZeneca UK Ltd. and AstraZeneca Pharms. LP v. Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s

Labs., Inc., Civil Action No. 08-3237 (MLC)(TJB), Answer to Complaint, ¶ 8.

23. DRL has further availed itself of the jurisdiction of this Court by previously initiating litigation in this Judicial District. See, e.g., Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s

Labs., Inc. v. Purdue Pharm. Prods. Ltd., et al., Civil Action No. 14-3230 (JLL)(JAD);

Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc. v. Eli Lilly & Co., Civil Action No. 09-192

(GEB)(LHG); and Dr. Reddy’s Labs., Ltd. and Dr. Reddy’s Labs., Inc. v. AstraZeneca AB, et al.,

Civil Action No. 08-2496 (MLC)(TJB).

24. Venue is proper in this Judicial District pursuant to 28 U.S.C. §§ 1391 and/or

1400(b).

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Acts Giving Rise To This Suit

25. Pursuant to Section 505 of the FFDCA, Defendants submitted DRL’s ANDA seeking approval to engage in the commercial manufacture, use, offer for sale, sale, or importation into the United States of pomalidomide capsules 1 mg, 2 mg, 3 mg, and 4 mg

(“DRL’s Proposed Products”), before the patents-in-suit expire.

26. On information and belief, following FDA approval of DRL’s ANDA,

DRL Ltd. and DRL Inc. will work in concert with one another and/or induce one another to make, use, offer to sell, or sell DRL’s Proposed Products throughout the United States, or import such generic products into the United States.

27. On information and belief, in connection with the filing of its ANDA as described above, DRL provided a written certification to the FDA, as called for by Section 505 of the FFDCA, 21 U.S.C. § 355(j)(2)(A)(vii)(IV) (“DRL’s Paragraph IV Certification”).

28. No earlier than May 31, 2019, DRL sent written notice of its Paragraph IV

Certification to Celgene (“DRL’s Notice Letter”). DRL’s Notice Letter alleged that the claims of the patents-in-suit are invalid and/or will not be infringed by the activities described in DRL’s

ANDA. DRL’s Notice Letter also informed Celgene that DRL seeks approval to market DRL’s

Proposed Products before the patents-in-suit expire. DRL specifically directed DRL’s Notice

Letter to Celgene’s headquarters in Summit, New Jersey, in this Judicial District.

Count I: Infringement of the ’262 Patent

29. Celgene repeats and realleges the allegations of the preceding paragraphs as if fully set forth herein.

30. DRL’s submission of its ANDA to engage in the commercial manufacture, use, offer for sale, sale, or importation into the United States of DRL’s Proposed Products, prior to

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the expiration of the ’262 patent, constitutes infringement of one or more of the claims of that patent under 35 U.S.C. § 271(e)(2)(A).

31. There is a justiciable controversy between Celgene and DRL as to the infringement of the ’262 patent.

32. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will infringe one or more claims of the ’262 patent under 35 U.S.C. § 271(a) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United States.

33. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will induce infringement of one or more claims of the ’262 patent under 35 U.S.C. § 271(b) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, upon FDA approval of DRL’s ANDA, DRL will intentionally encourage acts of direct infringement with knowledge of the ’262 patent and knowledge that its acts are encouraging infringement.

34. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will contributorily infringe one or more claims of the ’262 patent under 35 U.S.C. § 271(c) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, DRL has had and continues to have knowledge that DRL’s

Proposed Products are especially adapted for a use that infringes one or more claims of the

’262 patent and that there is no substantial non-infringing use for DRL’s Proposed Products.

35. Celgene will be substantially and irreparably damaged and harmed if DRL’s infringement of the ’262 patent is not enjoined.

36. Celgene does not have an adequate remedy at law.

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37. This case is an exceptional one, and Celgene is entitled to an award of its

reasonable attorneys’ fees under 35 U.S.C. § 285.

Count II: Infringement of the ’939 Patent

38. Celgene repeats and realleges the allegations of the preceding paragraphs as if

fully set forth herein.

39. DRL’s submission of its ANDA to engage in the commercial manufacture, use,

offer for sale, sale, or importation into the United States of DRL’s Proposed Products, prior to the expiration of the ’939 patent, constitutes infringement of one or more of the claims of that patent under 35 U.S.C. § 271(e)(2)(A).

40. There is a justiciable controversy between Celgene and DRL as to the infringement of the ’939 patent.

41. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will infringe one or more claims of the ’939 patent under 35 U.S.C. § 271(a) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United States.

42. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will induce infringement of one or more claims of the ’939 patent under 35 U.S.C. § 271(b) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, upon FDA approval of DRL’s ANDA, DRL will intentionally encourage acts of direct infringement with knowledge of the ’939 patent and knowledge that its acts are encouraging infringement.

43. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will contributorily infringe one or more claims of the ’939 patent under 35 U.S.C. § 271(c) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, DRL has had and continues to have knowledge that DRL’s

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Proposed Products are especially adapted for a use that infringes one or more claims of the

’939 patent and that there is no substantial non-infringing use for DRL’s Proposed Products.

44. Celgene will be substantially and irreparably damaged and harmed if DRL’s

infringement of the ’939 patent is not enjoined.

45. Celgene does not have an adequate remedy at law.

46. This case is an exceptional one, and Celgene is entitled to an award of its

reasonable attorneys’ fees under 35 U.S.C. § 285.

Count III: Infringement of the ’428 Patent

47. Celgene repeats and realleges the allegations of the preceding paragraphs as if

fully set forth herein.

48. DRL’s submission of its ANDA to engage in the commercial manufacture, use,

offer for sale, sale, or importation into the United States of DRL’s Proposed Products, prior to the expiration of the ’428 patent, constitutes infringement of one or more of the claims of that patent under 35 U.S.C. § 271(e)(2)(A).

49. There is a justiciable controversy between Celgene and DRL as to the infringement of the ’428 patent.

50. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will infringe one or more claims of the ’428 patent under 35 U.S.C. § 271(a) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United States.

51. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will induce infringement of one or more claims of the ’428 patent under 35 U.S.C. § 271(b) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, upon FDA approval of DRL’s ANDA, DRL will intentionally

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encourage acts of direct infringement with knowledge of the ’428 patent and knowledge that its

acts are encouraging infringement.

52. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will

contributorily infringe one or more claims of the ’428 patent under 35 U.S.C. § 271(c) by

making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, DRL has had and continues to have knowledge that DRL’s

Proposed Products are especially adapted for a use that infringes one or more claims of the

’428 patent and that there is no substantial non-infringing use for DRL’s Proposed Products.

53. Celgene will be substantially and irreparably damaged and harmed if DRL’s

infringement of the ’428 patent is not enjoined.

54. Celgene does not have an adequate remedy at law.

55. This case is an exceptional one, and Celgene is entitled to an award of its

reasonable attorneys’ fees under 35 U.S.C. § 285.

Count IV: Infringement of the ’427 Patent

56. Celgene repeats and realleges the allegations of the preceding paragraphs as if

fully set forth herein.

57. DRL’s submission of its ANDA to engage in the commercial manufacture, use,

offer for sale, sale, or importation into the United States of DRL’s Proposed Products, prior to the expiration of the ’427 patent, constitutes infringement of one or more of the claims of that patent under 35 U.S.C. § 271(e)(2)(A).

58. There is a justiciable controversy between Celgene and DRL as to the infringement of the ’427 patent.

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59. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will

infringe one or more claims of the ’427 patent under 35 U.S.C. § 271(a) by making, using,

offering to sell, selling, and/or importing DRL’s Proposed Products in the United States.

60. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will

induce infringement of one or more claims of the ’427 patent under 35 U.S.C. § 271(b) by

making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, upon FDA approval of DRL’s ANDA, DRL will intentionally

encourage acts of direct infringement with knowledge of the ’427 patent and knowledge that its

acts are encouraging infringement.

61. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will

contributorily infringe one or more claims of the ’427 patent under 35 U.S.C. § 271(c) by

making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, DRL has had and continues to have knowledge that DRL’s

Proposed Products are especially adapted for a use that infringes one or more claims of the

’427 patent and that there is no substantial non-infringing use for DRL’s Proposed Products.

62. Celgene will be substantially and irreparably damaged and harmed if DRL’s

infringement of the ’427 patent is not enjoined.

63. Celgene does not have an adequate remedy at law.

64. This case is an exceptional one, and Celgene is entitled to an award of its

reasonable attorneys’ fees under 35 U.S.C. § 285.

Count V: Infringement of the ’467 Patent

65. Celgene repeats and realleges the allegations of the preceding paragraphs as if fully set forth herein.

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66. DRL’s submission of its ANDA to engage in the commercial manufacture, use, offer for sale, sale, or importation into the United States of DRL’s Proposed Products, prior to the expiration of the ’467 patent, constitutes infringement of one or more of the claims of that patent under 35 U.S.C. § 271(e)(2)(A).

67. There is a justiciable controversy between Celgene and DRL as to the infringement of the ’467 patent.

68. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will infringe one or more claims of the ’467 patent under 35 U.S.C. § 271(a) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United States.

69. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will induce infringement of one or more claims of the ’467 patent under 35 U.S.C. § 271(b) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, upon FDA approval of DRL’s ANDA, DRL will intentionally encourage acts of direct infringement with knowledge of the ’467 patent and knowledge that its acts are encouraging infringement.

70. Unless enjoined by this Court, upon FDA approval of DRL’s ANDA, DRL will contributorily infringe one or more claims of the ’467 patent under 35 U.S.C. § 271(c) by making, using, offering to sell, selling, and/or importing DRL’s Proposed Products in the United

States. On information and belief, DRL has had and continues to have knowledge that DRL’s

Proposed Products are especially adapted for a use that infringes one or more claims of the

’467 patent and that there is no substantial non-infringing use for DRL’s Proposed Products.

71. Celgene will be substantially and irreparably damaged and harmed if DRL’s infringement of the ’467 patent is not enjoined.

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72. Celgene does not have an adequate remedy at law.

73. This case is an exceptional one, and Celgene is entitled to an award of its

reasonable attorneys’ fees under 35 U.S.C. § 285.

PRAYER FOR RELIEF

WHEREFORE, Plaintiff Celgene respectfully requests the following relief:

(A) A Judgment that DRL has infringed the patents-in-suit by submitting ANDA

No. 213234;

(B) A Judgment that DRL has infringed, and that DRL’s making, using, offering to

sell, selling, or importing DRL’s Proposed Products will infringe one or more claims of the

patents-in-suit;

(C) An Order that the effective date of FDA approval of ANDA No. 213234 be a date

which is not earlier than the later of the expiration of the patents-in-suit, or any later expiration of

exclusivity to which Celgene is or becomes entitled;

(D) Preliminary and permanent injunctions enjoining DRL and its officers, agents,

attorneys and employees, and those acting in privity or concert with them, from making, using,

offering to sell, selling, or importing DRL’s Proposed Products until after the expiration of the

patents-in-suit, or any later expiration of exclusivity to which Celgene is or becomes entitled;

(E) A permanent injunction, pursuant to 35 U.S.C. § 271(e)(4)(B), restraining and

enjoining DRL, its officers, agents, attorneys and employees, and those acting in privity or

concert with them, from practicing any methods of use and administration of pomalidomide, or

pharmaceutical compositions containing pomalidomide, as claimed in the patents-in-suit, or from

actively inducing or contributing to the infringement of any claim of the patents-in-suit, until after the expiration of the patents-in-suit, or any later expiration of exclusivity to which Celgene is or becomes entitled;

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(F) A Judgment that the commercial manufacture, use, offer for sale, sale, and/or importation into the United States of DRL’s Proposed Products will directly infringe, induce and/or contribute to infringement of the patents-in-suit;

(G) To the extent that DRL has committed any acts with respect to the methods of use and administration of pomalidomide, or pharmaceutical compositions containing pomalidomide, claimed in the patents-in-suit, other than those acts expressly exempted by 35 U.S.C. § 271(e)(1), a Judgment awarding Celgene damages for such acts;

(H) If DRL engages in the commercial manufacture, use, offer for sale, sale, and/or

importation into the United States of DRL’s Proposed Products prior to the expiration of the patents-in-suit, a Judgment awarding damages to Celgene resulting from such infringement, together with interest;

(I) A Judgment declaring that the patents-in-suit remain valid and enforceable;

(J) A Judgment that this is an exceptional case pursuant to 35 U.S.C. § 285 and awarding Celgene its attorneys’ fees incurred in this action;

(K) A Judgment awarding Celgene its costs and expenses incurred in this action; and

(L) Such further and other relief as this Court may deem just and proper.

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Dated: July 12, 2019 By: s/ Charles M. Lizza Charles M. Lizza Of Counsel: William C. Baton F. Dominic Cerrito SAUL EWING ARNSTEIN & LEHR LLP Eric C. Stops One Riverfront Plaza, Suite 1520 Andrew S. Chalson Newark, New Jersey 07102-5426 QUINN EMANUEL URQUHART & SULLIVAN, LLP (973) 286-6700 51 Madison Avenue, 22nd Floor [email protected] New York, New York 10010 (212) 849-7000 Attorneys for Plaintiff Celgene Corporation Anthony M. Insogna Cary Miller, Ph.D. JONES DAY 4655 Executive Drive San Diego, CA 92121 (858) 314-1200

Matthew J. Hertko JONES DAY 77 W. Wacker Drive, Suite 3500 Chicago, IL 60601 (312) 782-3939

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CERTIFICATION PURSUANT TO LOCAL CIVIL RULES 11.2 & 40.1

Pursuant to Local Civil Rules 11.2 and 40.1, I hereby certify that the matter captioned

Celgene Corp. v. Hetero Labs Ltd., et al., Civil Action No. 17-3387 (ES)(MAH) (D.N.J.) is

related to the matter in controversy because the matter in controversy involves the same plaintiff

and the same patents, and because the defendants are seeking FDA approval to market generic

versions of the same pharmaceutical product.

I further certify that, to the best of my knowledge, the matter in controversy is not the

subject of any other action pending in any court or of any pending arbitration or administrative

proceeding.

Dated: July 12, 2019 By: s/ Charles M. Lizza Charles M. Lizza Of Counsel: William C. Baton F. Dominic Cerrito SAUL EWING ARNSTEIN & LEHR LLP Eric C. Stops One Riverfront Plaza, Suite 1520 Andrew S. Chalson Newark, New Jersey 07102-5426 QUINN EMANUEL URQUHART & SULLIVAN, LLP (973) 286-6700 51 Madison Avenue, 22nd Floor [email protected] New York, New York 10010 (212) 849-7000 Attorneys for Plaintiff Celgene Corporation Anthony M. Insogna Cary Miller, Ph.D. JONES DAY 4655 Executive Drive San Diego, CA 92121 (858) 314-1200

Matthew J. Hertko JONES DAY 77 W. Wacker Drive, Suite 3500 Chicago, IL 60601 (312) 782-3939

- 17 - Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 18 of 148 PageID: 18

EXHIBIT A Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 19 of 148 PageID: 19 111111 1111111111111111111111111111111111111111111111111111111111111 US008198262B2 c12) United States Patent (10) Patent No.: US 8,198,262 B2 Zeldis (45) Date of Patent: Jun.12,2012

(54) METHODS FOR TREATING MULTIPLE 5,877,200 A 3/1999 Muller MYELOMA USING 4-(AMIN0)-2-(2,6- 5,929,117 A 7/1999 Muller eta!. 5,955,476 A 9/1999 Muller eta!. DIOX0(3-PIPERIDYL))-ISOINDOLINE- 6,020,358 A 212000 Muller eta!. 1,3-DIONE 6,071,948 A 6/2000 D' Amato 6,114,355 A 9/2000 D' Amato (75) Inventor: Jerome B. Zeldis, Princeton, NJ (US) 6,140,346 A 10/2000 Andrulis, Jr. eta!. 6,228,879 B1 5/2001 Green et a!. 6,235,756 B1 5/2001 D'Amato (73) Assignee: Celgene Corporation, Summit, NJ (US) 6,281,230 B1 8/2001 Muller eta!. 6,316,471 B1 1112001 Muller eta!. ( *) Notice: Subject to any disclaimer, the term of this 6,326,388 B1 12/2001 Man et al. patent is extended or adjusted under 35 6,335,349 B1 112002 Muller eta!. 6,380,239 B1 4/2002 Muller eta!. U.S.C. 154(b) by 468 days. 6,395,754 B1 5/2002 Muller eta!. 6,403,613 B1 6/2002 Man et al. (21) Appl. No.: 12/229,074 6,420,414 B1 7/2002 D'Amato 6,458,810 B1 10/2002 Muller eta!. (22) Filed: Aug. 19, 2008 6,469,045 B1 10/2002 D' Amato 6,476,052 B1 1112002 Muller eta!. 6,518,298 B2 2/2003 Green et a!. (65) Prior Publication Data 6,555,554 B2 4/2003 Muller eta!. US 2008/0317708 AI Dec. 25, 2008 6,673,828 B1 112004 Green et a!. 7,393,862 B2 7/2008 Zeldis 7,435,745 B2 10/2008 D' Amato Related U.S. Application Data 200110018445 A1 8/2001 Huang eta!. 200110056114 A1 12/2001 D'Amato (62) Division of application No. 10/438,213, filed on May 15, 2003, now Pat. No. 7,968,569. (Continued) (60) Provisional application No. 60/380,842, filed on May FOREIGN PATENT DOCUMENTS 17, 2002, provisional application No. 60/424,600, wo wo 92/14455 9/1992 filed on Nov. 6, 2002. wo wo 94/20085 9/1994 wo wo 98/03502 111998 (51) Int. Cl. wo wo 98/54170 12/1998 AOJN 43140 (2006.01) wo wo 01/70275 9/2001 wo wo 01187307 1112001 (52) U.S. Cl...... 514/58; 514/323; 514/329; 514/330 wo wo 02/15926 212002 (58) Field of Classification Search ...... 514/323, wo wo 02/059106 8/2002 514/329, 330 wo wo 02/064083 8/2002 See application file for complete search history. wo PCT/US03/11578 4/2003 wo wo 03086373 10/2003 (56) References Cited OTHER PUBLICATIONS

U.S. PATENT DOCUMENTS Kyle eta!. (Seminars in Oncology (Dec. 2001);28(6):583-7).* Carstensen, 1995, Drug Stability: Principles & Practice, 2"d. ed., 3,536,809 A 10/1970 Applezweig Marcel Dekker, New York, NY pp. 379-380. 3,598,123 A 8/1971 Zaffaroni Corral et a!., 1999, "Immunomodulation by thalidomide and 3,845,770 A 1111974 Theeuwes et al. thalidomide analogues," Ann. Rheum. Dis. 58(Suppl1)1107-113. 3,916,899 A 1111975 Theeuwes et al. 4,008,719 A 2/1977 Theeuwes et al. (Continued) 4,810,643 A 3/1989 Souza 4,999,291 A 3/1991 Souza 5,059,595 A 10/1991 Le Grazie Primary Examiner- Frederick Krass 5,073,543 A 12/1991 Marshall et a!. Assistant Examiner- Chris Simmons 5,120,548 A 6/1992 McClelland et a!. (74) Attorney, Agent, or Firm- Jones Day 5,134,127 A 7/1992 Stella et al. 5,229,496 A 7/1993 Deeley eta!. 5,354,556 A 10/1994 Sparks eta!. (57) ABSTRACT 5,385,901 A 111995 Kaplan eta!. Methods of treating, preventing and/or managing cancer as 5,391,485 A 2/1995 Deeley eta!. 5,393,870 A 2/1995 Deeley eta!. well as and diseases and disorders associated with, or char­ 5,528,823 A 6/1996 Rudy, Jr. et a!. acterized by, undesired angiogenesis are disclosed. Specific 5,580,755 A 12/1996 Souza methods encompass the administration of an immunomodu­ 5,591,767 A 111997 Mohr et al. latory compound alone or in combination with a second 5,593,990 A 111997 D'Amato active ingredient. The invention further relates to methods of 5,629,327 A 5/1997 D'Amato 5,635,517 A 6/1997 Muller eta!. reducing or avoiding adverse side effects associated with 5,639,476 A 6/1997 Oshlack et a!. chemotherapy, radiation therapy, hormonal therapy, biologi­ 5,674,533 A 10/1997 Santus eta!. cal therapy or immunotherapy which comprise the adminis­ 5,698,579 A 12/1997 Muller tration of an immunomodulatory compound. Pharmaceutical 5,712,291 A 111998 D'Amato compositions, single unit dosage forms, and kits suitable for 5,731,325 A 3/1998 Andrulis, Jr. eta!. 5,733,566 A 3/1998 Lewis use in methods of the invention are also disclosed. 5,798,368 A 8/1998 Muller eta!. 5,874,448 A 2/1999 Muller eta!. 29 Claims, 1 Drawing Sheet Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 20 of 148 PageID: 20

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Palumbo et a!., 2004, "A prospective randomized trial of oral Bartlett eta!., "The evolution of thalidomide and its IMiD derivatives melphalan prednisone, thalidomide (MPT) vs. oral melphalan, as anticancer agents," Nature Reviews Cancer, 2004, 4 (4): 1-9. prednisone (MP): an interim analysis," Am. Soc. Hematol. 46th Ann. Bartlett eta!., "Phase I study to determine the safety, tolerability and Meeting Dec. 4-7, 2004, San Diego, CA Abstract #207. immunostimulatory activity of thalidomide analogue CC-5013 in Raje eta!., 1999, "Thalidomide-a revival story," N. Engl. J. Med. patients with metastatic malignant melanoma and other advanced 341(21): 1606-1609. cancers," British Journal of Cancer, 2004, 90:955-961. Rajkumar et a!., 2004, "Thalidomide plus dexamethasone versus Battegay, "Angiogenesis: mechanistic insights, neovascular diseases, dexamethasone alone in newly diagnosed multiple myeloma and therapeutic prospects," J. Mol. Med., 1995, 73:333-346. 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Prescriptions Wohrer et al., 2004, "Effective treatment of primary plasma cell up 50%. Enhanced S.T.E.P.S.® launched. Pilot d-MPH data pre­ leukemia with thalidomide and dexamethasone-a case report," sented," Press Release, Oct. 2001. Hematol. J. 5(4):361-363. Celgene Corporation, "Celgene expands clinical development pro­ Bach, 1963, "Thalidomide in Cancer Chemotherapy," The Lancet, gram for Revimid™. Five additional trials of Revimid initiated in No. 1271, p. 71. hematological and solid tumor cancers," Press Release, Jun. 2002. Bach, 1963, "Studies on the Possible Anti-Neoplastic Effect of Thalidomide," Acta Pathologica Et Microbiologica Scandinavica Celgene Corporation, "Celgene Corporation announces third quarter 59:491-499. results. Thalomid® (thalidomide) revenue increases 41% to $30.5 Chaundhry, 1966, Cancer Research, "Effect of Prednisolone and million. Pivotal programs for Thalomid and Revimid™ finalized. Thalidomide on Induced Submandibular Gland Tumors in Hamster," Peer-reviewed publications ofThalomid and Revimid data. First JNK 26(part 1)1884-86. inhibitor advanced to Phase I clinical trial," Press Release, Oct. 2002. DiPaolo, 1963, "Effect ofThalidomide on a Variety ofTransplantable Celgene Corporation, "Blood reports Revimid™ has anti-tumor Tumors," Cancer Chemotherapy Reports No. 29, pp. 99-102. activity in patients with relapsed and refractory multiple myeloma," DiPaolo, 1963, "In vitro Test Systems for Cancer Chemotherapy, II. Press Release, Nov. 1, 2002. Correlation of in vitro Inhibition of Dehydrogenase and Growth with Celgene Corporation, "Celgene provides update on clinical pipeline. in vivo Inhibition of Ehrlich Asoites Tumor," Proceedings of the Celgene Announces first target indication for Actimid™, CC-8490. Society for Experimental Biology & Medicine, 114:384-387. SeiCID™program to advance based on results from Phase IIII trial of DiPaolo, 1964, "Thalidomide: Effects on Ehrlich Ascites Tumor CC-1088. First JNK inhibitor successfully completes phase I trial," Cells in vitro" Science 144:1583. Press Release, Jan. 2003. Mauad, 1963, "Clinical Improvements Obtained in Advanced Caner Celgene Corporation, "Celgene Corporation announces fourth quar­ Patients with Treatment with Thalidomide Associated with Hor­ ter and full year results for 2002," Press Release, Jan. 2003. mones," Anais Paulistas de Medicina e Cirurgia 86:13-40. Celgene Corporation, "Celgene receives fast track status from FDA Roe and Mitchley, 1963, "Thalidomide and Neoplasia" Nature for Revimid™ in multiple myloma," Press Release, Feb. 2003. 200:1016-1017. 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Revimid™ in myelodysplastic sydromes at the American Society of Barlogie et a!., "High-dose therapy immunomodulatory drugs in Hematology 45th annual meeting," Press Release, Dec. 2003. multiple myeloma," Seminars in Oncology, 2002, 29 (6):26-33. Celgene Corporation, "Celgene corporation reviews 2003 achieve­ Barlogie eta!., "Introduction: Thalidomide and the IMiDs in multiple ments and announces 2004 financial outlook," Press Release, Jan. myeloma," Seminars in Hematology, 2003,40 (4):1-2. 2004. Barlogie, "Thalidomide and CC-5013 in Multiple Myeloma: The Celgene Corporation, "Revlimid™ receives orphan drug designation University of Arkansas experience," Seminars in Hematology, 2003, from the European commission for multiple myeloma," Press 40 (4):33-38. Release, Feb. 2004. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 22 of 148 PageID: 22

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Celgene Corporation, "Revlimid™ receives orphan drug designation Hayashi eta!., "Mechanisms whereby immunomodulatory analogs from the European commission for myelodysplastic sydromes," of thalidomide augment autologous NK cell anti-myeloma immu­ Press Release, Mar. 2004. nity," Blood, Abstract #3219, Dec. 6-10, 2002, American Society of Celgene Corporation, "Celgene corporation reports record operating Hematology. performance in first quarter with strong revenue growth and profits," He, W., eta!., 1993, Abstract of papers, 206th American Chemical Press Release, Apr. 2004. Society, Chicago, IL; Med. Chern., paper 216. 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Masellis et a!., "Changes in gene expression in bone marrow Richardson et a!., "A multicenter, single-arm, open-label study to mesenchymal progenitor cells as a consequence of IMiD therapy in evaluate the efficacy and safety of single-agent lenalidomide in multiple myeloma patients," Blood, Abstract # 1548, Dec. 7-11, patients with relapsed and refractory multiple myeloma; preliminary 2001, American Society of Hematology. results," lOth International Myeloma Workshop, Apr. 10-14, 2005. 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Opin. myeloma cell lines," Blood, Abstract #2487, Dec. 1-5, 2000, Ameri­ Ther. Patents, 1998, 8 (5):531-544. can Society of Hematology. Sorbera eta!., "CC-50 13. Treatment of multiple myeloma. Treatment Payvandi eta!., "The thalidomide analogs IMiDs enhance expression of Melanoma. Treatment of myelodysplastic syndrome. ofCD69 stimulatory receptor on natural killer cells," Abstract# 1793, Angiogenesis inhibitor. TNF -y production inhibitor," Drugs of the American Association for Cancer Research, Mar. 24-28, 2001. Future, 2003, 28(5):425-431. Payvandi et a!., "Thaliomide analogs IMiDs inhibit expression of Streetly et al., "Thalidomide analogue CC-4047 is effective in the cyclooxygenase-2 in multiple myeloma cell line and LPS stimulated treatment of patients with relapsed and refractory multiple myeloma PBMCs," Blood, Abstract# 2689, Dec. 7-11, 200l,American Society (MM) and induces T-cell activation and IL-12 production," Abstract of Hematology. # 367, International Multiple Myeloma Workshop, May 23-27, 2003. Payvandi eta!., "Thalidomide and IMiDS inhibit microvessel forma­ Streetly et a!., "Changes in neutrophil phenotype following the tion from human arterial rings in the absence of human liver administration of CC-4047 (Actimid) to patients with multiple microsomes," Blood, Abstract# 5046, Dec. 6-10, 2002, American myeloma," Abstract# 2543, American Society of Hematology, Dec. Society of Hematology. 6-9, 2003. Payvandi eta!., "CC-5013 inhibits the expression of adhesion mol­ Streetly et a!., "An update of the use and outcomes of the new ecules ICAM -1 and CD44 and prevents metastasis ofB 16 F 10 mouse immunomodulatory agent CC-4047 (Actimid) in patients with melanoma cells in an animal model," American Society of Clinical relapsed/refractory myeloma," Abstract #829, American Society of Oncology, Abstract# 992, 2003. Hematology, Dec. 6-9, 2003. Payvandi et a!., "Immunomodulatory drugs inhibit expression of Teo et a!., "A phase I, single-blind, placebo-controlled, ascending cyclooxygenase-2 from TNF-y, IL-ly, and LPS-stimulated human single oral dose, safety, tolerability and pharmacokinetic study of PBMC in a partially IL-10-dependent manner," Cellular Immunol­ CDC-50 1, a novel immunomodulatory- oncologic agent, in healthy ogy, 2004, 81-88. male subjects with a comparison of fed and fasted," Clinical Phar­ Raje et a!., "Combination of the mTOR inhibitor rapamycin and macology and Therapeutics, 2002, 71 (2)93. CC-50 13 has synergistic activity in multiple myeloma," Blood, Dec. Teo et a!., "Chiral inversion of the second generation IMiD™ 15, 2004, 104 (13)4188-4193. 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Weber et al., "A multicenter, randomized, parallel-group, double­ Davies, F. E., Raje, N., Hideshima, T., Lentzsch, S., Young, G., Tai, Y., blind, placebo-controlled study oflenalidomide plus dexamethasone Lin, B.K., Podar, K., Chauhan, D., Treon, S.P., Gupta, D., Mitsiades, versus dexamethasone alone in previously treated subjects with mul­ C., Mitsiades, N., Hayashi, T., Richardson, P.G., Schlossman, R.L., tiple myeloma," Abstract# P0.738, International Multiple Myeloma Muller, G.W., Stirling, D. I., Anderson, K.C., Thalidomide (THAL) Workshop, Apr. 10-14, 2005. and Immunomodulatory Derivatives (IMiDS) Augment Natural Ye eta!., "Novel IMiD drugs enhance expansion and regulate differ­ Killer (NK) Cell Cytotocixity in Multiple Myeloma (MM). Abstract entiation of human cord blood CD34+ cells with cytokines," Blood, #3617. American Society of Hematology, Dec. 1-5, 2000. Abstract #4099, American Society of Hematology, Dec. 6-10, 2002. Hideshima, T., Chauhan, D., Castro, A., Hayashi, T., Mitsiades, C., Zangari eta!., "Risk factors for deep vein thrombosis (DVT) in a large Mitsiades, N., Akiyama, M., Richardson, P.G., Schlossman, R.L., group of myeloma patients (Pts) treated with thalidomide (Thai): The Adams, J., Anderson, K.C., NF-yB as a Therapeutic Target in Mul­ Arkansas Experience," Blood, Abstract# 681, American Society of tiple Myeloma (MM). Abstract #1581. American Society of Hema­ Hematology, Dec. 7-11, 2001. tology, Dec. 7-11,2001. Zangari eta!., "Revimid 25 mg (REV 25)x20 versus 50 mg (REV 50)x10 q 28 days with bridging of 5 mgx10 versus 10 mgx5 as Lentsch, S., Rogers, M., Leblanc, R., Birsner, A., Shah, J., Anderson post -transplant salvage therapy for multiple myeloma (MM)," Blood, K., D' Amato R., 3-Amino-Phthalimido-Glutarimide (S-3APG) Abstract# 1642, American Society of Hematology, Dec. 6-9, 2003. 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Payvandi, F., Wu, L., Haley M., Gupta, D., Zhang, L., Schafer, P., Anderson, "The Role of Immunomodulatory Drugs in Multiple Muller, G.W., Chen, R., Anderson, K.C., Stirling, D., Thalidomide Myeloma," Seminars in Hematology, vol. 40, No.4, Suppl4, 2003: Analogs IMiDS Inhibit Expression ofCyclooxygenase-2 in Multiple pp. 23-32. Myeloma Cell Line and LPS Stimulated PBMCs. Abstract #2689. Weber, "Thalidomide and Its Derivatives: New Promise for Multiple American Society of Hematology, Dec. 7-11,2001. Myeloma," Cancer Control, vol. 10, No.5, 375-383, 2003. Mitsiades, N., Mitsiades, C., Poulaki, V., Akiyama, M., Tai, Y., Lin, Part, Yehuda A.; Hassan, Mana! M.; Lozano, Richard D.; Ellis, Lee B., Hayashi, T., Catley, L., Hideshima, T., Chauhan, D., Treon, S.P., M.; Peterson, J. 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U.S. Patent Jun.12,2012 US 8,198,262 B2

Effects of RevimidTMand Thalidomide on MM Cell Proliferation lVIM.lS Cells Hs Sultan Cells

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0 0.0:0\ O.CO'I 0.01 0.. t 10 ICO 0 O.

Legend: +Thalidomide •lMiDl A Revimid TM e IMiD2 Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 27 of 148 PageID: 27

US 8,198,262 B2 1 2 METHODS FOR TREATING MULTIPLE A variety of other diseases and disorders are also associ­ MYELOMA USING 4-(AMIN0)-2-(2,6- ated with, or characterized by, undesired angiogenesis. For DIOX0(3-PIPERIDYL))-ISOINDOLINE- example, enhanced or unregulated angiogenesis has been 1,3-DIONE implicated in a number of diseases and medical conditions including, but not limited to, ocular neovascular diseases, This application is a divisional application of U.S. patent choroidal neovascular diseases, retina neovascular diseases, application Ser. No. 10/438,213, filed May 15, 2003, now rubeosis (neovascularization of the angle), viral diseases, U.S. Pat. No. 7,968,569, which claims the benefit of U.S. genetic diseases, inflammatory diseases, allergic diseases, provisional application Nos. 60/380,842, filed May 17, 2002, and autoimmune diseases. Examples of such diseases and and 60/424,600, filed Nov. 6, 2002, the entireties of which are 10 conditions include, but are not limited to: diabetic retinopa­ incorporated herein by reference. thy; retinopathy of prematurity; corneal graft rejection; neovascular glaucoma; retrolental fibroplasia; and prolifera­ 1. FIELD OF THE INVENTION tive vitreoretinopathy. Accordingly, compounds that can control angiogenesis or This invention relates to methods of treating, preventing 15 inhibit the production of certain cytokines, including TNF -a, and/or managing specific cancers, and other diseases includ­ may be useful in the treatment and prevention of various ing, but not limited to, those associated with, or characterized diseases and conditions. by, undesired angiogenesis, by the administration of one or 2.2 Methods of Treating Cancer more immunomodulatory compounds alone or in combina­ Current cancer therapy may involve surgery, chemo- tion with other therapeutics. In particular, the invention 20 therapy, hormonal therapy and/or radiation treatment to encompasses the use of specific combinations, or "cocktails," eradicate neoplastic cells in a patient (see, for example, of drugs and other therapy, e.g., radiation to treat these spe­ Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, cific cancers, including those refractory to conventional eds. Chapter 12, Section IV). Recently, cancer therapy could therapy. The invention also relates to pharmaceutical compo­ also involve biological therapy or immunotherapy. All of sitions and dosing regimens. 25 these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the 2. BACKGROUND OF THE INVENTION health of a patient or may be unacceptable to the patient. Additionally, surgery may not completely remove neoplastic 2.1 Pathobiology of Cancer and Other Diseases tissue. Radiation therapy is only effective when the neoplastic Cancer is characterized primarily by an increase in the 30 tissue exhibits a higher sensitivity to radiation than normal number of abnormal cells derived from a given normal tissue, tissue. Radiation therapy can also often elicit serious side invasion of adjacent tissues by these abnormal cells, or lym­ effects. Hormonal therapy is rarely given as a single agent. phatic or blood-borne spread of malignant cells to regional Although hormonal therapy can be effective, it is often used lymph nodes and to distant sites (metastasis). Clinical data to prevent or delay recurrence of cancer after other treatments and molecular biologic studies indicate that cancer is a mul­ 35 have removed the majority of cancer cells. Biological thera­ tistep process that begins with minor preneoplastic changes, pies and immunotherapies are limited in number and may which may under certain conditions progress to neoplasia. produce side effects such as rashes or swellings, flu-like The neoplastic lesion may evolve clonally and develop an symptoms, including fever, chills and fatigue, digestive tract increasing capacity for invasion, growth, metastasis, and het­ problems or allergic reactions. erogeneity, especially under conditions in which the neoplas- 40 With respect to chemotherapy, there are a variety of che- tic cells escape the host's immune surveillance. Raitt. I., motherapeutic agents available for treatment of cancer. A Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., majority of cancer chemotherapeutics act by inhibiting DNA Mosby, St. Louis. Mo. 1093). synthesis, either directly, or indirectly by inhibiting the bio­ There is an enormous variety of cancers which are synthesis of deoxyribonucleotide triphosphate precursors, to described in detail in the medical literature. Examples 45 prevent DNA replication and concomitant cell division. Gil­ includes cancer of the lung, colon, rectum, prostate, breast, man eta!., Goodman and Gilman's: The Pharmacological brain, and intestine. The incidence of cancer continues to Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York). climb as the general population ages, as new cancers develop, Despite availability of a variety of chemotherapeutic and as susceptible populations (e.g., people infected with agents, chemotherapy has many drawbacks. Stockdale. Medi- AIDS or excessively exposed to sunlight) grow. A tremen­ 50 cine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, dous demand therefore exists for new methods and composi­ 1998. Almost all chemotherapeutic agents are toxic, and che­ tions that can be used to treat patients with cancer. motherapy causes significant, and often dangerous side Many types of cancers are associated with new blood ves- effects including severe nausea, bone marrow depression, and sel formation, a process known as angiogenesis. Several of immunosuppression. Additionally, even with administration the mechanisms involved in tumor-induced angiogenesis 55 of combinations of chemotherapeutic agents, many tumor have been elucidated. The most direct of these mechanisms is cells are resistant or develop resistance to the chemothera­ the secretion by the tumor cells of cytokines with angiogenic peutic agents. In fact, those cells resistant to the particular properties. Examples of these cytokines include acidic and chemotherapeutic agents used in the treatment protocol often basic fibroblastic growth factor (a,b-FGF), angiogenin, vas­ prove to be resistant to other drugs, even if those agents act by cular endothelial growth factor (VEGF), and TNF-a. Alter­ 60 different mechanism from those of the drugs used in the natively, tumor cells can release angiogenic peptides through specific treatment. This phenomenon is referred to as pleio­ the production of proteases and the subsequent breakdown of tropic drug or multi drug resistance. Because ofthe drug resis­ the extracellular matrix where some cytokines are stored tance, many cancers prove refractory to standard chemothera- (e.g., b-FGF). Angiogenesis can also be induced indirectly peutic treatment protocols. through the recruitment of inflammatory cells (particularly 65 Other diseases or conditions associated with, or character­ macrophages) and their subsequent release of angiogenic ized by, undesired angiogenesis are also difficult to treat. cytokines (e.g., TNF-a, bFGF). However, some compounds such as protamine, hepain and Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 28 of 148 PageID: 28

US 8,198,262 B2 3 4 steroids have been proposed to be useful in the treatment of or prophylactically effective amount of an immunomodula­ certain specific diseases. Tayloretai.,Nature 297:307 (1982); tory compound, or a pharmaceutically acceptable salt, sol­ Folkman et a!. Science 221:719 (1983); and U.S. Pat. Nos. vate, hydrate, stereoisomer, clathrate, or prodrug thereof. 5,001,116 and 4,994,443. Thalidomide and certain deriva­ In other methods of the invention, an immunomodulatory tives of it have also been proposed for the treatment of such compound is administered in combination with a therapy diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, conventionally used to treat, prevent or manage diseases or 5,712,291, 6,071,948 and 6,114,355 to D' Amato. disorders associated with, or characterized by, undesired Still, there is a significant need for safe and effective meth­ angiogenesis. Examples of such conventional therapies ods of treating, preventing and managing cancer and other include, but are not limited to, surgery, chemotherapy, radia- diseases and conditions, particularly for diseases that are 10 tion therapy, hormonal therapy, biological therapy and immu­ refractory to standard treatments, such as surgery, radiation notherapy. therapy, chemotherapy and hormonal therapy, while reducing This invention encompasses pharmaceutical composi­ or avoiding the toxicities and/or side effects associated with tions, single unit dosage forms, dosing regimens and kits the conventional therapies. which comprise an immunomodulatory compound, or a phar­ 2.3 IMIDS™ 15 A number of studies have been conducted with the aim of maceutically acceptable salt, solvate, hydrate, stereoisomer, providing compounds that can safely and effectively be used clathrate, or prodrug thereof, and a second, or additional, to treat diseases associated with abnormal production of active agent. Second active agents include specific combina­ TNF-a. See. e.g., Marriott, J. B., eta!., Expert Opin. Biol. tions, or "cocktails," of drugs. Ther. 1(4):1-8 (2001); G. W. Muller, eta!., Journal of Medici- 20 nal Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, 4. BRIEF DESCRIPTION OF FIGURE et a!. Bioorganic & Medicinal Chemistry Letters 8:2669- 2674 (1998). Some studies have focused on a group of com­ FIG. 1 shows a comparison of the effects of3-(4-amino-1- pounds selected for their capacity to potently inhibit TNF -a oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Revi­ production by LPS stimulated PBMC. L. G. Corral, et a!., 25 mid™) and thalidomide in inhibiting the proliferation of mul­ Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These tiple myeloma (MM) cell lines in an in vitro study. The uptake compounds, which are referred to as IMiDs™ (Celgene Cor­ of [3 H]-thymidine by different MM cell lines (MM.1S, Hs poration) or Immunomodulatory Drugs, show not only potent Sultan, U266 and RPMI-8226) was measured as an indicator inhibition of TNF -a but also marked inhibition of LPS of the cell proliferation. induced monocyte ILl~ and IL12 production. LPS induced 30 IL6 is also inhibited by immunomodulatory compounds, 5. DETAILED DESCRIPTION OF THE albeit partially. These compounds are potent stimulators of INVENTION LPS induced ILlO. Id. Particular examples of IMiD™s include, but are not limited to, the substituted 2-(2,6-dioxopi­ A first embodiment of the invention encompasses methods peridin-3-yl) phthalimides and substituted 2-(2,6-dioxopip- 35 of treating, managing, or preventing cancer which comprises eridin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. administering to a patient in need of such treatment or pre­ 6,281,230 and 6,316,471, both to G. W. Muller, eta!. vention a therapeutically or prophylactically effective amount of an immunomodulatory compound of the inven­ 3. SUMMARY OF THE INVENTION tion, or a pharmaceutically acceptable salt, solvate, hydrate, 40 stereoisomer, clathrate, or prodrug thereof. This invention encompasses methods of treating and pre­ In particular methods encompassed by this embodiment, venting certain types of cancer, including primary and meta­ the immunomodulatory compound is administered in combi­ static cancer, as well as cancers that are refractory or resistant nation with another drug ("second active agent") or method of to conventional chemotherapy. The methods comprise treating, managing, or preventing cancer. Second active administering to a patient in need of such treatment or pre­ 45 agents include small molecules and large molecules (e.g., vention a therapeutically or prophylactically effective proteins and antibodies), examples of which are provided amount of an immunomodulatory compound, or a pharma­ herein, as well as stem cells. Methods, or therapies, that can ceutically acceptable salt, solvate, hydrate, stereoisomer, be used in combination with the administration of the immu- clathrate, or pro drug thereof. The invention also encompasses nomodulatory compound include, but are not limited to sur­ methods of managing certain cancers (e.g., preventing or 50 gery, blood transfusions, immunotherapy, biological therapy, prolonging their recurrence, or lengthening the time of remis­ radiation therapy, and other non-drug based therapies pres- sion) which comprise administering to a patient in need of ently used to treat, prevent or manage cancer. such management a prophylactically effective amount of an Another embodiment of the invention encompasses meth­ immunomodulatory compound of the invention, or a pharma­ ods of treating, managing or preventing diseases and disor­ ceutically acceptable salt, solvate, hydrate, stereoisomer, 55 ders other than cancer that are characterized by undesired clathrate, or prodrug thereof. angiogenesis. These methods comprise the administration of In particular methods of the invention, an immunomodu­ a therapeutically or prophylactically effective amount of an latory compound is administered in combination with a immunomodulatory compound, or a pharmaceutically therapy conventionally used to treat, prevent or manage can­ acceptable salt, solvate, hydrate, stereoisomer, clathrate, or cer. Examples of such conventional therapies include, but are 60 prodrug thereof. not limited to, surgery, chemotherapy, radiation therapy, hor­ Examples of diseases and disorders associated with, or monal therapy, biological therapy and immunotherapy. characterized by, undesired angiogenesis include, but are not This invention also encompasses methods oftreating, man­ limited to, inflammatory diseases, autoimmune diseases, aging or preventing diseases and disorders other than cancer viral diseases, genetic diseases, allergic diseases, bacterial that are associated with, or characterized by, undesired angio- 65 diseases, ocular neovascular diseases, choroidal neovascular genesis, which comprise administering to a patient in need of diseases, retina neovascular diseases, and rubeosis (neovas- such treatment, management or prevention a therapeutically cularization of the angle). Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 29 of 148 PageID: 29

US 8,198,262 B2 5 6 In particular methods encompassed by this embodiment, aminothalidomide, as well as analogs, hydrolysis products, the immunomodulatory compound is administer in combina­ metabolites, derivatives and precursors of aminothalidomide, tion with a second active agent or method of treating, man­ and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and aging, or preventing the disease or condition. Second active substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles agents include small molecules and large molecules (e.g., 5 such as those described in U.S. Pat. Nos. 6,281,230 and proteins and antibodies), examples of which are provided 6,316,471; isoindole-imide compounds such as those herein, as well as stem cells. Methods, or therapies, that can described in U.S. patent application Ser. No. 09/972,487 filed be used in combination with the administration of the immu­ on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 nomodulatory compound include, but are not limited to, sur­ filed on Dec. 21, 2001, and International Application No. gery, blood transfusions, immunotherapy, biological therapy, 10 PCTIUS01/50401 (International Publication No. WO radiation therapy, and other non-drug based therapies pres­ 02/059106). The entireties of each of the patents and patent ently used to treat, prevent or manage disease and conditions applications identified herein are incorporated herein by ref­ associated with, or characterized by, undesired angiogenesis. erence. Immunomodulatory compounds of the invention do The invention also encompasses pharmaceutical composi­ not include thalidomide. tions (e.g., single unit dosage forms) that can be used in 15 Other specific immunomodulatory compounds of the methods disclosed herein. Particular pharmaceutical compo­ invention include, but are not limited to, 1-oxo- and 1,3 sitions comprise an immunomodulatory compound of the dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted invention, or a pharmaceutically acceptable salt, solvate, with amino in the benzo ring as described in U.S. Pat. No. hydrate, stereoisomer, clathrate, or prodrug thereof, and a 5,635,517 which is incorporated herein by reference. These second active agent. 20 compounds have the structure I: 5.1 Immunomodulatory Compounds Compounds used in the invention include immunomodu­ latory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, clathrates, and pro­ drugs thereof. Preferred compounds used in the invention are 25 small organic molecules having a molecular weight less than about 1.000 g/mol, and are not proteins, peptides, oligonucle­ otides, oligosaccharides or other macromolecules. As used herein and unless otherwise indicated, the terms "immunomodulatory compounds" and "IMiDs™" (Celgene 30 Corporation) encompasses small organic molecules that in which one ofX andY is C=O, the otherofX andY is C=O 2 markedly inhibit TNF -a, LPS induced monocyte ILl~ and or CH2 , and R is hydrogen or lower alkyl, in particular IL12, and partially inhibit IL6 production. Specific immuno­ methyl. Specific immunomodulatory compounds include, but modulatory compounds are discussed below. are not limited to: TNF -a is an inflammatory cytokine produced by macroph- 35 1-oxo-2-(2, 6-dioxopiperidin-3-y 1)-4-aminoisoindoline; ages and monocytes during acute inflammation. TNF -a is 1-oxo-2-(2, 6-dioxopiperidin-3-y 1)-5 -aminoisoindoline; responsible for a diverse range of signaling events within 1-oxo-2-(2, 6-dioxopiperidin-3-y 1)-6-aminoisoindoline; cells. TNF -a may play a pathological role in cancer. Without 1-oxo-2-(2,6-dioxopiperidin-3-yl)-7 -aminoisoindoline; being limited by theory, one of the biological effects exerted 1,3 -dioxo-2-(2,6-dioxopiperidin-3 -y 1)-4-aminoisoindo- by the immunomodulatory compounds of the invention is the 40 line; and reduction of synthesis of TNF -a. Immunomodulatory com- 1,3 -dioxo-2-(2,6-dioxopiperidin-3 -y 1)-5 -aminoisoindo­ pounds of the invention enhance the degradation of TNF -a line. mRNA. Other specific immunomodulatory compounds of the Further, without being limited by theory, immunomodula­ invention belong to a class of substituted 2-(2,6-dioxopiperi- tory compounds used in the invention may also be potent din-3-yl) phthalimides and substituted 2-(2,6-dioxopiperi­ co-stimulators ofT cells and increase cell proliferation dra­ 45 din-3-yl)-1-oxoisoindoles, such as those described in U.S. matically in a dose dependent marmer. Immunomodulatory Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, compounds of the invention may also have a greater co­ and International Patent Application No. PCTIUS97/13375 stimulatory effect on the CDS+ T cell subset than on the (International Publication No. WO 98/03502), each of which CD4+ T cell subset. In addition, the compounds preferably is incorporated herein by reference. Compounds representa- have anti-inflammatory properties, and efficiently co-stimu­ 50 tive of this class are of the formulas: late T cells. Specific examples of immunomodulatory compounds of the invention, include, but are not limited to, cyano and car­ boxy derivatives of substituted styrenes such as those dis­ closed in U.S. Pat. No. 5,929,117; 1-oxo-2-(2,6-dioxo-3- 55 fluoropiperidin-3-yl) isoindolines and 1,3-dioxo-2-(2,6- dioxo-3-fluoropiperidine-3-yl) isoindolines such as those described in U.S. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in U.S. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-diox­ opiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of 60 thalidomide and EM-12), including, but not limited to, those disclosed in U.S. Pat. No. 5,635,517; and a class of non­ polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698, 579 and 5,877,200; analogs and derivatives of thalidomide, including hydrolysis products, metabolites, derivatives and 65 precursors of thalidomide, such as those described in U.S. Pat. Nos. 5,593,990, 5,629,327, and 6,071.948 to D' Amato: Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 30 of 148 PageID: 30

US 8,198,262 B2 7 8 3 4 6 -continued (C2 -C5)heteroaryl, C(O)R , C(O)OR , (C1-C 8)alkyl-N(R ) 2 , 5 5 3 0 (C -C )alkyl-OR , (C -C )alkyl-C(O)OR , C(S)NHR , or 1 8 51 8 (C1-C8)alkyl-O(CO)R ; 2 R isH or (C1-C8)alkyl; and R3 is (C -C )alkyl, (C -C )cycloalkyl, (C -C )alkenyl, o=)N-0v" 1 8 3 7 2 8 (C2 -C8)alkynyl, benzyl, aryl, (C0 -C4)alkyl-(C1-C 6 )heterocy­ H2N H2 u.O cloalkyl, (C0 -C4)alkyl-(C2 -C5)heteroaryl, (C5-C8)alkyl-N 6 5 5 0 (R ) 2 ; (C0 -C8)alkyl-NH-C(O)O-R ; (C1-C8)alkyl-OR , 5 5 (C1-C8)alkyl-C(O)OR , (C1-C8)alkyl-O(CO)R , or C(O) 10 OR5; and the other variables have the same definitions. rr: ~N/H In other specific compounds of formula II, R2 is H or 7 (C1-C 4)alkyl. 1 YH2 u.o In other specific compounds of formula II, R is (C1-C8) NH2 alkyl or benzyl. 15 In other specific compounds of formula II, R 1 is H, (C - 1 1 wherein R is hydrogen or methyl. In a separate embodiment, C8)alkyl, benzyl, CH2 0CH3 , CH2 CH2 0CH3 , or the invention encompasses the use of enantiomerically pure forms (e.g. optically pure (R) or (S) enantiomers) of these compounds. Still other specific immunomodulatory compounds of the 20 invention belong to a class of isoindole-imides disclosed in In another embodiment of the compounds of formula II, R 1 U.S. patent application Ser. Nos. 10/032,286 and 09/972,487, IS and International Application No. PCTIUS01/50401 (Inter­ national Publication No. WO 02/059106), each of which are incorporated herein by reference. Representative compounds 25 are of formula II:

II 30

wherein Q is 0 or S, and each occurrence ofR7 is indepen-

35 dently H, (C1-C8)alkyl, benzyl, CH2 0CH3 , or CH2 CH2 0CH3 . 1 3 In other specific compounds offormula II. R is C(O)R . 3 In other specific compounds of formula II. R is (C0 -C4) and pharmaceutically acceptable salts, hydrates, solvates, alkyl-(C2 -C5)heteroaryl, (C1-C8)alkyl, aryl, or (C0 -C4)alkyl­ clathrates, enantiomers, diastereomers, racemates, and mix- OR5. 40 tures of stereoisomers thereof, wherein: In other specific compounds of formula II, heteroaryl is one of X andY is C=O and the other is CH2 or C=O; pyridyl, fury!, or thienyl. 1 1 4 R isH, (C1-C8)alkyl, (C3 -C7 )cycloalkyl, (C2 -C8)alkenyl, In other specific compounds offormula II. R is C(O)OR . (C2 -C8)alkynyl, benzyl, aryl, (C0 -C4)alkyl-(C1-C6)heterocy- 3 3 In other specific compounds of formula II, the II of C(O) cloalkyl, (C0 -C4)alkyl-(C2 -C5)heteroaryl, C(O)R , C(S)R , NHC(O) can be replaced with (C -C )alkyl, aryl, or benzyl. 4 6 5 1 4 C(O)OR , (C1-C8)alkyl-N(R ) 2 , (C 1 -C~alkyl-OR , (C1-C8) 45 5 3 3 3 Still other specific immunomodulatory compounds of the alkyl-C(O)OR , C(O)NHR , C(S)NHR , C(O)NR R ', C(S) 3 3 5 invention belong to a class of isoindole-imides disclosed in NR R ' or (C1-C8)alkyl-O(CO)R ; 2 U.S. patent application Ser. No. 09/781,179, International R is H, F, benzyl, (C -C )alkyl, (C -C )alkenyl, or (C - 1 8 2 8 2 Publication No. WO 98/54170, and U.S. Pat. No. 6,395, 754, C8)alkynyl; 3 3 each of which are incorporated herein by reference. Repre­ R and R ' are independently (C -C )alkyl, (C -C )cy- 50 1 8 3 7 sentative compounds are of formula III: cloalkyl, (C2 -C8)alkenyl, (C2 -C8)alkynyl, benzyl, aryl, (C0 - C4)alkyl-(C1 -C 6 )heterocycloalkyl, (C0 -C4)alkyl-(C2 -C5)het­ III 6 5 eroaryl, (C -C )alkyl-N(R ) , (C -C )alkyl-OR , (C -C ) 0 58 2 1 85 5 1 8 alkyl-C(O)OR , (C1-C8)alkyl-O(CO)R , or C(O)OR ; R4 is (C -C )alkyl, (C -C )alkenyl, (C -C )alkynyl, (C - 1 5 8 2 8 2 8 1 55 C4)alkyl-OR , benzyl, aryl, (C0 -C4)alkyl-(C1-C6)heterocy­ cloalkyl, or (C -C )alkyl-(C -C )heteroaryl; 5 0 4 2 5 R is (C1-C8)alkyl, (C2 -C8)alkenyl, (C2 -C8)alkynyl, ben­ zyl, aryl, or (C2 -C5)heteroaryl; 6 each occurrence of R is independently H, (C1-C8)alkyl, 60 (C2 -C8)alkenyl, (C2 -C8)alkynyl, benzyl, aryl, (C2 -C5)het- 5 6 and pharmaceutically acceptable salts, hydrates, solvates, eroaryl, or (C0 -C8)alkyl-C(O)O-R or the R groups can join to form a heterocycloalkyl group; clathrates, enantiomers, diastereomers, racemates, and mix­ n is 0 or 1 ; and tures of stereoisomers thereof, wherein: * represents a chiral-carbon center. one of X andY is C=O and the other is CH2 or C=O; 1 In specific compounds of formula II, when n is 0 then R is 65 R is H or CH2 0COR'; 1 2 3 4 , , (C3 -C7 )cycloalkyl, (C2 -C8)alkenyl, (C2 -C8)alkynyl, benzyl, (i) eachofR , R R or R , independently of the others, is aryl, (C0 -C4)alkyl-(C1-C 6 )heterocycloalkyl, (C0 -C4)alkyl- halo, alkyl of 1 to 4-carbon atoms, or alkoxy of 1 to 4 carbon Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 31 of 148 PageID: 31

US 8,198,262 B2 9 10 2 3 4 1 atoms or (ii) one ofR\ R , R , or R is nitro or-NHR and Compounds that are acidic in nature are capable of forming 1 2 3 4 the remaining ofR , R , R , or R are hydrogen; salts with various pharmaceutically acceptable bases. The R5 is hydrogen or alkyl of 1 to 8 carbons bases that can be used to prepare pharmaceutically acceptable R6 hydrogen, alkyl ofl to 8 carbon atoms, benzo, chloro, or base addition salts of such acidic compounds are those that fluoro; form non-toxic base addition salts, i.e., salts containing phar­ 7 10 8 9 R' is R -CHR -N(R R ); macologically acceptable cations such as, but not limited to, 7 alkali metal or alkaline earth metal salts and the calcium, R is m-phenylene or p-phenylene or -(CnH2n)- in which n has a value of 0 to 4; magnesium, sodium or potassium salts in particular. Suitable each of R8 and R9 taken independently of the other is organic bases include, but are not limited to, N,N-dibenzyl­ 8 9 10 ethylenediamine, chloroprocaine, choline, diethanolamine, hydrogen or alky I of 1 to 8 carbon atoms, or R and R taken ethylenediamine, meglumaine (N-methylglucamine), lysine, together are tetramethylene, pentamethylene, hexamethyl­ and procaine. ene, or ---CH CH [X]X CH CH - in which [X]X is 2 2 1 2 2 1 As used herein and unless otherwise indicated, the term -0-, -S-, or -NH-; "prodrug" means a derivative of a compound that can hydro- R10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl; and 15 lyze, oxidize, or otherwise react under biological conditions * represents a chiral-carbon center. (in vitro or in vivo) to provide the compound. Examples of The most preferred immunomodulatory compounds of the prodrugs include, but are not limited to derivatives of immu­ invention are 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindo­ nomodulatory compounds of the invention that comprise bio­ line-1,3-dione and 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol- hydrolyzable moieties such as biohydrolyzable amides, bio- 2-yl)-piperidine-2,6-dione. The compounds can be obtained 20 hydrolyzable esters, biohydrolyzable carbamates, via standard, synthetic methods (see e.g., U.S. Pat. No. 5,635, biohydrolyzable carbonates, biohydrolyzable ureides, and 517, incorporated herein by reference). The compounds are biohydrolyzable phosphate analogues. Other examples of available from Celgene Corporation. Warren, N.J. prodrugs include derivatives of immunomodulatory com­

4-(Amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1 ,3-dione pounds of the invention that comprise -NO, -N02 , (ACTIMID™) has the following chemical structure: 25 ---ONO, or ---ON02 moieties. Prodrugs can typically be pre­ pared using well-known methods, such as those described in 1 Burger's Medicinal Chemistry and Drug Discovery, 172- 178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Else! vier, New York 30 1985). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohy­ drolyzable carbamate," "biohydrolyzable carbonate," "bio­ hydrolyzable ureide," "biohydrolyzable phosphate" mean an 35 amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere The compound 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2- with the biological activity of the compound but can confer yl)-piperidine-2,6-dione (REVIMID™) has the following upon that compound advantageous properties in vivo, such as chemical structure: uptake, duration of action, or onset of action; or 2) is biologi- 40 cally inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters include, but are not limited to, lower alkyl esters, lower acy­ loxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, ami­ nocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxy- 45 ethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbony1-oxymethy I, ethoxycarbony loxyethy I and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetami- Compounds of the invention can either be commercially 50 domethyl esters). Examples of biohydrolyzable amides purchased or prepared according to the methods described in include, but are not limited to, lower alkyl amides, a-amino the patents or patent publications disclosed herein. Further, acid amides, alkoxyacyl amides, and alkylaminoalkylcarbo­ optically pure compounds can be asymmetrically synthesized nyl amides. Examples of biohydrolyzable carbamates or resolved using known resolving agents or chiral colunms include, but are not limited to, lower alkylamines, substituted as well as other standard synthetic organic chemistry tech­ 55 ethylenediamines, amino acids, hydroxyalkylamines, hetero­ niques. cyclic and heteroaromatic amines, and poly ether amines. As used herein and unless otherwise indicated, the term Various immunomodulatory compounds of the invention "pharmaceutically acceptable salt" encompasses non-toxic contain one or more chiral centers, and can exist as racemic acid and base addition salts of the compound to which the mixtures of enantiomers or mixtures of diastereomers. This term refers. Acceptable non-toxic acid addition salts include 60 invention encompasses the use of stereomerically pure forms those derived from organic and inorganic acids or bases know of such compounds, as well as the use of mixtures of those in the art, which include, for example, hydrochloric acid, forms. For example, mixtures comprising equal or unequal hydrobromic acid, phosphoric acid, sulfuric acid, methane­ amounts ofthe enantiomers of a particular immunomodula­ sulphonic acid, acetic acid, tartaric acid, lactic acid, succinic tory compounds of the invention may be used in methods and acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic 65 compositions of the invention. These isomers may be asym­ acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, metrically synthesized or resolved using standard techniques and the like. such as chiral columns or chiral resolving agents. See. e.g. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 32 of 148 PageID: 32

US 8,198,262 B2 11 12 Jacques. J., eta!., Enantiomers, Racemates and Resolutions ecule active agents are biological molecules, such as naturally (Wiley-Interscience, New York. 1981); Wilen, S. H., eta!., occurring or artificially made proteins. Proteins that are par­ Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of ticularly useful in this invention include proteins that stimu­ Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. late the survival and/or proliferation ofhematopoietic precur­ H., Tables ofResolving Agents and Optical Resolutions p. 268 sor cells and immunologically active poietic cells in vitro or (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, in vivo. Others stimulate the division and differentiation of Ind., 1972). committed erythroid progenitors in cells in vitro or in vivo. As used herein and unless otherwise indicated, the term Particular proteins include, but are not limited to: interleu- "stereomerically pure" means a composition that comprises kins, such as IL-2 (including recombinant IL-II ("riL2") and one stereoisomer of a compound and is substantially free of 10 canarypox IL-2), IL-10, IL-12, and IL-18; interferons, such other stereoisomers of that compound. For example, a stereo­ as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, merically pure composition of a compound having one chiral interferon alfa-n3, interferon beta-I a, and interferon center will be substantially free of the opposite enantiomer of gamma-! b; GM-CF and GM-CSF; and EPO. the compound. A stereomerically pure composition of a com­ Particular proteins that can be used in the methods and pound having two chiral centers will be substantially free of 15 compositions of the invention include, but are not limited to: other diastereomers of the compound. A typical stereomeri­ filgrastim, which is sold in the United States under the trade cally pure compound comprises greater than about 80% by name Neupogen® (Amgen, Thousand Oaks, Calif.); sargra­ weight of one stereoisomer of the compound and less than mostim, which is sold in the United States under the trade about 20% by weight of other stereoisomers of the com­ name Leukine® (Immunex, Seattle, Wash.); and recombinant pound, more preferably greater than about 90% by weight of 20 EPO, which is sold in the United States under the trade name one stereoisomer of the compound and less than about 10% Epogen® (Amgen, Thousand Oaks, Calif.). by weight of the other stereoisomers of the compound, even Recombinant and mutated forms of GM-CSF can be pre- more preferably greater than about 95% by weight of one pared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; stereoisomer of the compound and less than about 5% by and 5,229,496; all of which are incorporated herein by refer­ weight of the other stereoisomers of the compound, and most 25 ence. Recombinant and mutated forms of G-CSF can be preferably greater than about 97% by weight of one stereoi­ prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; somer of the compound and less than about 3% by weight of 5,528,823; and 5,580,755; all of which are incorporated the other stereoisomers of the compound. As used herein and herein by reference. unless otherwise indicated, the term "stereomerically This invention encompasses the use of native, naturally enriched" means a composition that comprises greater than 30 occurring, and recombinant proteins. The invention further about 60% by weight of one stereoisomer of a compound, encompasses mutants and derivatives (e.g., modified forms) preferably greater than about 70% by weight, more preferably of naturally occurring proteins that exhibit, in vivo, at least greater than about 80% by weight of one stereoisomer of a some of the pharmacological activity of the proteins upon compound. As used herein and unless otherwise indicated, which they are based. Examples of mutants include, but are the term "enantiomerically pure" means a stereomerically 35 not limited to, proteins that have one or more amino acid pure composition of a compound having one chiral center. residues that differ from the corresponding residues in the Similarly, the term "stereomerically enriched" means a ste­ naturally occurring forms of the proteins. Also encompassed reomerically enriched composition of a compound having by the term "mutants" are proteins that lack carbohydrate one chiral center. moieties normally present in their naturally occurring forms It should be noted that if there is a discrepancy between a 40 (e.g., nonglycosylated forms). Examples of derivatives depicted structure and a name given that structure, the include, but are not limited to, pegylated derivatives and depicted structure is to be accorded more weight. In addition, fusion proteins, such as proteins formed by fusing IgG 1 or if the stereochemistry of a structure or a portion of a structure IgG3 to the protein or active portion of the protein of interest. is not indicated with, for example, bold or dashed lines, the See. e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. structure or portion of the structure is to be interpreted as 45 Methods 248:91-101 (2001). encompassing all stereoisomers of it. Antibodies that can be used in combination with com­ 5.2 Second Active Agents pounds of the invention include monoclonal and polyclonal Immunomodulatory compounds can be combined with antibodies. Examples of antibodies include, but are not lim- other pharmacologically active compounds ("second active ited to, trastuzumab (Herceptin®), rituximab (Rituxan®), agents") in methods and compositions of the invention. It is 50 bevacizumab (Avastin™), pertuzumab (Onmitarg™), tositu­ believed that certain combinations work synergistically in the momab (Bexxar®), edrecolomab (Panorex®), and G250. treatment of particular types of cancer and certain diseases Compounds of the invention can also be combined with, or and conditions associated with, or characterized by, undes­ used in combination with, anti-TNF -a antibodies. ired angiogenesis. Immunomodulatory compounds can also Large molecule active agents may be administered in the work to alleviate adverse effects associated with certain sec- 55 form of anti-cancer vaccines. For example, vaccines that ond active agents, and some second active agents can be used secrete, or cause the secretion of, cytokines such as IL-2, to alleviate adverse effects associated with immunomodula­ G-CSF, and GM-CSF can be used in the methods, pharma- tory compounds. ceutical compositions, and kits of the invention. See, e.g., One or more second active ingredients or agents can be Emens, L.A., eta!., Curr. Opinion Mol. Ther. 3(1): 77-84 used in the methods and compositions of the invention 60 (2001 ). together with an immunomodulatory compound. Second In one embodiment of the invention, the large molecule active agents can be large molecules (e.g., proteins) or small active agent reduces, eliminates, or prevents an adverse effect molecules (e.g., synthetic inorganic, organometallic, or associated with the administration of an immunomodulatory organic molecules). compound. Depending on the particular immunomodulatory Examples of large molecule active agents include, but are 65 compound and the disease or disorder begin treated, adverse not limited to, hematopoietic growth factors, cytokines, and effects can include, but are not limited to, drowsiness and monoclonal and polyclonal antibodies. Typical large mol- sonmolence, dizziness and orthostatic hypotension, neutro- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 33 of 148 PageID: 33

US 8,198,262 B2 13 14 penia, infections that result from neutropenia, increased HIV­ rosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; viralload, bradycardia, Stevens-Johnson Syndrome and toxic zinostatin; and zorubicin hydrochloride. epidermal necrolysis, and seizures (e.g., grand mal convul­ Other anti-cancer drugs include, but are not limited to: sions). A specific adverse effect is neutropenia. 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater­ Second active agents that are small molecules can also be one; aclarubicin; acylfulvene; adecypenol; adozelesin; used to alleviate adverse effects associated with the adminis­ aldesleukin; ALL-TK antagonists; altretamine; ambamus­ tration of an immunomodulatory compound. However, like tine; amidox; amifostine; aminolevulinic acid; amrubicin; some large molecules, many are believed to be capable of amsacrine; anagrelide; anastrozole; andrographolide; angio­ providing a synergistic effect when administered with (e.g., genesis inhibitors; antagonist D; antagonist G; antarelix; anti- 10 dorsalizing morphogenetic protein-!; antiandrogen, prostatic before, after or simultaneously) an immunomodulatory com­ carcinoma; antiestrogen; antineoplaston; antisense oligo­ pound. Examples of small molecule second active agents nucleotides; aphidicolin glycinate; apoptosis gene modula­ include, but are not limited to anti-cancer agents, antibiotics, tors; apoptosis regulators; apurinic acid; ara-CDP-DL­ immunosuppressive agents, and steroids. PTBA; argmme deaminase; asulacrine; atamestane; Examples of anti-cancer agents include, but are not limited 15 atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza­ to: acivicin; aclarubicin; acodazole hydrochloride; acronine; setron; azatoxin; azatyrosine; baccatin III derivatives; bal­ adozelesin; aldesleukin; altretamine; ambomycin; amet­ anol; batimastat; BCR/ABL antagonists; benzochlorins; ben­ antrone acetate; amsacrine; anastrozole; anthramycin; zoylstaurosporine; beta lactam derivatives; beta-alethine; asparaginase; asperlin; azacitidine; azetepa; azotomycin; betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta- batimastat; benzodepa; bicalutamide; bisantrene hydrochlo­ 20 mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene ride; bisnafide dimesylate; bizelesin; bleomycin sulfate; bre­ A; bizelesin; breflate; bropirimine; budotitane; buthionine quinar sodium; bropirimine; busulfan; cactinomycin; calus­ sulfoximine; calcipotriol; calphostin C; camptothecin deriva­ terone; caracemide; carbetimer; carboplatin; carmustine; tives; capecitabine; carboxamide-amino-triazole; carboxya­ carubicin hydrochloride; carzelesin; cedefingol; celecoxib midotriazole; CaRest M3; CARN 700; cartilage derived (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; 25 inhibitor; carzelesin; casein kinase inhibitors (ICOS); cladribine; crisnatol mesylate; cyclophosphamide; cytara­ castanospermine; cecropinB; cetrorelix; chlorlns; chloroqui­ bine; dacarbazine; dactinomycin; daunorubicin hydrochlo­ noxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; ride; decitabine; dexormaplatin; dezaguanine; dezaguanine clomifene analogues; clotrimazole; collismycinA; collismy­ mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin cin B; combretastatin A4; combretastatin analogue; conage- hydrochloride; droloxifene; droloxifene citrate; dromo­ 30 nin; crambescidin 816; crisnatol; cryptophycin 8; cryptophy­ stanolone propionate; duazomycin; edatrexate; eflomithine cin A derivatives; curacin A; cyclopentanthraquinones; hydrochloride; elsamitrucin; enloplatin; enpromate; epipro­ cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic fac­ pidine; epirubicin hydrochloride; erbulozole; esorubicin tor; cytostatin; dacliximab; decitabine; dehydrodidenmin B; hydrochloride; estramustine; estramustine phosphate deslorelin; dexamethasone; dexifosfamide; dexrazoxane; sodium; etanidazole; etoposide; etoposide phosphate; eto­ 35 dexverapamil; diaziquone; didenmin B; didox; diethylnor­ prine; fadrozole hydrochloride; fazarabine; fenretinide; spermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamy­ floxuridine; fludarabine phosphate; fluorouracil; fluorocitab­ cin; diphenyl spiromustine; docetaxel; docosanol; dolas­ ine; fosquidone; fostriecin sodium; gemcitabine; gemcitab­ etron; doxifluridine; doxorubicin; droloxifene; dronabinol; ine hydrochloride; hydroxyurea; idarubicin hydrochloride; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolo- ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan 40 mab; eflornithine; elemene; emitefur; epirubicin; epristeride; hydrochloride; lanreotide acetate; letrozole; leuprolide estramustine analogue; estrogen agonists; estrogen antago­ acetate; liarozole hydrochloride; lometrexol sodium; lomus­ nists; etanidazole; etoposide phosphate; exemestane; fadro­ tine; losoxantrone hydrochloride; masoprocol; maytansine; zole; fazarabine; fenretinide; filgrastim; finasteride; fla­ mechlorethamine hydrochloride; megestrol acetate; vopiridol; flezelastine; fluasterone; fludarabine; melengestrol acetate; melphalan; menogaril; mercaptopu­ 45 fluorodaunorunicin hydrochloride; forfenimex; formestane; rine; methotrexate; methotrexate sodium; metoprine; meture­ fostriecin; fotemustine; gadolinium texaphyrin; gallium depa; mitindomide; mitocarcin; mitocromin; mitogillin; nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit­ mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone abine; glutathione inhibitors; hepsulfam; heregulin; hexam­ hydrochloride; mycophenolic acid; nocodazole; nogalamy­ ethylene bisacetamide; hypericin; ibandronic acid; idarubi- cin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomy­ 50 cin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib cin; pentamustine; peplomycin sulfate; perfosfamide; pipo­ (e.g., Gleevec®), imiquimod; immunostimulant peptides; broman; piposulfan; piroxantrone hydrochloride; insulin-like growth factor-! receptor inhibitor; interferon plicamycin; plomestane; porfimer sodium; porfiromycin; agonists; interferons; interleukins; iobenguane; iododoxoru­ prednimustine; procarbazine hydrochloride; puromycin; bicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; iso- puromycin hydrochloride; pyrazofurin; riboprine; safingol; 55 homohalicondrin B; itasetron; jasplakinolide; kahalalide F; safingol hydrochloride; semustine; simtrazene; sparfosate lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; sodium; sparsomycin; spiro germanium hydrochloride; spiro­ lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting mustine; spiroplatin; streptonigrin; streptozocin; sulofenur; factor; leukocyte alpha interferon; leuprolide+estrogen+ talisomycin; tecogalan sodium; taxotere; tegafur; telox­ progesterone; leuprorelin; levamisole; liarozole; linear antrone hydrochloride; temoporfin; teniposide; teroxirone; 60 polyamine analogue; lipophilic disaccharide peptide; lipo­ testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; philic platinum compounds; lissoclinamide 7; lobaplatin; tirapazamine; toremifene citrate; trestolone acetate; trieirib­ lombricine; lometrexol; lonidamine; losoxantrone; loxorib­ ine phosphate; trimetrexate; trimetrexate glucuronate; trip­ ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep­ torelin; tubulozole hydrochloride; uracil mustard; uredepa; tides; maitansine; marmostatin A; marimastat; masoprocol; vapreotide; verteporfin: vinblastine sulfate; vincristine sul­ 65 maspin; matrilysin inhibitors; matrix metalloproteinase fate; vindesine; vindesine sulfate; vinepidine sulfate; vingly­ inhibitors; menogaril; merbarone; meterelin; methioninase; cinate sulfate: vinleurosine sulfate; vinorelbine tartrate; vin- metoclopramide; MIF inhibitor; mifepristone; miltefosine; Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 34 of 148 PageID: 34

US 8,198,262 B2 15 16 mirimostim; mitoguazone; mitolactol; mitomycin analogues; liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, mitonafide; mitotoxin fibroblast growth factor-saporin; vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, mitoxantrone; mofarotene; molgramostim; Erbitux, human zoledronic acid, palmitronate, biaxin, busulphan, prednisone, chorionic gonadotrophin; monophosphoryllipidA+myobac­ bisphosphonate, arsenic trioxide, vincristine, doxorubicin terium cell wall sk; mopidamol; mustard anticancer agent; (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine mycaperoxide B; mycobacterial cell wall extract; myriapor­ sodium phosphate (Emcyt®), sulindac, and etoposide. one; N-acetyldinaline; N-substituted benzamides; nafarelin; 5.3 Methods of Treatments and Prevention nagrestip; naloxone+pentazocine; napavin; naphterpin; nar­ Methods of this invention encompass methods of treating, tograstim; nedaplatin; nemorubicin; neridronic acid; niluta­ preventing and/or managing various types of cancer and dis­ mide; nisamycin; nitric oxide modulators; nitroxide antioxi- 10 eases and disorders associated with, or characterized by, dant; nitrullyn; oblimersen (Genasense®); undesired angiogenesis. As used herein, unless otherwise 0 6 -benzyl guanine; octreotide; okicenone; oligonucleotides; specified, the term "treating" refers to the administration of a onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; compound of the invention or other additional active agent after the onset of symptoms of the particular disease or dis­ paclitaxel; paclitaxel analogues; paclitaxel derivatives; 15 palauamine; palmitoylrhizoxin; pamidronic acid; panax­ order. As used herein, unless otherwise specified, the term ytriol; panomifene; parabactin; pazelliptine; pegaspargase; "preventing" refers to the administration prior to the onset of peldesine; pentosan polysulfate sodium; pentostatin; pentro­ symptoms, particularly to patients at risk of cancer, and other zole; perflubron; perfosfamide; perillyl alcohol; phenazino­ diseases and disorders associated with, or characterized by, mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo- 20 undesired angiogenesis. The term "prevention" includes the carpine hydrochloride; pirarubicin; piritrexim; placetin A; inhibition of a symptom of the particular disease or disorder. placetin B; plasminogen activator inhibitor; platinum com­ Patients with familial history of cancer and diseases and plex; platinum compounds; platinum-triamine complex; par­ disorders associated with, or characterized by, undesired timer sodium; porfiromycin; prednisone; propyl bis-acri­ angiogenesis are preferred candidates for preventive regi­ done; prostaglandin J2; proteasome inhibitors; protein 25 mens. As used herein and unless otherwise indicated, the term A-based immune modulator; protein kinase C inhibitor; pro­ "managing" encompasses preventing the recurrence of the tein kinase C inhibitors, microalgal; protein tyrosine phos­ particular disease or disorder in a patient who had suffered phatase inhibitors; purine nucleoside phosphorylase inhibi­ from it, and/or lengthening the time a patient who had suf­ tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin fered from the disease or disorder remains in remission. polyoxyethylene conjugate; raf antagonists; raltitrexed; 30 As used herein, the term "cancer" includes, but is not ramosetron; ras farnesyl protein transferase inhibitors; ras limited to, solid tumors and blood born tumors. The term inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe­ "cancer" refers to disease of skin tissues, organs, blood, and nium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; vessels, including, but not limited to, cancers of the bladder, rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; bone or blood, brain, breast, cervix, chest, colon, safingol; saintopin; SarCNU; sarcophytol A; sargramostim; 35 endrometrium, esophagus, eye, head, kidney, liver, lymph Sdi 1 mimetics; semustine; senescence derived inhibitor 1; nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, sense oligonucleotides; signal transduction inhibitors; sizofi­ stomach, testis, throat, and uterus. Specific cancers include, ran; sobuzoxane; sodium borocaptate; sodium phenylacetate; but are not limited to, advanced malignancy, amyloidosis, solverol; somatomedin binding protein; sonermin; sparfosic neuroblastoma, meningioma, hemangiopericytoma, multiple acid; spicamycin D; spiromustine; splenopentin; spongistatin 40 brain metastase, glioblastoma multiforms, glioblastoma, 1; squalamine; stipiamide; stromelysin inhibitors; sulfi­ brain stem glioma, poor prognosis malignant brain tumor, nosine; superactive vasoactive intestinal peptide antagonist; malignant glioma, recurrent malignant giolma, anaplastic suradista; suramin; swainsonine; tallimustine; tamoxifen astrocytoma, anaplastic oligodendroglioma, neuroendocrine methiodide; tauromustine; tazarotene; tecogalan sodium; tumor, rectal adenocarcinoma, Dukes C & D colorectal can­ tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; 45 cer, unresectable colorectal carcinoma, metastatic hepatocel­ teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; lular carcinoma, Kaposi's sarcoma, karotype acute myelo­ thiocoraline; thrombopoietin; thrombopoietin mimetic; thy­ blastic leukemia, Hodgkin's lymphoma, non-Hodgkin's malfasin; thymopoietin receptor agonist; thymotrinan; thy­ lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell roid stimulating hormone; tin ethyl etiopurpurin; tira­ lymphoma, diffuse large B-Celllymphoma, low grade folli­ pazamine; titanocene bichloride; topsentin; toremifene; 50 cular lymphoma, malignant melanoma, malignant mesothe­ translation inhibitors; tretinoin; triacetyluridine; triciribine; lioma, malignant pleural effusion mesothelioma syndrome, trimetrexate; triptorelin; tropisetron; turosteride; tyrosine peritoneal carcinoma, papillary serous carcinoma, gyneco­ kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; logic sarcoma, soft tissue sarcoma, scleroderma, cutaneous urogenital sinus-derived growth inhibitory factor; urokinase vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, receptor antagonists; vapreotide; variolin B; velaresol; 55 fibrodysplasia ossificans progressive, hormone refractory veramine; verdins; verteporfin; vinorelbine; vinxaltine; prostate cancer, resected high-risk soft tissue sarcoma, vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and unrescectable hepatocellular carcinoma, Waldenstrom's zinostatin stimalamer. macroglobulinemia, smoldering myeloma, indolent Specific second active agents include, but are not limited myeloma, fallopian tube cancer, androgen independent pros­ to, oblimersen (Genasense®), remicade, docetaxel, cele- 60 tate cancer, androgen dependent stage IV non-metastatic coxib, melphalan, dexamethasone (Decadron®), steroids, prostate cancer, hormone-insensitive prostate cancer, chemo­ gemcitabine, cisplatinum, temozolomide, etoposide, cyclo­ therapy-insensitive prostate cancer, papillary thyroid carci­ phosphamide, temodar, carboplatin, procarbazine, gliadel, noma, follicular thyroid carcinoma, medullary thyroid carci­ tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, noma, and leiomyoma. In a specific embodiment, the cancer fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, inter- 65 is metastatic. In another embodiment, the cancer is refractory feron alpha, pegylated interferon alpha (e.g., PEG INTRON­ or resistance to chemotherapy or radiation; in particular, A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, refractory to thalidomide. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 35 of 148 PageID: 35

US 8,198,262 B2 17 18 As used herein to refer to diseases and conditions other undue experimentation specific secondary agents, types of than cancer, the terms "diseases or disorders associated with, surgery, and types of non-drug based standard therapy that or characterized by, undesired angiogenesis," "diseases or can be effectively used to treat an individual patient with disorders associated with undesired angiogenesis," and "dis­ cancer and other diseases or disorders. eases or disorders characterized by undesired angiogenesis" Methods encompassed by this invention comprise admin­ refer to diseases, disorders and conditions that are caused, istering one or more immunomodulatory compound of the mediated or attended by undesired, unwanted or uncontrolled invention, or a pharmaceutically acceptable salt, solvate, angiogenesis, including, but not limited to, inflammatory dis­ hydrate, stereoisomer, clathrate, or prodrug thereof, to a eases, autoimmune diseases, genetic diseases, allergic dis­ patient (e.g., a human) suffering, or likely to suffer, from eases, bacterial diseases, ocular neovascular diseases, chor­ 10 cancer or a disease or disorder mediated by undesired angio- oidal neovascular diseases, and retina neovascular diseases. genesis. Examples of such diseases or disorders associated with In one embodiment of the invention, an immunomodula­ undesired angiogenesis include, but are not limited to, dia­ tory compound of the invention can be administered orally betic retinopathy, retinopathy of prematurity, corneal graft and in single or divided daily doses in an amount of from rejection, neovascular glaucoma, retrolental fibroplasia, pro- 15 about 0.10 to about 150 mg/day. In a particular embodiment, liferative vitreoretinopathy, trachoma, myopia, optic pits, 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-1 ,3-dione epidenmic keratoconjunctivitis, atopic keratitis, superior lim­ (Actimid™) may be administered in an amount of from about bic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, 0.1 to about 1 mg per day, or alternatively from about 0.1 to phylectenulosis, syphilis, lipid degeneration, bacterial ulcer, about 5 mg every other day. In a preferred embodiment, fungal ulcer, Herpes simplex infection, Herpes zoster infec- 20 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl-piperidine-2,6- tion, protozoan infection, Kaposi sarcoma, Mooren ulcer, dione (Revimid™) may be administered in an amount of from Terrien's marginal degeneration, mariginal keratolysis, rheu­ about 5 to 25 mg per day, or alternatively from about 10 to matoid arthritis, systemic lupus, polyarteritis, trauma, Wege­ about 50 mg every other day. ners sarcoidosis, Scleritis, Steven's Johnson disease, periph­ In a specific embodiment, 4-(amino)-2-(2,6-dioxo(3-pip­ igoid radial keratotomy, sickle cell anemia, sarcoid, 25 eridyl))-isoindoline-1,3-dione (Actimid™) may be adminis­ pseudoxanthoma elasticum, Pagets disease, vein occlusion, tered in an amount of about 1, 2, or 5 mg per day to patients artery occlusion, carotid obstructive disease, chronic uveitis, with relapsed multiple myeloma. In a particular embodiment, chronic vitritis, Lyme's disease, Eales disease, Bechets dis­ 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2, ease, retinitis, choroiditis, presumed ocular histoplasmosis, 6-dione (Revimid™) may be administered initially in an Bests disease, Stargarts disease, pars planitis, chronic retinal 30 amount of 5 mg/day and the dose can be escalated every week detachment, hyperviscosity syndromes, toxoplasmosis, to 10, 20, 25, 30 and 50 mg/day. In a specific embodiment. rubeosis, sarcodisis, sclerosis, soriatis, psoriasis, primary Revimid™ can be administered in an amount of up to about sclerosing cholangitis, proctitis, primary biliary srosis, idio­ 30 mg/day to patients with solid tumor. In a particular pathic pulmonary fibrosis, and alcoholic hepatitis. embodiment, Revimid™ can be administered in an amount of In specific embodiments of the invention, diseases or dis- 35 up to about 40 mg/day to patients with glioma. orders associated with undesired angiogenesis do not include 5.3 .1 Combination Therapy with a Second Active Agent congestive heart failure, cardiomyopathy, pulmonary edema, Specific methods of the invention comprise administering endotoxin-mediated septic shock, acute viral myocarditis, an immunomodulatory compound of the invention, or a phar­ cardiac allograft rejection, myocardial infarction, HIV, hepa­ maceutically acceptable salt, solvate, hydrate, stereoisomer, titis, adult respiratory distress syndrome, bone-resorption 40 clathrate, or prodrug thereof, in combination with one or disease, chronic obstructive pulmonary diseases, chronic pul­ more second active agents, and/ or in combination with radia­ monary inflammatory disease, dermatitis, cystic fibrosis, sep- tion therapy, blood transfusions, or surgery. Examples of tic shock, sepsis, endotoxic shock, hemodynamic shock, sep- immunomodulatory compounds of the invention are dis­ sis syndrome, post ischemic reperfusion injury, meningitis, closed herein (see, e.g., section 5.1). Examples of second psoriasis, fibrotic disease, cachexia, graft rejection, rheuma- 45 active agents are also disclosed herein (see, e.g., section 5.2). toid spondylitis, osteoporosis, Crohn's disease, ulcerative Administration of the immunomodulatory compounds and colitis, inflammatory-bowel disease, multiple sclerosis, sys­ the second active agents to a patient can occur simultaneously temic lupus erythematosus, erythema nodosum leprosum in or sequentially by the same or different routes of administra­ leprosy, radiation damage, asthma, hyperoxic alveolar injury, tion. The suitability of a particular route of administration malaria, mycobacterial infection, and opportunistic infec- 50 employed for a particular active agent will depend on the tions resulting from HIV. active agent itself (e.g., whether it can be administered orally This invention encompasses methods of treating patients without decomposing prior to entering the blood stream) and who have been previously treated for cancer or diseases or the disease being treated. A preferred route of administration disorders associated with, or characterized by, undesired for an immunomodulatory compound of the invention is angiogenesis, but are non-responsive to standard therapies, as 55 orally. Preferred routes of administration for the second active well as those who have not previously been treated. The agents or ingredients of the invention are known to those of invention also encompasses methods of treating patients ordinary skill in the art. See, e.g., Physicians' Desk Refer­ regardless of patient's age, although some diseases or disor­ ence, 1755-1760 (56'h ed., 2002). ders are more common in certain age groups. The invention In one embodiment of the invention, the second active further encompasses methods of treating patients who have 60 agent is administered intravenously or subcutaneously and undergone surgery in an attempt to treat the disease or con­ once or twice daily in an amount of from about 1 to about dition at issue, as well as those who have not. Because patients 1000 mg, from about 5 to about 500 mg, from about 10 to with cancer and diseases and disorders characterized by about 350 mg, or from about 50 to about 200 mg. The specific undesired angiogenesis have heterogenous clinical manifes­ amount of the second active agent will depend on the specific tations and varying clinical outcomes, the treatment given to 65 agent used, the type of disease being treated or managed, the a patient may vary, depending on his/her prognosis. The severity and stage of disease, and the amount( s) of immuno­ skilled clinician will be able to readily determine without modulatory compounds of the invention and any optional Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 36 of 148 PageID: 36

US 8,198,262 B2 19 20 additional active agents concurrently administered to the In another embodiment, an immunomodulatory compound patient. In a particular embodiment, the second active agent is is administered with temozolomide to patients with neuroen­ oblimersen (Genasense®), GM-CSF. G-CSF. EPO, taxotere, docrine tumors. irinotecan, dacarbazine, transretinoic acid, topotecan, pen­ In another embodiment, an immunomodulatory compound toxifylline, ciprofloxacin, dexamethasone, vincristine, doxo­ is administered with gemcitabine to patients with recurrent or rubicin. COX-2 inhibitor, IL2. ILS, ILlS, IFN, Ara-C, metastatic head or neck cancer. In another embodiment, an vinorelbine, or a combination thereof. immunomodulatory compound is administered with gemcit­ In a particular embodiment, GM-CSF, G-CSF or EPO is abine to patients with pancreatic cancer. administered subcutaneously during about five days in a four In another embodiment, an immunomodulatory compound 10 is administered to patients with colon cancer in combination or six week cycle in an amount of from about 1 to about 750 with Arisa®, taxol and/or taxotere. mg/m2 /day, preferably in an amount offrom about 25 to about In another embodiment, an immunomodulatory compound 500 mg/m2/day, more preferably in an amount of from about 2 is administered with capecitabine to patients with refractory 50 to about 250 mg/m /day, and most preferably in an amount colorectal cancer or patients who fail first line therapy or have of from about 50 to about 200 mg/m2 /day. In a certain 15 poor performance in colon or rectal adenocarcinoma. embodiment, GM -CSF may be administered in an amount of In another embodiment, an immunomodulatory compound 2 from about 60 to about 500 mcg/m intravenously over 2 is administered in combination with fluorouracil, leucovorin, 2 hours, or from about 5 to about 12 mcg/m /day subcutane­ and irinotecan to patients with Dukes C & D colorectal cancer ously. In a specific embodiment, G-CSF may be administered or to patients who have been previously treated for metastatic subcutaneously in an amount of about 1 meg/kg/day initially 20 colorectal cancer. and can be adjusted depending on rise of total granulocyte In another embodiment, an immunomodulatory compound counts. The maintenance dose ofG-CSF may be administered is administered to patients with refractory colorectal cancer in in an amount of about 300 (in smaller patients) or 480 meg combination with capecitabine, xeloda, and/or CPT-11. subcutaneously. In a certain embodiment, EPO may be In another embodiment, an immunomodulatory compound administered subcutaneously in an amount of 10,000 Unit 3 25 of the invention is administered with capecitabine and irino­ times per week. tecan to patients with refractory colorectal cancer or to In another embodiment, Revimid™ in an amount of about patients with unresectable or metastatic colorectal carci­ 25 mg/d and dacarbazine in an amount of about from 200 to noma. 1,000 mg/m2 /dare administered to patients with metastatic In another embodiment, an immunomodulatory compound malignant melanoma. In a specific embodiment, Revimid™ 30 is administered alone or in combination with interferon alpha is administered in an amount offrom about 5 to about 25 mg/d or capecitabine to patients with unresectable or metastatic to patients with metastatic malignant melanoma whose dis­ hepatocellular carcinoma; or with cisplatin and thiotepa to ease has progressed on treatment with dacarbazine, IL-2 or patients with primary or metastatic liver cancer. IFN. In a specific embodiment, Revimid™ is administered to In another embodiment, an immunomodulatory compound patients with relapsed or refractory multiple myeloma in an 35 is administered in combination with pegylated interferon amount of about 15 mg/d twice a day or about 30 mg/d four alpha to patients with Kaposi's sarcoma. times a day in a combination with dexamethasone. In another embodiment, an immunomodulatory compound In another embodiment, an immunomodulatory compound is administered in combination with fludarabine, carboplatin, is administered with melphalan and dexamethasone to and/or topotecan to patients with refractory or relapsed or patients with amyloidosis. In a specific embodiment, an 40 high-risk acuted myelogenous leukemia. immunomodulatory compound of the invention and steroids In another embodiment, an immunomodulatory compound can be administered to patients with amyloidosis. is administered in combination with liposomal daunorubicin, In another embodiment, an immunomodulatory compound topotecan and/or cytarabine to patients with unfavorable is administered with gemcitabine and cisplatinum to patients karotype acute myeloblastic leukemia. with locally advanced or metastatic transitional cell bladder 45 In another embodiment, an immunomodulatory compound cancer. is administered in combination with gemcitabine and irino­ In another embodiment, an immunomodulatory compound tecan to patients with non-small cell lung cancer. In one is administered in combination with a second active ingredi­ embodiment, an immunomodulatory compound is adminis­ ent as follows: temozolomide to pediatric patients with tered in combination with carboplatin and irinotecan to relapsed or progressive brain tumors or recurrent neuroblas­ 50 patients with non-small cell lung cancer. In one embodiment, toma; celecoxib, etoposide and cyclophosphamide for an immunomodulatory compound is administered with dox­ relapsed or progressive CNS cancer; temodar to patients with etaxol to patients with non-small cell lung cancer who have recurrent or progressive meningioma, malignant menin­ been previously treated with carbo/VP 16 and radiotherapy. gioma, hemangiopericytoma, multiple brain metastases, In another embodiment, an immunomodulatory compound relapsed brain tumors, or newly diagnosed glioblastoma mul­ 55 is administered in combination with carboplatin and/or taxo­ tiforms; irinotecan to patients with recurrent glioblastoma; tere, or in combination with carboplatin, pacilitaxel and/or carboplatin to pediatric patients with brain stem glioma; pro­ thoracic radiotherapy to patients with non-small cell lung carbazine to pediatric patients with progressive malignant cancer. In a specific embodiment, an immunomodulatory gliomas; cyclophosphamide to patients with poor prognosis compound is administered in combination with taxotere to malignant brain tumors, newly diagnosed or recurrent glio­ 60 patients with stage IIIB or IV non-small cell lung cancer. blastoma multiforms; Gliadel® for high grade recurrent In another embodiment, an immunomodulatory compound malignant gliomas; temozolomide and tamoxifen for ana­ of the invention is administered in combination with plastic astrocytoma; or topotecan for gliomas, glioblastoma, oblimersen (Genasense®) to patients with small cell lung anaplastic astrocytoma or anaplastic oligodendroglioma. cancer. In another embodiment, an immunomodulatory compound 65 In another embodiment, an immunomodulatory compound is administered with methotrexate and cyclophosphamide to is administered alone or in combination with a second active patients with metastatic breast cancer. ingredient such as vinblastine or fludarabine to patients with Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 37 of 148 PageID: 37

US 8,198,262 B2 21 22 various types of lymphoma, including, but not limited to, cancer drugs for treating a specific cancer of the skin, subcu­ Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous taneous tissue, lymph nodes, brain, lung, liver, bone, intes­ T-Celllymphoma, cutaneous B-Celllymphoma, diffuse large tine, colon, heart, pancreas, adrenal, kidney, prostate, breast, B-Celllymphoma or relapsed or refractory low grade folli­ colorectal, or combinations thereof. The administration of an cular lymphoma. immunomodulatory compound of the invention alleviates or In another embodiment, an immunomodulatory compound reduces adverse effects which are of such severity that it is administered in combination with taxotere, IL-2, IFN, GM­ would otherwise limit the amount of anti -cancer drug. CSF, and/or dacarbazine to patients with various types or In one embodiment, an immunomodulatory compound of stages of melanoma. the invention can be administered orally and daily in an In another embodiment, an immunomodulatory compound 1 o amount of from about 0.1 to about 150 mg, and preferably is administered alone or in combination with vinorelbine to from about 1 to about 50 mg, more preferably from about 2 to patients with malignant mesothelioma, or stage IIIB non­ about 25 mg prior to, during, or after the occurrence of the small cell lung cancer with pleural implants or malignant adverse effect associated with the administration of an anti­ pleural effusion mesothelioma syndrome. cancer drug to a patient. In a particular embodiment, an In another embodiment, an immunomodulatory compound 15 immunomodulatory compound of the invention is adminis­ is administered to patients with various types or stages of tered in combination with specific agents such as heparin, multiple myeloma in combination with dexamethasone, aspirin, Coumadin, or G-CSF to avoid adverse effects that are zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, associated with anti-cancer drugs such as but not limited to melphalan, busulphan, cyclophosphamide, IFN, palmidr­ neutropenia or thrombocytopenia. onate, prednisone, bisphosphonate, celecoxib, arsenic triox- 20 In one embodiment, an immunomodulatory compound of ide, PEG INTRON-A, vincristine, or a combination thereof. the invention can be administered to patients with diseases In another embodiment, an immunomodulatory compound and disorders associated with, or characterized by, undesired is administered to patients with relapsed or refractory mul­ angiogenesis in combination with additional active ingredi­ tiple myeloma in combination with doxorubicin (Doxil®), ents including but not limited to anti-cancer drugs, anti-in- vincristine, and/or dexamethasone (Decadron®). 25 flmatories, antihistamines, antibiotics, and steroids. In another embodiment, an immunomodulatory compound In another embodiment, this invention encompasses a is administered to patients with various types or stages of method of treating, preventing and/or managing cancer, ovarian cancer such as peritoneal carcinoma, papillary serous which comprises administering an immunomodulatory com­ carcinoma, refractory ovarian cancer or recurrent ovarian pound of the invention, or a pharmaceutically acceptable salt, cancer, in combination with taxol, carboplatin, doxorubicin, 30 solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or in conjunction with (e.g. before, during, or after) conven- a combination thereof. tional therapy including, but not limited to, surgery, immu­ In another embodiment, an immunomodulatory compound notherapy, biological therapy, radiation therapy, or other non­ is administered to patients with various types or stages of drug based therapy presently used to treat, prevent or manage prostate cancer, in combination with xeloda, 5 FU/LV, gem- 35 cancer. The combined use of the immunomodulatory com­ citabine, irinotecan plus gemcitabine, cyclophosphamide, pounds of the invention and conventional therapy may pro- vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, vide a unique treatment regimen that is unexpectedly effec­ ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, tive in certain patients. Without being limited by theory, it is Emcyt, or a combination thereof. believed that immunomodulatory compounds of the inven­ In another embodiment, an immunomodulatory compound 40 tion may provide additive or synergistic effects when given is administered to patients with various types or stages of concurrently with conventional therapy. renal cell cancer, in combination with capecitabine, IFN, As discussed elsewhere herein, the invention encompasses tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination a method of reducing, treating and/or preventing adverse or thereof. undesired effects associated with conventional therapy In another embodiment, an immunomodulatory compound 45 including, but not limited to surgery, chemotherapy, radiation is administered to patients with various types or stages of therapy, hormonal therapy, biological therapy and immuno­ gynecologic, uterus or soft tissue sarcoma cancer in combi­ therapy. One or more immunomodulatory compounds of the nation with IFN, a COX-2 inhibitor such as Celebrex®, and/ invention and other active ingredient can be administered to a or sulindac. patient prior to, during, or after the occurrence of the adverse In another embodiment, an immunomodulatory compound 50 effect associated with conventional therapy. is administered to patients with various types or stages of In one embodiment, an immunomodulatory compound of solid tumors in combination with celebrex, etoposide, cyclo­ the invention can be administered in an amount of from about phosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, 0.1 to about 150 mg, and preferably from about 1 to about 25 GM-CSF, or a combination thereof. mg, more preferably from about 2 to about 10 mg orally and In another embodiment, an immunomodulatory compound 55 daily alone, or in combination with a second active agent is administered to patients with scleroderma or cutaneous disclosed herein (see, e.g., section 5.2), prior to, during, or vasculitis in combination with celebrex, etoposide, cyclo­ after the use of conventional therapy. phosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, Ina specific embodiment ofthis method, an immunomodu­ GM-CSF, or a combination thereof. latory compound of the invention and doxetaxol are admin- This invention also encompasses a method of increasing 60 istered to patients with non-small cell lung cancer who were the dosage of an anti -cancer drug or agent that can be safely previously treated with carbo/VP 16 and radiotherapy. and effectively administered to a patient, which comprises 5.3.2 Use with Transplantation Therapy administering to a patient (e.g. a human) an immunomodula­ Compounds of the invention can be used to reduce the risk tory compound of the invention, or a pharmaceutically of Graft Versus Host Disease (GVHD). Therefore, the inven- acceptable derivative, salt, solvate, clathrate, hydrate, or pro­ 65 tion encompasses a method of treating, preventing and/or drug thereof. Patients that can benefit by this method are those managing cancer, which comprises administering the immu­ likely to suffer from an adverse effect associated with anti- nomodulatory compound of the invention, or a pharmaceuti- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 38 of 148 PageID: 38

US 8,198,262 B2 23 24 cally acceptable salt, solvate, hydrate, stereoisomer, clath­ dose of melphalan and the transplantation of peripheral blood rate, or prodrug thereof, in conjunction with transplantation stem cell to 65 years of age or older patients with multiple therapy. myeloma. As those of ordinary skill in the art are aware, the treatment 5 .3 .3 Cycling Therapy of cancer is often based on the stages and mechanism of the In certain embodiments, the prophylactic or therapeutic disease. For example, as inevitable leukemic transformation agents of the invention are cyclically administered to a develops in certain stages of cancer, transplantation ofperiph­ patient. Cycling therapy involves the administration of an eral blood stem cells, hematopoietic stem cell preparation or active agent for a period of time, followed by a rest for a bone marrow may be necessary. The combined use of the period of time, and repeating this sequential administration. 10 Cycling therapy can reduce the development of resistance to immunomodulatory compound of the invention and trans- one or more of the therapies, avoid or reduce the side effects plantation therapy provides a unique and unexpected syner­ of one of the therapies, and/or improves the efficacy of the gism. In particular, an immunomodulatory compound of the treatment. invention exhibits immunomodulatory activity that may pro­ Consequently, in one specific embodiment of the inven­ vide additive or synergistic effects when given concurrently 15 tion, an immunomodulatory compound of the invention is with transplantation therapy in patients with cancer. administered daily in a single or divided doses in a four to six An immunomodulatory compound of the invention can week cycle with a rest period of about a week or two weeks. work in combination with transplantation therapy reducing The invention further allows the frequency, number, and complications associated with the invasive procedure of length of dosing cycles to be increased. Thus, another specific transplantation and risk of GVHD. This invention encom- 20 embodiment of the invention encompasses the administration passes a method of treating, preventing and/or managing of an immunomodulatory compound of the invention for cancer which comprises administering to a patient (e.g. a more cycles than are typical when it is administered alone. In human) an immunomodulatory compound of the invention, yet another specific embodiment of the invention, an immu­ or a pharmaceutically acceptable salt, solvate, hydrate, stere­ nomodulatory compound of the invention is administered for oisomer, clathrate, or prodrug thereof, before, during, or after 25 a greater number of cycles that would typically cause dose­ the transplantation of umbilical cord blood, placental blood, limiting toxicity in a patient to whom a second active ingre- peripheral blood stem cell, hematopoietic stem cell prepara­ dient is not also being administered. tion or bone marrow. Examples of stem cells suitable for use In one embodiment, an immunomodulatory compound of in the methods of the invention are disclosed in U.S. provi­ the invention is administered daily and continuously for three sional patent application No. 60/372,348, filed Apr. 12, 2002 30 or four weeks at a dose of from about 0.1 to about 150 mg/d followed by a break of one or two weeks. Actimid™is pref- by R. Hariri eta!., the entirety of which is incorporated herein erably administered daily and continuously at an initial dose by reference. of0.1 to 5 mg/d with dose escalation (every week) by 1 to 10 In one embodiment of this method, an immunomodulatory mg/d to a maximum dose of 50 mg/d for as long as therapy is compound of the invention is administered to patients with 35 tolerated. In a particular embodiment, Revimid™ is admin­ multiple myeloma before, during, or after the transplantation istered in an amount of about 5, 10, or 25 mg/day, preferably of autologous peripheral blood progenitor cell. in an amount of about 10 mg/day for three to four weeks, In another embodiment, an immunomodulatory compound followed by one week or two weeks of rest in a four or six is administered to patients with relapsing multiple myeloma week cycle. after the stem cell transplantation. 40 In one embodiment of the invention, an immunomodula­ In another embodiment, an immunomodulatory compound tory compound of the invention and a second active ingredi­ and prednisone are administered as maintenance therapy to ent are administered orally, with administration of an immu­ patients with multiple myeloma following the transplantation nomodulatory compound of the invention occurring 30 to 60 of autologous stem cell. minutes prior to a second active ingredient, during a cycle of In another embodiment, an immunomodulatory compound 45 four to six weeks. In another embodiment ofthe invention, the and dexamethasone are administered as salvage therapy for combination of an immunomodulatory compound of the low risk post transplantation to patients with multiple invention and a second active ingredient is administered by myeloma. intravenous infusion over about 90 minutes every cycle. In a In another embodiment, an immunomodulatory compound specific embodiment, one cycle comprises the administration and dexamethasone are administered as maintenance therapy 50 offrom about 10 to about 25 mg/day ofRevimid™ and from to patients with multiple myeloma following the transplanta­ about 50 to about 200 mg/m2/day of a second active ingredi- tion of autologous bone marrow. ent daily for three to four weeks and then one or two weeks of In another embodiment, an immunomodulatory compound rest. In another specific embodiment, each cycle comprises is administered following the administration of high dose of the administration of from about 5 to about 10 mg/day of 2 melphalan and the transplantation of autologous stem cell to 55 Actimid™ and from about 50 to about 200 mg/m /day of a patients with chemotherapy responsive multiple myeloma. second active ingredient for 3 to 4 weeks followed by one or In another embodiment, an immunomodulatory compound two weeks of rest. Typically, the number of cycles during and PEG INTRO-A are administered as maintenance therapy which the combinatorial treatment is administered to a patient to patients with multiple myeloma following the transplanta­ will be from about one to about 24 cycles, more typically from tion of autologous CD34-selected peripheral stem cell. 60 about two to about 16 cycles, and even more typically from In another embodiment, an immunomodulatory compound about four to about three cycles. is administered with post transplant consolidation chemo­ 5.4 Pharmaceutical Compositions and Dosage Forms therapy to patients with newly diagnosed multiple myeloma Pharmaceutical compositions can be used in the prepara­ to evaluate anti-angiogenesis. tion of individual, single unit dosage forms. Pharmaceutical In another embodiment, an immunomodulatory compound 65 compositions and dosage forms of the invention comprise an and dexamethasone are administered as maintenance therapy immunomodulatory compound of the invention, or a pharma- after DCEP consolidation, following the treatment with high ceutically acceptable salt, solvate, hydrate, stereoisomer, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 39 of 148 PageID: 39

US 8,198,262 B2 25 26 clathrate, or prodrug thereof. Pharmaceutical compositions Lactose-free compositions of the invention can comprise and dosage forms of the invention can further comprise one or excipients that are well known in the art and are listed, for more excipients. example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). Pharmaceutical compositions and dosage forms of the In general, lactose-free compositions comprise active ingre­ invention can also comprise one or more additional active dients, a binder/filler, and a lubricant in pharmaceutically ingredients. Consequently, pharmaceutical compositions and compatible and pharmaceutically acceptable amounts. Pre­ dosage forms of the invention comprise the active ingredients ferred lactose-free dosage forms comprise active ingredients, disclosed herein (e.g., an immunomodulatory compound and microcrystalline cellulose, pre-gelatinized starch, and mag­ a second active agent). Examples of optional second, or addi­ nesium stearate. 10 This invention further encompasses anhydrous pharma­ tional, active ingredients are disclosed herein (see, e.g., sec- ceutical compositions and dosage forms comprising active tion 5.2). ingredients, since water can facilitate the degradation of some Single unit dosage forms of the invention are suitable for compounds. For example, the addition of water (e.g., 5%) is oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rec­ widely accepted in the pharmaceutical arts as a means of tal), parenteral (e.g., subcutaneous, intravenous, bolus injec- 15 simulating long-term storage in order to determine character­ tion, intramuscular, or intraarterial), topical (e.g., eye drops or istics such as shelf-life or the stability of formulations over other ophthalmic preparations), transdermal or transcutane­ time. See, e.g., Jens T. Carstensen, Drug Stability: Principles ous administration to a patient. Examples of dosage forms & Practice, 2d. Ed. Marcel Dekker, NY, N.Y., 1995, pp. include, but are not limited to: tablets; caplets; capsules, such 379-80. In effect, water and heat accelerate the decomposi­ as soft elastic gelatin capsules; cachets; troches; lozenges; 20 tion of some compounds. Thus, the effect of water on a dispersions; suppositories; powders; aerosols (e.g., nasal formulation can be of great significance since moisture and/or sprays or inhalers); gels; liquid dosage forms suitable for oral humidity are commonly encountered during manufacture, or mucosal administration to a patient, including suspensions handling, packaging, storage, shipment, and use of formula­ (e.g., aqueous or non-aqueous liquid suspensions, oil-in-wa- tions. ter emulsions, or a water-in-oil liquid emulsions), solutions, 25 Anhydrous pharmaceutical compositions and dosage and elixirs; liquid dosage forms suitable for parenteral admin­ forms of the invention can be prepared using anhydrous or istration to a patient; eye drops or other ophthalmic prepara­ low moisture containing ingredients and low moisture or low tions suitable for topical administration; and sterile solids humidity conditions. Pharmaceutical compositions and dos­ (e.g., crystalline or amorphous solids) that can be reconsti­ age forms that comprise lactose and at least one active ingre­ tuted to provide liquid dosage forms suitable for parenteral 30 dient that comprises a primary or secondary amine are pref­ administration to a patient. erably anhydrous if substantial contact with moisture and/or The composition, shape, and type of dosage forms of the humidity during manufacturing, packaging, and/or storage is invention will typically vary depending on their use. For expected. example, a dosage form used in the acute treatment of a An anhydrous pharmaceutical composition should be pre­ disease may contain larger amounts of one or more of the 35 pared and stored such that its anhydrous nature is maintained. active ingredients it comprises than a dosage form used in the Accordingly, anhydrous compositions are preferably pack­ chronic treatment of the same disease. Similarly, a parenteral aged using materials known to prevent exposure to water such dosage form may contain smaller amounts of one or more of that they can be included in suitable formulary kits. Examples the active ingredients it comprises than an oral dosage form of suitable packaging include, but are not limited to, hermeti­ used to treat the same disease. These and other ways in which 40 cally sealed foils, plastics, unit dose containers (e.g., vials), specific dosage forms encompassed by this invention will blister packs, and strip packs. vary from one another will be readily apparent to those skilled The invention further encompasses pharmaceutical com­ in the art. See, e.g., Remington's Pharmaceutical Sciences, positions and dosage forms that comprise one or more com­ 18th ed., Mack Publishing, Easton Pa. (1990). pounds that reduce the rate by which an active ingredient will Typical pharmaceutical compositions and dosage forms 45 decompose. Such compounds, which are referred to herein as comprise one or more excipients. Suitable excipients are well "stabilizers," include, but are not limited to, antioxidants such known to those skilled in the art of pharmacy, and non­ as ascorbic acid, pH buffers, or salt buffers. limiting examples of suitable excipients are provided herein. Like the amounts and types of excipients, the amounts and Whether a particular excipient is suitable for incorporation specific types of active ingredients in a dosage form may into a pharmaceutical composition or dosage form depends 50 differ depending on factors such as, but not limited to, the on a variety of factors well known in the art including, but not route by which it is to be administered to patients. However, limited to, the way in which the dosage form will be admin­ typical dosage forms of the invention comprise an immuno­ istered to a patient. For example, oral dosage forms such as modulatory compound of the invention or a pharmaceutically tablets may contain excipients not suited for use in parenteral acceptable salt, solvate, hydrate, stereoisomer, clathrate, or dosage forms. The suitability of a particular excipient may 55 pro drug thereof in an amount offrom about 0.10 to about 150 also depend on the specific active ingredients in the dosage mg. Typical dosage forms comprise an immunomodulatory form. For example, the decomposition of some active ingre­ compound of the invention or a pharmaceutically acceptable dients may be accelerated by some excipients such as lactose, salt, solvate, hydrate, stereoisomer, clathrate, or prodrug or when exposed to water. Active ingredients that comprise thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, primary or secondary amines are particularly susceptible to 60 17.5, 20, 25, 50, 100, 150 or 200 mg. In a particular embodi­ such accelerated decomposition. Consequently, this inven­ ment, a preferred dosage form comprises 4-(amino)-2-(2,6- tion encompasses pharmaceutical compositions and dosage dioxo(3-piperidyl))-isoindoline-l ,3-dione (Actimid™) in an forms that contain little, if any, lactose other mono- or di­ amount of about 1, 2, 5, 10, 25 or 50 mg. In a specific saccharides. As used herein, the term "lactose-free" means embodiment, a preferred dosage form comprises 3-(4-amino- that the amount of lactose present, if any, is insufficient to 65 1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Re­ substantially increase the degradation rate of an active ingre­ vimid™) in an amount of about 5, 10, 25 or 50 mg. Typical dient. dosage forms comprise the second active ingredient in an Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 40 of 148 PageID: 40

US 8,198,262 B2 27 28 amount of 1 to about 1000 mg, from about 5 to about 500 mg, sodium carboxymethyl cellulose sold as AVICEL RC-581. from about 10 to about 350 mg, or from about 50 to about 200 Suitable anhydrous or low moisture excipients or additives mg. Of course, the specific amount of the anti-cancer drug includeAVICEL-PH-103™ and Starch 1500 LM. will depend on the specific agent used, the type of cancer Examples of fillers suitable for use in the pharmaceutical being treated or managed, and the amount(s) of an immuno­ compositions and dosage forms disclosed herein include, but modulatory compound of the invention and any optional are not limited to, talc, calcium carbonate (e.g., granules or additional active agents concurrently administered to the powder), microcrystalline cellulose, powdered cellulose, patient. dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre­ 5.4.1 Oral Dosage Forms gelatinized starch, and mixtures thereof. The binder or filler in Pharmaceutical compositions of the invention that are suit- 10 pharmaceutical compositions of the invention is typically able for oral administration can be presented as discrete dos­ present in from about 50 to about 99 weight percent of the age forms, such as, but are not limited to, tablets (e.g., chew­ pharmaceutical composition or dosage form. able tablets), caplets, capsules, and liquids (e.g., flavored Disintegrants are used in the compositions of the invention syrups). Such dosage forms contain predetermined amounts to provide tablets that disintegrate when exposed to an aque­ of active ingredients, and may be prepared by methods of 15 ous environment. Tablets that contain too much disintegrant pharmacy well known to those skilled in the art. See gener­ may disintegrate in storage, while those that contain too little ally, Remington's Pharmaceutical Sciences, 18th ed., Mack may not disintegrate at a desired rate or under the desired Publishing, Easton Pa. (1990). conditions. Thus, a sufficient amount of disintegrant that is Typical oral dosage forms of the invention are prepared by neither too much nor too little to detrimentally alter the combining the active ingredients in an intimate admixture 20 release of the active ingredients should be used to form solid with at least one excipient according to conventional pharma­ oral dosage forms of the invention. The amount of disinte­ ceutical compounding techniques. Excipients can take a wide grant used varies based upon the type of formulation, and is variety of forms depending on the form of preparation desired readily discernible to those of ordinary skill in the art. Typical for administration. For example, excipients suitable for use in pharmaceutical compositions comprise from about 0.5 to oral liquid or aerosol dosage forms include, but are not limited 25 about 15 weight percent of disintegrant, preferably from to, water, glycols, oils, alcohols, flavoring agents, preserva­ about 1 to about 5 weight percent of disintegrant. tives, and coloring agents. Examples of excipients suitable for Disintegrants that can be used in pharmaceutical compo­ use in solid oral dosage forms (e.g., powders, tablets, cap­ sitions and dosage forms of the invention include, but are not sules, and caplets) include, but are not limited to, starches, limited to agar-agar, alginic acid, calcium carbonate, micro­ sugars, micro-crystalline cellulose, diluents, granulating 30 crystalline cellulose, croscarmellose sodium, crospovidone, agents, lubricants, binders, and disintegrating agents. polacrilin potassium, sodium starch glycolate, potato or tapi­ Because of their ease of administration, tablets and cap­ oca starch, other starches, pre-gelatinized starch, other sules represent the most advantageous oral dosage unit forms, starches, clays, other a! gins, other cell uloses, gums, and mix­ in which case solid excipients are employed. If desired, tab­ tures thereof. lets can be coated by standard aqueous or nonaqueous tech- 35 Lubricants that can be used in pharmaceutical composi­ niques. Such dosage forms can be prepared by any of the tions and dosage forms of the invention include, but are not methods of pharmacy. In general, pharmaceutical composi­ limited to, calcium stearate, magnesium stearate, mineral oil, tions and dosage forms are prepared by uniformly and inti­ light mineral oil, glycerin, sorbitol, mannitol, polyethylene mately admixing the active ingredients with liquid carriers, glycol, other glycols, stearic acid, sodium Iaury! sulfate, talc, finely divided solid carriers, or both, and then shaping the 40 hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, product into the desired presentation if necessary. sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), For example, a tablet can be prepared by compression or zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures molding. Compressed tablets can be prepared by compress­ thereof. Additional lubricants include, for example, a syloid ing in a suitable machine the active ingredients in a free­ silica gel (AEROSIL200, manufactured by W.R. Grace Co. of flowing form such as powder or granules, optionally mixed 45 Baltimore, Md.), a coagulated aerosol of synthetic silica with an excipient. Molded tablets can be made by molding in (marketed by Degussa Co. of Plano, Tex.), CAB-0-SIL (a a suitable machine a mixture of the powdered compound pyrogenic silicon dioxide product sold by Cabot Co. of Bos­ moistened with an inert liquid diluent. ton, Mass.), and mixtures thereof. If used at all, lubricants are Examples of excipients that can be used in oral dosage typically used in an amount of less than about 1 weight forms of the invention include, but are not limited to binders, 50 percent of the pharmaceutical compositions or dosage forms fillers, disintegrants, and lubricants. Binders suitable for use into which they are incorporated. in pharmaceutical compositions and dosage forms include, A preferred solid oral dosage form of the invention com­ but are not limited to, corn starch, potato starch, or other prises an immunomodulatory compound of the invention, starches, gelatin, natural and synthetic gums such as acacia, anhydrous lactose, microcrystalline cellulose, polyvinylpyr­ sodium alginate, alginic acid, other alginates, powdered 55 rolidone, stearic acid, colloidal anhydrous silica, and gelatin. tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl 5.4.2 Delayed Release Dosage Forms cellulose, cellulose acetate, carboxymethyl cellulose cal­ Active ingredients of the invention can be administered by cium, sodium carboxymethyl cellulose), polyvinyl pyrroli­ controlled release means or by delivery devices that are well done, methyl cellulose, pre-gelatinized starch, hydroxy-pro­ known to those of ordinary skill in the art. Examples include, pyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), 60 but are not limited to, those described in U.S. Pat. Nos. 3,845, microcrystalline cellulose, and mixtures thereof. 770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674, Suitable forms of microcrystalline cellulose include, but 533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, are not limited to, the materials sold as AVICEL-PH-101, 5,354,556, and 5,733,566, each of which is incorporated AVICEL-PH-1 03 AVICEL RC-581 ,AVICEL-PH-1 05 (avail­ herein by reference. Such dosage forms can be used to pro­ able from FMC Corporation, American Viscose Division, 65 vide slow or controlled-release of one or more active ingre­ Avice! Sales, Marcus Hook, Pa.), and mixtures thereof. An dients using, for example, hydropropylmethyl cellulose, specific binder is a mixture of microcrystalline cellulose and other polymer matrices, gels, permeable membranes, osmotic Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 41 of 148 PageID: 41

US 8,198,262 B2 29 30 systems, multilayer coatings, microparticles, liposomes, emulsions, suspensions, eye drops or other ophthalmic prepa­ microspheres, or a combination thereof to provide the desired rations, or other forms known to one of skill in the art. See, release profile in varying proportions. Suitable controlled­ e.g., Remington's Pharmaceutical Sciences, 16th and 18th release formulations known to those of ordinary skill in the eds., Mack Publishing, Easton Pa. (1980 & 1990); and Intro­ art, including those described herein, can be readily selected duction to Pharmaceutical Dosage Forms, 4th ed., Lea & for use with the active ingredients ofthe invention. The inven­ Febiger, Philadelphia (1985). Dosage forms suitable for treat­ tion thus encompasses single unit dosage forms suitable for ing mucosal tissues within the oral cavity can be formulated as mouthwashes or as oral gels. oral administration such as, but not limited to, tablets, cap­ Suitable excipients (e.g., carriers and diluents) and other sules, gelcaps, and caplets that are adapted for controlled­ 10 materials that can be used to provide topical and mucosal release. dosage forms encompassed by this invention are well known All controlled-release pharmaceutical products have a to those skilled in the pharmaceutical arts, and depend on the common goal of improving drug therapy over that achieved particular tissue to which a given pharmaceutical composi­ by their non-controlled counterparts. Ideally, the use of an tion or dosage form will be applied. With that fact in mind, optimally designed controlled-release preparation in medical typical excipients include, but are not limited to, water, 15 treatment is characterized by a minimum of drug substance acetone, ethanol, ethylene glycol, propylene glycol, butane- being employed to cure or control the condition in a minimum 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral amount of time. Advantages of controlled-release formula­ oil, and mixtures thereof to form solutions, emulsions or gels, tions include extended activity of the drug, reduced dosage which are non-toxic and pharmaceutically acceptable. Mois­ frequency, and increased patient compliance. In addition, turizers or humectants can also be added to pharmaceutical controlled-release formulations can be used to affect the time 20 compositions and dosage forms if desired. Examples of such of onset of action or other characteristics, such as blood levels additional ingredients are well known in the art. See, e.g., of the drug, and can thus affect the occurrence of side (e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds., adverse) effects. Mack Publishing, Easton Pa. (1980 & 1990). Most controlled-release formulations are designed to ini­ The pH of a pharmaceutical composition or dosage form tially release an amount of drug (active ingredient) that 25 may also be adjusted to improve delivery of one or more promptly produces the desired therapeutic effect, and gradu­ active ingredients. Similarly, the polarity of a solvent carrier, ally and continually release of other amounts of drug to main­ its ionic strength, or tonicity can be adjusted to improve tain this level of therapeutic or prophylactic effect over an delivery. Compounds such as stearates can also be added to extended period of time. In order to maintain this constant pharmaceutical compositions or dosage forms to advanta- level of drug in the body, the drug must be released from the 30 geously alter the hydrophilicity or lipophilicity of one or dosage form at a rate that will replace the amount of drug more active ingredients so as to improve delivery. In this being metabolized and excreted from the body. Controlled­ regard, stearates can serve as a lipid vehicle for the formula­ release of an active ingredient can be stimulated by various tion, as an emulsifying agent or surfactant, and as a delivery­ conditions including, but not limited to, pH, temperature, enhancing or penetration-enhancing agent. Different salts, enzymes, water, or other physiological conditions or com­ 35 hydrates or solvates of the active ingredients can be used to pounds. further adjust the properties of the resulting composition. 5.4.3 Parenteral Dosage Forms 5.4.5 Kits Parenteral dosage forms can be administered to patients by Typically, active ingredients of the invention are preferably various routes including, but not limited to, subcutaneous, not administered to a patient at the same time or by the same intravenous (including bolus injection), intramuscular, and 40 route of administration. This invention therefore encom­ intraarterial. Because their administration typically bypasses patients' natural defenses against contaminants, parenteral passes kits which, when used by the medical practitioner, can dosage forms are preferably sterile or capable of being ster­ simplifY the administration of appropriate amounts of active ilized prior to administration to a patient. Examples of ingredients to a patient. parenteral dosage forms include, but are not limited to, solu­ A typical kit ofthe invention comprises a dosage form of an tions ready for injection, dry products ready to be dissolved or 45 immunomodulatory compound of the invention, or a pharma­ suspended in a pharmaceutically acceptable vehicle for injec­ ceutically acceptable salt, solvate, hydrate, stereoisomer, pro­ tion, suspensions ready for injection, and emulsions. drug, or clathrate thereof. Kits encompassed by this invention Suitable vehicles that can be used to provide parenteral can further comprise additional active ingredients such as dosage forms of the invention are well known to those skilled oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, in the art. Examples include, but are not limited to: Water for 50 EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, Injection USP; aqueous vehicles such as, but not limited to, COX-2 inhibitor, pentoxi:tylline, ciprofloxacin, dexametha- Sodium Chloride Injection. Ringer's Injection, Dextrose sone, IL2, ILS, ILlS, Ara-C, vinorelbine, isotretinoin, 13 Injection, Dextrose and Sodium Chloride Injection, and Lac­ cis-retinoic acid, or a pharmacologically active mutant or tated Ringer's Injection; water-miscible vehicles such as, but derivative thereof, or a combination thereof. Examples of the not limited to, ethyl alcohol, polyethylene glycol, and 55 additional active ingredients include, but are not limited to, polypropylene glycol; and non-aqueous vehicles such as, but those disclosed herein (see, e.g., section 5.2). not limited to, com oil, cottonseed oil, peanut oil, sesame oil, Kits of the invention can further comprise devices that are ethyl oleate, isopropyl myristate, and benzyl benzoate. used to administer the active ingredients. Examples of such Compounds that increase the solubility of one or more of the active ingredients disclosed herein can also be incorpo­ devices include, but are not limited to, syringes, drip bags, rated into the parenteral dosage forms of the invention. For 60 patches, and inhalers. example, cyclodextrin and its derivatives can be used to Kits ofthe invention can further comprise cells or blood for increase the solubility of an immunomodulatory compound transplantation as well as pharmaceutically acceptable of the invention and its derivatives. See, e.g., U.S. Pat. No. vehicles that can be used to administer one or more active 5,134,127, which is incorporated herein by reference. ingredients. For example, if an active ingredient is provided in 5.4.4 Topical and Mucosal Dosage Forms 65 a solid form that must be reconstituted for parenteral admin­ Topical and mucosal dosage forms of the invention istration, the kit can comprise a sealed container of a suitable include, but are not limited to, sprays, aerosols, solutions, vehicle in which the active ingredient can be dissolved to Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 42 of 148 PageID: 42

US 8,198,262 B2 31 32 form a particulate-free sterile solution that is suitable for 6.2 Inhibition ofMM Cell Proliferation parenteral administration. Examples of pharmaceutically The ability of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2- acceptable vehicles include, but are not limited to: Water for yl)-piperidine-2,6-dione (Revimid™) and thalidomide for Injection USP; aqueous vehicles such as, but not limited to, comparison to effect the proliferation of MM cell lines has Sodium Chloride Injection, Ringer's Injection, Dextrose 5 been investigated in an in vitro study. Uptake [3 H]-thymidine Injection, Dextrose and Sodium Chloride Injection, and Lac­ by different MM cell lines (MM.lS, Hs Sultan, U266 and tated Ringer's Injection; water-miscible vehicles such as, but RPMI-8226) was measured as an indicator of cell prolifera­ not limited to, ethyl alcohol, polyethylene glycol, and tion. Cells were incubated in the presence of compounds for polypropylene glycol; and non-aqueous vehicles such as, but 48 hours; [3 H]-thymidine was included for the last 8 hours of not limited to, com oil, cottonseed oil, peanut oil, sesame oil, 10 the incubation period. Addition of 3-(4-amino-1-oxo-1 ,3-di­ ethyl oleate, isopropyl myristate, and benzyl benzoate. hydro-isoindol-2-yl)-piperidine-2,6-dione to MM.l Sand Hs Sultan cells resulted in 50% inhibition of cell proliferation at 6. EXAMPLES concentrations of0.4 f.tm and 1 f.tm, respectively. In contrast,

15 addition of thalidomide at concentrations up to 100 f.tm Certain embodiments of the invention are illustrated by the resulted in only 15% and 20% inhibition of cell proliferation following non-limiting examples. in MM.lS and Hs Sultan cells, respectively. These data are 6.1 Modulation of Cytokine Production sunmwrized in FIG. 1. A series of non-clinical pharmacology and toxicology 6.3 Toxicology Studies studies have been performed to support the clinical evaluation 20 The effects of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2- of an immunomodulatory compound of the invention in yl)-piperidine-2,6-dione (Revimid™) on cardiovascular and human subjects. These studies were performed in accordance respiratory function are investigated in anesthetized dogs. with internationally recognized guidelines for study design Two groups ofBeagle dogs (2/sex/group) are used. One group and in compliance with the requirements of Good Laboratory receives three doses of vehicle only and the other receives Practice (GLP), unless otherwise noted. 25 three ascending doses of 3-(4-amino-1-oxo-1 ,3-dihydro­ Inhibition of TNF-a production following LPS-stimula­ isoindol-2-yl)-piperidine-2,6-dione (2, 10, and 20 mg/kg). In tion of human PBMC and human whole blood by 4-( amino)- all cases, doses of3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2- 2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione (Ac­ yl)-piperidine-2,6-dione or vehicle are successively adminis­ timid™), 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)­ tered via infusion through the jugular vein separated by inter- piperidine-2,6-dione and thalidomide (Revimid™) was 30 vals of at least 30 minutes. investigated in vitro (Muller et a!., Bioorg. Me d. Chern. Lett. The cardiovascular and respiratory changes induced by 9:1625-1630, 1999). The IC50's of 4-(amino)-2-(2,6-dioxo 3-( 4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2, (3-piperidyl))-isoindoline-1 ,3-dione for inhibiting produc­ 6-dione are minimal at all doses when compared to the tion of TNF -a following LPS-stimulation of PBMC and vehicle control group. The only statistically significant dif­ 35 human whole blood were -24 nM (6.55 ng/mL) and -25 nM ference between the vehicle and treatment groups is a small (6.83 ng/mL), respectively. In vitro studies suggest a pharma­ increase in arterial blood pressure (from 94 mmHg to 101 cological activity profile for 3-( 4-amino-1-oxo-1 ,3-dihydro­ mmHg) following administration of the low dose of 3-(4- isoindol-2-yl)-piperidine-2,6-dione that is similar to, but at amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-di­ least 200 times more potent than, thalidomide. In vitro studies 40 one. This effect lasts approximately 15 minutes and is not have also demonstrated that concentrations of 4-(amino)-2- seen at higher doses. Deviations in femoral blood flow, res­ (2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione of 2.73 to piratory parameters, and Qtc interval are common to both the 27.3 ng/mL (0.01 to 0.1 f.LM) achieved 50% inhibition of the control and treated groups and are not considered treatment­ proliferation ofMM.lS and Hs Sultan cells. related.

The IC50's of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2- 45 6.4 Cycling Therapy in Patients yl)-piperidine-2,6-dione for inhibiting production of TNF -a In a specific embodiment, an immunomodulatory com­ following LPS-stimulation ofPBMC and human whole blood pound of the invention are cyclically administered to patients were -100 nM (25.9 ng/mL) and f1480 nM (103.6 ng/mL), with cancer. Cycling therapy involves the administration of a respectively. Thalidomide, in contrast, had an IC50 of -194 first agent for a period of time, followed by a rest for a period f.LM ( 50.2 flg/mL) for inhibiting production ofTNF -a follow- 50 of time and repeating this sequential administration. Cycling ing LPS-stimulation of PBMC. In vitro studies suggest a therapy can reduce the development of resistance to one or pharmacological activity profile for 3-(4-amino-1-oxo-1 ,3- more of the therapies, avoid or reduce the side effects of one dihydro-isoindol-2-yl)-piperidine-2,6-dione that is similar ofthe therapies, and/or improves the efficacy ofthe treatment. to, but 50 to 2000 times more potent than, thalidomide. It has In a specific embodiment, prophylactic or therapeutic been shown that the compound is approximately 50-100 55 agents are administered in a cycle of about 4 to 6 weeks, about times more potent than thalidomide in stimulating the prolif­ once or twice every day. One cycle can comprise the admin­ eration of T-cells following primary induction by T-cell istration of a therapeutic on prophylactic agent for three to receptor (TCR) activation. 3-( 4-amino-1-oxo-1 ,3-dihydro­ four weeks and at least a week or two weeks of rest. The isoindol-2-yl)-piperidine-2,6-dione is also approximately 50 number of cycles administered is from about one to about 24 to 100 times more potent than thalidomide in augmenting the 60 cycles, more typically from about two to about 16 cycles, and production of IL-2 and IFN-y following TCR activation of more typically from about four to about eight cycles. PBMC (IL-2) or T-cells (IFN-y). In addition, 3-(4-amino-1- For example, in a cycle of four weeks, on day 1, the admin­ oxo-1 ,3-dihydro-isoindol-2-y 1)-piperidine-2,6-dione exhib­ istration of 25 mg/d of3-(4-amino-1-oxo-1 ,3-dihydro-isoin­ ited dose-dependent inhibition ofLPS-stimulated production dol-2-yl)-piperidine-2,6-dione is started. On day 22, the of the pro-inflmatory cytokines TNF-a. IL-l~, and IL-6 65 administration of the compound is stopped for a week of rest. by PBMC while it increased production of the anti-inflam­ On day 29, the administration of25 mg/d 3-(4-amino-1-oxo- matory cytokine IL-l 0. 1,3-dihydro-isoindol-2-yl)-piperidin-2,6-dione is begun. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 43 of 148 PageID: 43

US 8,198,262 B2 33 34 6.5 Clinical Studies in Patients 2.5 and 2.8 hours post-dose at Day 1 and between 3 and 4 6.5.1 Treatment of Relapsed Multiple Myeloma hours post-dose at Week 4. At all doses, plasma concentra­ 4-(amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1 ,3-di- tions declined in a monophasic manner after reaching cmax· one (Actimid™) was administered to patients with relapsed/ The start of the elimination phase occurred between 3 and 10 refractory multiple myeloma. The study was conducted in hours post-dose at Day 1 and Week 4, respectively. compliance with Good Clinical Practices. Patients were at These data also showed that after 4 weeks of dosing, least 18 years old, had been diagnosed with multiple 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-1 ,3-dione myeloma (with paraprotein in serum and/or urine), and were accumulated to a small extent (mean accumulation ratios considered refractory to treatment after at least two cycles of -1.02 to 1.52 and -0.94 to 1.62 forCmax andAUCco--r)' respec- treatment, or have relapsed after two cycles of treatment. 10 tively). There was almost a dose proportional increase in Patients who have progressive disease, according to the AUCco--.:) and Cmax values with increasing dose. A five-fold Southwest Oncology Group (SWOG) criteria, on their prior higher dose of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoin­ regimen are considered treatment refractory. Relapse follow­ doline-1,3-dione produced a 3.2- and 2.2-fold increase in ing remission is defined as >25% increase in M component Cmax at Day 1 and Week 4, respectively. Similarly, a 5-fold from baseline levels; reappearance of theM paraprotein that 15 increase in dose resulted in a 3.6- and 2.3-fold increase in had previously disappeared; or a definite increase in the size AUCco--r)' at Day 1 and Week 4, respectively. and number oflytic bone lesions recognized on radiographs. Patients may have had prior therapy with thalidomide, pro­ TABLE 1 vided they were able to tolerate the treatment. A Zubrod Pharmacokinetic parameters of Actimid TM in relapsed performance status ofO to 2 is required for all patients. 20 4-(amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1 ,3-di­ multiple myeloma patients oneis administered to patients at doses of!, 2, 5, or 10mg/day 1mg 2mg 5mg for up to four weeks; at each dose level, three patients are Parameter (N~ 6) (N~2) (N ~ 3) initially enrolled. Dosing occurs at approximately the same Day 1 time each morning; all doses are administered in the fasted 25 state (no eating for at least two hours prior to dosing and two em= ng/mL 15.03 (4.04) 24.4* (12.1) 48.56 (14.03) hours after dosing). 4-(amino)-2-(2,6-dioxo(3-piperidyl))­ tm= h 3.3 (2.6) 2.7* (0.3) 2.3 (0.3) isoindoline-1 ,3 -diane doses are administered in an ascending AUe(O-oo)ng · 152.90 (36.62) 279.18 (51.10) 593.10 (335.23) h/mL fashion such that patients in the first cohort receive the lowest AUe(O-") 134.21 (27.14) 249.57 (29.26) 520.94 (267.32) dose of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-1, 30 tl/2 h 7.3 (3.4) 6.3 (1.4) 6.5 (2.2) 3-dione (1 mg/day) and escalation to the next higher dose eL/F mL/min 114.75 (29.20) 121.43 (22.22) 182.31 (117.06) level occurs only following the establishment of safety and Vz/f L 69.55 (44.97) 65.31 (2.80) 87.24 (22.61) tolerability at the current dose. If one out of three patients at t = 24hours any dose level experience dose limiting toxicity (DLT), three NIA =not available additional patients are enrolled at that dose. If none of the 35 three additional patients experience DLT, escalation to the next dose level occurs; dose escalations continue in a similar TABLE2 fashion until the MTD is established or the maximum daily Pharmacokinetic parameters of Actimid TM following multiple dose (10 mg/day) is attained. However, if one of the three oral doses (1, 2. and 5 mg/day) in relapsed multiple myeloma patients additional patients enrolled experiences DLT, the MTD has 40 been reached. If two or more of the three additional patients 1mg 2mg 5mg (N~5) (N~2) (N ~ 3) enrolled experience DLT, the MTD is judged to have been Parameter exceeded and three additional patients are enrolled at the Week4 preceding dose level to confirm the MTD. Once the MTD has ng/mL 23.20 (7 .48) 30.05* (15.64) 58.07 (38.08) been identified, four additional patients are enrolled at that 45 em= tm= h 3.6 (1.5) 2.8* (0.3) 5.0 (2.6) dose level so that a total of 10 patients is treated at the MTD. AUe(O-oo)ng · N!A N!A N!A Blood sampling for analysis of pharmacokinetic param­ h/mL eters is performed on Days 1 and 28 according to the follow­ AUe(O-") 239.31 (122.59) 269.36 (186.34) 597.24 (354.23) 1 ing sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, t /2 h 6.2* (0.6) 7.7 (2.8) 7.8 (4.0) eL/F mL/min 87.85 (48.48) 162.68 (112.54) 207.50 (175.41) 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. An additional 50 Vz/f L 41.35* (8.84) 95.04 (35.39) 103.95 (27.25) blood sample is collected at each weekly visit for the deter­ mination of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindo­ -r = 24hours line-1,3-dione levels. Total urine collections are also made NIA =not available *N = 3 patients with urine pooled according to the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours. Safety 55 6.5.2 Treatment of Relapsed Multiple Myeloma assessments are made by monitoring adverse events, vital Two Phase 1 clinical studies of3-(4-amino-1-oxo-1,3-di­ signs, ECGs, clinical laboratory evaluations (blood chemis­ hydro-isoindol-2-yl)-piperidine-2,6-dione (Revimid™) have try, hematology, lymphocyte phenotyping, and urinalysis), been conducted to identifY the maximum tolerated dose and physical examination at specific times during the study. (MTD) in patients with refractory or relapsed multiple Results of interim pharmacokinetic analyses obtained fol- 60 myeloma. These studies have also characterized the safety lowing single- and multiple-dose administration of profile of 3-( 4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-pip­ 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-1 ,3-dione eridine-2,6-dione when ascending doses of 3-( 4-amino-1- to multiple myeloma patients are presented below in Tables 1 oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione were and 2. These data show that 4-(amino)-2-(2,6-dioxo(3-pip­ given orally for up to 4 weeks. Patients started 3-(4-amino- eridyl))-isoindoline-1,3-dione was steadily absorbed at all 65 1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione treat­ dose levels in relapsed multiple myeloma patients. Maximum ment at 5 mg/day with subsequent escalation to 10, 25, and 50 plasma concentrations occurred at a median T max of between mg/day. Patients were enrolled for 28 days at their assigned Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 44 of 148 PageID: 44

US 8,198,262 B2 35 36 dose, with the option of extended treatment for those who did 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks not exhibit disease progression or experience dose limiting of treatment. Patients who, experienced clinical benefit were toxicity (DLT). Patients were evaluated for adverse events at permitted to continue on treatment as Named Patients. each visit and the severity of these events was graded accord­ The study initially enrolled 20 patients and was subse­ ing to the National Cancer Institute (NCI) Common Toxicity 5 quently amended to enroll 16 additional patients (adrenal Criteria. Patients were discontinued if they experienced DLT carcinoma, NSCLC, malignant mesothelioma, breast cancer, (Grade 3 or greater non-hematological, or Grade 4 hemato­ malignant melanoma (8), renal cell cancer (4)) at a higher logical toxicity). dose. The 16 additional patients were given weekly escalating In this study, 27 patients were enrolled. All patients had doses of25 mg/day, 50 mg/day, 75 mg/day, 100mg/day, 125 relapsed multiple myeloma and 18 (72%) were refractory to 10 mg/day, and 150 mg/day over a 6-week period with continu­ salvage therapy. Among these patients, 15 had undergone ing treatment for an additional six weeks. prior autologous stem cell transplantation and 16 patients had The study of Phase 1 study was designed to determine a received prior thalidomide treatment. The median number of maximum tolerated dose (MTD) of 3-(4-amino-1-oxo-1,3- prior regimens was 3 (range 2 to 6). dihydro-isoindol-2-yl)-piperidine-2,6-dione in patients with Blood and urine samples were collected for analysis of 15 refractory solid tumors and/or lymphoma, as well as to char­ pharmacokinetic parameters on Days 1 and 28. Blood acterize the pharmacokinetic and side effect profiles of3-(4- samples were collected according to the following sampling amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-di­ schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, one in this patient population. The study design dictates that 12, 18, and 24 hours post-dose. In addition, a blood sample at least 3 patients must be enrolled at a dose level and have was collected at each weekly clinic visit for 3-(4-amino-1- 20 completed 28 days oftreatment prior to enrollment of patients oxo-1 ,3-dihydro-isoindol-2-y 1)-piperidine-2,6-dione deter­ at the next higher dose level. Patients in the first cohort began mination. Total urine was collected and pooled according to dosing at 5 mg/day of 3-(4-amino-1-oxo-1 ,3-dihydro-isoin­ the following time intervals post-dose: 0 to 4, 4to 8, 8 to 12, dol-2-yl)-piperidine-2,6-dione. Patients will be escalated to and 12 to 24 hours. Response to treatment was assessed by 10, 20, 25, and 30 mg/day provided there is no toxicity. M-protein quantification (by immunoelectrophoresis) from 25 In this study, the MTD is defined as the highest dose level serum and a 24-hour urine collection, with creatinine clear­ in which fewer than two of six patients treated did not expe­ ance and 24-hour protein calculations undertaken at screen­ rience Grade 3 or greater non-hematological toxicity or ing, baseline, Weeks 2 and 4, and monthly thereafter (or upon Grade 4 or greater hematological toxicity. If, at any given early termination). Bone marrow aspirations and/or tissue dose level in either study, one out of three patients experi­ biopsy are also performed at Months 3, 6 and 12 if a patient's 30 ences toxicity, three additional patients must be treated at that paraprotein serum concentration or 24-hour urine protein particular dose. If, however, two out of six patients experience excretion declined to the next lower level, based on best DLT, the MTD is judged to have been exceeded. No further response criteria. Preliminary results for the 28-day treatment dose escalations are to occur and additional patients are to be period are summarized below. enrolled at the previous dose level. The dose of3-(4-amino- Preliminary pharmacokinetic analyses based on these two 35 1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione studies indicated that AUC and Cmax values increase propor­ administered is escalated until the MTD is achieved or the tionally with dose following single and multiple doses in maximum daily dose of is reached. multiple myeloma patients (as was seen in healthy volun­ No DLTs were reported in the initial group of 20 patients teers). Further, there was no evidence of accumulation with enrolled in the study. Thirteen of the original 20 trial patients, multiple dosing as single dose AU Ceo--.:) was comparable to 40 along with 2 non-trial patients, continued on treatment as multiple doseAUC0 _, following the same dose of3-(4-amino- named patients at doses up to 150 mg/day. 1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. 6.5.4 Treatment of Gliomas Similar to healthy volunteer studies, double peaks were This study was performed to find toxicity in patients with observed. Exposure in multiple myeloma patients appeared to recurrent, high-grade gliomas. The study is designed such be slightly higher based on Cmax andAUC values as compared 45 that patients are given increasingly higher doses of 3-(4- to healthy male volunteers while clearance in multiple amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-di­ myeloma patients was lower than it was in healthy volunteers, one until a maximum tolerated dose (MTD) is established. consistent with their poorer renal function (both as a conse­ The study also seeks to obtain preliminary toxicity informa­ quence of their age and their disease). Finally, 3-(4-amino-1- tion and pharmacokinetic data on 3-(4-amino-1-oxo-1,3-di­ oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione half- 50 hydro-isoindol-2-yl)-piperidine-2,6-dione, as well as to live in patients was shorter than in healthy volunteers (mean 8 develop exploratory data concerning surrogate end points of hours, ranging up to 17 hours). angiogenic activity in vivo using functional neuro-imaging In this study, the first cohort of3 patients was treated for 28 studies, and in vitro assays of serum angiogenic peptides. days at 5 mg/day without any dose limiting toxicity (DLT). Patients enrolled in the first cohort receive 2.5 mg/m2 /day The second cohort of 3 patients subsequently commenced 55 for a 4-week cycle. During each 4-week cycle of therapy, therapy at 10 mg/day. Patients in the second 10 mg/day of 3-( 4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2, 3 -( 4-amino-1-oxo-1 ,3-dihydro-isoindol-2-y 1)-piperidine-2, 6-dione administered once daily for 3 weeks followed by a 6-dione cohort tolerated treatment well. week of rest. Patients who complete a treatment cycle may 6.5.3 Treatment of Solid Tumors receive another cycle of 3-(4-amino-1-oxo-1 ,3-dihydro­ Study with 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)- 60 isoindol-2-yl)-piperidine-2,6-dione treatment if two criteria piperidine-2,6-dione (Revimid™) was conducted in patients are met. First, the patient must have stable disease or have with varying types of solid tumors, including malignant mela­ experienced a partial response or complete response, or the noma (13), carcinoma of the pancreas (2), carcinoid-un­ patient is benefiting from the therapy with 3-(4-amino-1-oxo- known primary (1 ), renal carcinoma (1 ), breast carcinoma (1) 1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as evi­ and NSCLC (2). Patients received 5 mg/day 3-(4-amino-1- 65 denced by a decrease in tumor-related symptoms such as oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for neurological deficits. Second, the patient must have recov­ seven days and are subsequently escalated every seven days to ered from toxicity related to 3-(4-amino-1-oxo-1 ,3-dihydro- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 45 of 148 PageID: 45

US 8,198,262 B2 37 38 isoindol-2-yl)-piperidine-2,6-dione which occurred in the the invention and monthly dexamethasone are continued until prior cycle by Day 42 or sooner (28-day cycle plus limit of 2 the disease progression. The therapy using an immunomodu­ weeks to recover) as evidenced by a return to Grade~ 1 tox­ latory compound of the invention in combination with mel­ icity level. Patients who experience DLT in the previous cycle phalan and dexamethasone is highly active and generally should have their dose modified. DLT is defined as an non­ tolerated in heavily pretreated multiple myeloma patients hematological event Grade~3 toxicity or hematological whose prognosis is otherwise poor. event of Grade 4 toxicity thought to be related to the study The embodiments of the invention described above are medication. Patients who experience DLT in the first cycle intended to be merely exemplary, and those skilled in the art and have no response to therapy are removed from the study. will recognize, or will be able to ascertain using no more than 3-(4-amino-1-oxo-1 ,3-dihydro-isoindol-2-yl)-piperidine- 10 routine experimentation, numerous equivalents of specific 2,6-dione doses are subsequently escalated to 5, 8, 11, 15, and compounds, materials, and procedures. All such equivalents 20 mg/m2 /day to a maximum total daily dose of 40 mg. are considered to be within the scope of the invention and are Patients continue to receive 3-(4-amino-1-oxo-1 ,3-dihydro­ encompassed by the appended claims. isoindol-2-yl)-piperidine-2,6-dione on a 4-week cycle per dose level until one of the off-study criteria are met. 15 Three patients are enrolled in each cohort. If at least one What is claimed is: DLT occurs, three additional patients are added to the cohort 1. A method of treating multiple myeloma, which com­ at that particular dose level. If two DLTs occur, the MTD, prises administering to a patient having multiple myeloma: defined as the dose at which fewer than one-third of patients (a) from about 1 mg to about 5 mg per day of a compound at each dose level experiences DLT has been exceeded and 20 having the formula: four more patients are treated at the previous dose. Patients who experience DLT during the first 4-week cycle are removed from the study, except if they have a response to therapy. For patients who have completed their first 4-week cycle of without DLT, but who subsequently experience 25 Grade 3 or 4 hematological and/or nonhematological toxicity, treatment is suspended for a minimum of a week. If the toxicity resolves to proteasome inhibitor, The duration of response was approximately six months. The stem cell transplantation, or a combination thereof. result suggests that the compound appears is a promising new 10. The method of claim 1, wherein the compound is anti-cancer agent and has both antiangiogenic and immuno­ 55 administered in an amount of about 4 mg per day. modulatory properties. 11. The method of claim 1, wherein the compound is 6.5.6 Treatment of Relapsed or Refractory Multiple administered in an amount of about 3 mg per day. Myeloma 12. The method of claim 1, wherein the compound is Patients with relapsed and refractory Dune-Salmon stage administered in an amount of about 2 mg per day. III multiple myeloma, who have either failed at least three 60 13. The method of claim 1, wherein the compound is previous regimens or presented with poor performance status, administered in an amount of about 1 mg per day. neutropenia or thrombocytopenia, are treated with up to four 14. The method of claim 1, wherein the dexamethasone is cycles of combination of melphalan (50 mg intravenously), orally administered in an amount of 40 mg once daily on days an immunomodulatory compound of the invention (about 1 to 1, 8, 15 and 22 of each 28 day cycle. 150 mg orally daily), and dexamethasone (40 mg/day orally 65 15. The method of claim 1, wherein the dexamethasone is on days 1 to 4) every four to six weeks. Maintenance treat­ orally administered in an amount of about 40 mg once a week ment consisting of daily an immunomodulatory compound of of each 28 day cycle. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 46 of 148 PageID: 46

US 8,198,262 B2 39 40 16. The method of claim 1, wherein the compound is cycle, and (b) 40 mg of dexamethasone on at least one of days administered in a capsule. 1-21 of said cycle. 17. The method of claim 1, wherein the compound is 21. The method of claim 20, wherein the compound is administered in a tablet. administered in an amount of about 4 mg per day. 18. The method of claim 1, wherein the compound is 5 22. The method of claim 20, wherein the compound is administered orally in a capsule of 1 mg, 2 mg, 3 mg, or 4 mg. administered in an amount of about 3 mg per day. 19. The method of claim 18, wherein the capsule comprises 23. The method of claim 20, wherein the compound is the compound, mannitol and pre-gelatinized starch. administered in an amount of about 2 mg per day. 20. A method of treating multiple myeloma, which com­ 24. The method of claim 20, wherein the compound is prises administering to a patient having multiple myeloma: 10 administered in an amount of about 1 mg per day. (a) from about 1 mg to about 5 mg per day of a compound having the formula: 25. The method of claim 20, wherein the dexamethasone is administered once daily on days 1, 8, 15 and 22 in a 28 day cycle. 15 26. The method of claim 20, wherein the compound is administered in a capsule of 1 mg, 2 mg, 3 mg, or 4 mg. 27. The method of claim 26, wherein the capsule comprises the compound, mannitol and pre-gelatinized starch. 28. The method of claim 1, where the compound is a 20 pharmaceutically acceptable salt, solvate or stereoisomer. 29. The method of claim 20, where the multiple myeloma is relapsed and refractory multiple myeloma. for 21 consecutive days followed by seven consecutive days of rest from administration of said compound in a 28 day * * * * * Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 47 of 148 PageID: 47

EXHIBIT B Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 48 of 148 PageID: 48 IIIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111 US008673939B2 c12) United States Patent (IO) Patent No.: US 8,673,939 B2 Zeldis (45) Date of Patent: *Mar. 18, 2014

(54) METHODS FOR TREATING MULTIPLE 5,580,755 A 12/1996 Souza MYELOMA WITH 4-(AMIN0)-2-(2,6- 5,591,767 A 1/ 1997 Mohr et al. DIOX0(3-PIPERIDYL))-ISOINDOLINE-1,3- 5,593,990 A 1/1997 D' Amato 5,629,327 A 5/1997 D' Amato DIONE 5,635,517 A 6/1997 Muller et al. 5,639,476 A 6/ 1997 Oshlack et al. (71) Applicant: Celgene Corporation, Summit, NJ (US) 5,674,533 A 10/ 1997 Santus et al. 5,698,579 A 12/1997 Muller (72) Inventor: Jerome B. Zeldis, Princeton, NJ (US) 5,712,291 A 1/1998 D' Amato 5,731,325 A 3/1998 Andrulis, Jr. et al. 5,733,566 A 3/ 1998 Lewis (73) Assignee: Celgene Corporation, Summit, NJ (US) 5,798,368 A 8/1998 Muller et al. 5,874,448 A 2/1999 Muller et al. ( *) Notice: Subject to any disclaimer, the term ofthis 5,877,200 A 3/1999 Muller patent is extended or adjusted under 35 5,929,117 A 7/1999 Muller et al. U.S.C. 154(b) by O days. 5,955,476 A 9/1999 Muller et al. 6,020,358 A 2/2000 Muller et al. This patent is subject to a terminal dis­ 6,071,948 A 6/2000 D' Amato claimer. 6,114,355 A 9/2000 D' Amato 6,140,346 A 10/2000 Andrulis, Jr. et al. 6,228,879 Bl 5/2001 Green et al. (21) Appl. No.: 13/782,728 6,235,756 Bl 5/2001 D' Amato 6,281,230 Bl 8/2001 Muller et al. (22) Filed: Mar.1, 2013 6,316,471 Bl 11/2001 Muller et al. 6,326,388 Bl 12/2001 Man et al. (65) Prior Publication Data (Continued) US 2013/0177642 Al Jul. 11, 2013 FOREIGN PATENT DOCUMENTS

Related U.S. Application Data WO WO 92/14455 9/1992 WO WO 94/20085 9/1994 (63) Continuation of application No. 13/488,888, filed on (Continued) Jun. 5, 2012, which is acontinuationofapplicationNo. 12/640,702, filed on Dec. 17, 2009, now Pat. No. 8,198,306, which is a continuation of application No. OTHER PUBLICATIONS 10/438,213, filed on May 15, 2003, now Pat. No. Jagannath et al. (J Clin Oncol 31, 2013 (suppl; abstr 8532). Published 7,968,569. at ://meetinglibrary.asco.org/content/ 112438-132. 2013. * (60) Provisional application No. 60/380,842, filed on May Siegel et al. ( J Clin Oncol 31, 2013 (suppl; abstr 8588). Published at 17, 2002, provisional application No. 60/424,600, http://meetinglibrary.asco.org/content/l 12890-132. 2013. * filed on Nov. 6, 2002. U.S. Appl. No. 60/499,723, Markian. U.S. Appl. No. 60/372,348, Hariri et al. (51) Int. Cl. AOJN 43/40 (2006.01) (Continued) (52) U.S. Cl. USPC ...... 514/321; 514/323; 514/329; 514/330 Primary Examiner - Jeffrey S. Lundgren ( 58) Field of Classification Search USPC ...... 514/323, 329, 330 Assistant Examiner - Chris Simmons See application file for complete search history. (74) Attorney, Agent, or Firm - Jones Day (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Methods of treating, preventing and/or managing cancer as 3,536,809 A 10/1970 Applezweig 3,598,123 A 8/1971 Zaffaroni et al. well as and diseases and disorders associated with, or char­ 3,845,770 A 11/1974 Theeuwes et al. acterized by, undesired angiogenesis are disclosed. Specific 3,916,899 A 11/1975 Theeuwes et al. methods encompass the administration of an immunomodu­ 4,008,719 A 2/1977 Theeuwes et al. 4,551,177 A * 11/1985 Trubiano et al. 106/206.1 latory compound alone or in combination with a second 4,810,643 A 3/ 1989 Souza active ingredient. The invention further relates to methods of 4,999,291 A 3/ 1991 Souza reducing or avoiding adverse side effects associated with 5,059,595 A 10/1991 Le Grazie chemotherapy, radiation therapy, hormonal therapy, biologi­ 5,073,543 A 12/1991 Marshall et al. 5,120,548 A 6/ 1992 McClelland et al. cal therapy or immunotherapy which comprise the adminis­ 5,134,127 A 7/1992 Stella et al. tration of an immunomodulatory compound. Pharmaceutical 5,229,496 A 7I 1993 Deeley et al. compositions, single unit dosage forms, and kits suitable for 5,354,556 A 10/ 1994 Sparks et al. use in methods of the invention are also disclosed. 5,385,901 A 1/1995 Kaplan et al. 5,391,485 A 2/1995 Deeley et al. 5,393,870 A 2/1995 Deeley et al. 5,528,823 A 6/ 1996 Rudy, Jr. et al. 35 Claims, 1 Drawing Sheet Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 49 of 148 PageID: 49

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Dimopoulos et al., "Pomalidomide in Combination with Low-Dose Richardson et al., "A Phase 2 Study ofElotuzurnab (Elo) in Combi­ Dexamethasone: Demonstrates a Significant Progression Free Sur­ nation with Lenalidomide and Low-Dose Dexamethasone (Ld) in vival and Overall Survival Advantage, in Relapsed/Refractory MM: Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R A Phase 3, Multicenter, Randomized, Open-Label Study," presented MM): Updated Results", presented at 54thASH Annual Meeting and at 54th ASH Annual Meeting and Exposition, Atlanta, Georgia, Dec. Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract #202. 8-11, 2012, Abstract #LBA-6. Sacchi et al., "A Phase I/II Study of Bendamushne, Low-Dose Shastri et al., "A Phase II Study of Low-Dose Pornalidomide (0.5mg/ Dexamethasone, and Lenalidomide (BdL) for the Treatment of day) and Prednisone Combination Therapy in Patients with Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 56 of 148 PageID: 56

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(56) References Cited English translation of Japanese IP High Court decision in Application No. JP 2004-505051, dated Apr. 11, 2013. OTHER PUBLICATIONS Jagannath, S. et al., "Pomalidomide (POM) with or without low-dose dexamethasone (Lo DEX) in patients (Pts) with relapsed and refrac­ Myelofibrosis and Significant Anemia," presented at 54th ASH tory multiple myeloma (RRMM): MM-002 phase II age subgroup Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, analysis," J Clin Oncol 31, 2013 (suppl; abstr 8532). Abstract# 1728. Siegel, D. et al, "Long-term safety and efficacy of pomalidomide Shah et al., "A Multi-Center Phase I/II Trial of Carfilzomib and (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with in the MM-002 phase II trial," J Clin Oncol 31, 2013 (suppl; abstr Relapsed/Refractory Multiple Myeloma," presented at 54th ASH 8588). Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Richardson, P.G. et al., A Phase 1/2 Multi-Center, Randomized, Open Abstract #74. Label Dose Escalation Study to Determine the Maximum Tolerated Office Action in corresponding CN Application No.2011102567 52.0 Dose (MTD), Safety, and Efficacy of Pomalidomide (POM) Alone or dated Feb. 8, 2013. in Combination with Low-Dose Dexamethasone (DEX) in Patients Stirling, D., "Thalidomide: A Novel Template for Anticancer Drugs." (PTS) with Relapsed and Refractory Multiple Myeloma (RRMM) Seminars in Oncology, Dec. 2001, 2816002-606. Who Have Received Prior Treatment (TX) That Includes Celgene Press Release, "Celgene Will Discontinue Phase III ORI­ Lenalidomide (LEN) and Bortezomib (BORT), Haematologica, 1 GIN® Trial in Previously Untreated Elderly Patients with B-Cell 200 l; 96(sl):S31, Abstract 0-12, 13 h international Myeloma Work­ Chronic Lymphocytic Leukemia," published on Celgene Newsroom, shop, Paris, France-May 3-6, 2011. http://newsroom.celgene.com on Jul. 18, 2013 at 7:30 am EDT. MacNeil, J.S., "Pomalidomide Picks Up Where Both Earlier IMiDs Mateos, M.-V., Ph.D. et al., "Lenalidomide plus Dexamethasone for Stop Working," The Oncology Report, Mar.I Apr.2010, p. 34. High-Risk Smoldering Multiple Myeloma," New England Journal of Medicine, Aug. 2013, 369(5):438-447. * cited by examiner Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 57 of 148 PageID: 57

U.S. Patent Mar.18,2014 US 8,673,939 B2

Hs,...... ,_,...... Sultan CeHs...... Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 58 of 148 PageID: 58

US 8,673,939 B2 1 2 METHODS FOR TREATING MULTIPLE (e.g., b-FGF). Angiogenesis can also be induced indirectly MYELOMA WITH 4-(AMIN0)-2-(2,6- through the recruitment of inflammatory cells (particularly DIOX0(3-PIPERIDYL))-ISOINDOLINE-1,3- macrophages) and their subsequent release of angiogenic DIONE cytokines (e.g., TNF-a, bFGF). 5 A variety of other diseases and disorders are also associ- This application is a continuation of U.S. patent applica­ ated with, or characterized by, undesired angiogenesis. For tion Ser. No. 13/488,888, filed Jun. 5, 2012, which is a con­ example, enhanced or unregulated angiogenesis has been tinuation ofU. S. patent application Ser. No. 12/640, 702, filed implicated in a number of diseases and medical conditions Dec. 17, 2009, now U.S. Pat. No. 8,198,306, which is a including, but not limited to, ocular neovascular diseases, continuation application of U.S. patent application Ser. No. 10 choroidal neovascular diseases, retina neovascular diseases, 10/438,213, filed May 15, 2003,nowU.S. Pat. No. 7,968,569, rubeosis (neovascularization of the angle), viral diseases, which claims the benefit of U.S. provisional application Nos. genetic diseases, inflammatory diseases, allergic diseases, 60/380,842, filed May 17, 2002, and 60/424,600, filed Nov. 6, and autoimmune diseases. Examples of such diseases and 2002, the entireties of which are incorporated herein by ref­ conditions include, but are not limited to: diabetic retinopa­ erence. 15 thy; retinopathy of prematurity; corneal graft rejection; 1. FIELD OF THE INVENTION neovascular glaucoma; retrolental fibroplasia; and prolifera­ tive vitreoretinopathy. This invention relates to methods of treating, preventing Accordingly, compounds that can control angiogenesis or and/or managing specific cancers, and other diseases includ­ 20 inhibit the production of certain cytokines, including TNF-a, ing, but not limited to, those associated with, or characterized may be useful in the treatment and prevention of various by, undesired angiogenesis, by the administration of one or diseases and conditions. more immunomodulatory compounds alone or in combina­ 2.2 Methods of Treating Cancer tion with other therapeutics. In particular, the invention Current cancer therapy may involve surgery, chemo- encompasses the use of specific combinations, or "cocktails," 25 therapy, hormonal therapy and/or radiation treatment to of drugs and other therapy, e.g., radiation to treat these spe­ eradicate neoplastic cells in a patient (see, for example, cific cancers, including those refractory to conventional Stockdale, 1998, Medicine, vol. 3, RubensteinandFederman, therapy. The invention also relates to pharmaceutical compo­ eds., Chapter 12, Section IV). Recently, cancer therapy could sitions and dosing regimens. also involve biological therapy or immunotherapy. All of 30 these approaches pose significant drawbacks for the patient. 2. BACKGROUND OF THE INVENTION Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. 2.1 Pathobiology of Cancer and Other Diseases Additionally, surgery may not completely remove neoplastic Cancer is characterized primarily by an increase in the tissue. Radiation therapy is only effective when the neoplastic number of abnormal cells derived from a given normal tissue, 35 invasion of adjacent tissues by these abnormal cells, or lym­ tissue exhibits a higher sensitivity to radiation than normal phatic or blood-borne spread of malignant cells to regional tissue. Radiation therapy can also often elicit serious side lymph nodes and to distant sites (metastasis). Clinical data effects. Hormonal therapy is rarely given as a single agent. and molecular biologic studies indicate that cancer is a mul­ Although hormonal therapy can be effective, it is often used tistep process that begins with minor preneoplastic changes, 40 to prevent or delay recurrence of cancer after other treatments which may under certain conditions progress to neoplasia. have removed the majority of cancer cells. Biological thera­ The neoplastic lesion may evolve clonally and develop an pies and immunotherapies are limited in number and may increasing capacity for invasion, growth, metastasis, and het­ produce side effects such as rashes or swellings, flu-like erogeneity, especially under conditions in which the neoplas­ symptoms, including fever, chills and fatigue, digestive tract tic cells escape the host's immune surveillance. Raitt, I., 45 problems or allergic reactions. Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., With respect to chemotherapy, there are a variety of che­ Mosby, St. Louis, Mo., 1993). motherapeutic agents available for treatment of cancer. A There is an enormous variety of cancers which are majority of cancer chemotherapeutics act by inhibiting DNA described in detail in the medical literature. Examples synthesis, either directly, or indirectly by inhibiting the bio- includes cancer of the lung, colon, rectum, prostate, breast, 50 synthesis of deoxyribonucleotide triphosphate precursors, to brain, and intestine. The incidence of cancer continues to prevent DNA replication and concomitant cell division. Gil­ climb as the general population ages, as new cancers develop, man et al., Goodman and Gilman 's: The Pharmacological and as susceptible populations (e.g., people infected with Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York). AIDS or excessively exposed to sunlight) grow. A tremen­ Despite availability of a variety of chemotherapeutic dous demand therefore exists for new methods and composi­ 55 agents, chemotherapy has many drawbacks. Stockdale, Medi­ tions that can be used to treat patients with cancer. cine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, Many types of cancers are associated with new blood ves­ 1998. Almost all chemotherapeutic agents are toxic, and che­ sel formation, a process known as angiogenesis. Several of motherapy causes significant, and often dangerous side the mechanisms involved in tumor-induced angiogenesis effects including severe nausea, bone marrow depression, and have been elucidated. The most direct of these mechanisms is 60 immunosuppression. Additionally, even with administration the secretion by the tumor cells of cytokines with angiogenic of combinations of chemotherapeutic agents, many tumor properties. Examples of these cytokines include acidic and cells are resistant or develop resistance to the chemothera­ basic fibroblastic growth factor (a,b-FGF), angiogenin, vas­ peutic agents. In fact, those cells resistant to the particular cular endothelial growth factor (VEGF), and TNF-a. Alter­ chemotherapeutic agents used in the treatment protocol often natively, tumor cells can release angiogenic peptides through 65 prove to be resistant to other drugs, even if those agents act by the production of proteases and the subsequent breakdown of different mechanism from those of the drugs used in the the extracellular matrix where some cytokines are stored specific treatment. This phenomenon is referred to as pleio- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 59 of 148 PageID: 59

US 8,673,939 B2 3 4 tropic drug or multi drug resistance. Because of the drug resis­ not limited to, surgery, chemotherapy, radiation therapy, hor­ tance, many cancers prove refractory to standard chemothera­ monal therapy, biological therapy and immunotherapy. peutic treatment protocols. This invention also encompasses methods of treating, man­ Other diseases or conditions associated with, or character­ aging or preventing diseases and disorders other than cancer ized by, undesired angiogenesis are also difficult to treat. 5 that are associated with, or characterized by, undesired angio­ However, some compounds such as protamine, hepain and genesis, which comprise administering to a patient in need of steroids have been proposed to be useful in the treatment of such treatment, management or prevention a therapeutically certain specific diseases. Tayloretal.,Nature 297:307 (1982); or prophylactically effective amount of an immunomodula­ Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos. tory compound, or a pharmaceutically acceptable salt, sol- 5,001,116 and 4,994,443. Thalidomide and certain deriva­ IO vate, hydrate, stereoisomer, clathrate, or prodrug thereof. tives of it have also been proposed for the treatment of such In other methods of the invention, an immunomodulatory diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, compound is administered in combination with a therapy 5,712,291, 6,071,948 and 6,114,355 to D' Amato. conventionally used to treat, prevent or manage diseases or

Still, there is a significant need for safe and effective meth­ 15 disorders associated with, or characterized by, undesired ods of treating, preventing and managing cancer and other angiogenesis. Examples of such conventional therapies diseases and conditions, particularly for diseases that are include, but are not limited to, surgery, chemotherapy, radia­ refractory to standard treatments, such as surgery, radiation tion therapy, hormonal therapy, biological therapy and immu- therapy, chemotherapy and hormonal therapy, while reducing notherapy. or avoiding the toxicities and/or side effects associated with 20 This invention encompasses pharmaceutical composi- the conventional therapies. tions, single unit dosage forms, dosing regimens and kits 2.3 IMiDs™ which comprise an immunomodulatory compound, or a phar­ A number of studies have been conducted with the aim of maceutically acceptable salt, solvate, hydrate, stereoisomer, providing compounds that can safely and effectively be used clathrate, or prodrug thereof, and a second, or additional, to treat diseases associated with abnormal production of 25 active agent. Second active agents include specific combina­ TNF-a. See, e.g., Marriott, J. B., et al., Expert Opin. Biol. tions, or "cocktails," of drugs. Ther. 1(4): 1-8 (2001); G. W. Muller, et al., Journal of Medici­ nal Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, 4. BRIEF DESCRIPTION OF FIGURE et al., Bioorganic & Medicinal Chemistry Letters 8: 2669- 2674 (1998). Some studies have focused on a group of com- 30 FIG. 1 shows a comparison of the effects of3-(4-amino-l­ pounds selected for their capacity to potently inhibit TNF -a oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Re­ production by LPS stimulated PBMC. L. G. Corral, et al., vimid™) and thalidomide in inhibiting the proliferation of Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These multiple mycloma (MM) cell lines in an in vitro study. The compounds, which are referred to as IMiDs™ (Celgene Cor­ uptake of [3 H]-thymidine by different MM cell lines poration) or Immunomodulatory Drugs, show not only potent 35 (MM. IS, Hs Sultan, U266 and RPMI-8226) was measured as inhibition of TNF-a but also marked inhibition of LPS an indicator of the cell proliferation. induced monocyte ILi~ and IL12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, 5. DETAILED DESCRIPTION OF THE albeit partially. These compounds are potent stimulators of INVENTION LPS induced ILlO. Id. Particular examples of IMiD™s 40 include, but are not limited to, the substituted 2-(2,6-dioxopi­ A first embodiment of the invention encompasses methods peridin-3-yl) phthalimides and substituted 2-(2,6-dioxopip­ of treating, managing, or preventing cancer which comprises eridin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. administering to a patient in need of such treatment or pre­ 6,281,230 and 6,316,471, both to G. W. Muller, et al. vention a therapeutically or prophylactically effective 45 amount of an immunomodulatory compound of the inven­ 3. SUMMARY OF THE INVENTION tion, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. This invention encompasses methods of treating and pre­ In particular methods encompassed by this embodiment, venting certain types of cancer, including primary and meta­ the immunomodulatory compound is administered in combi- static cancer, as well as cancers that are refractory or resistant 50 nation with another drug ("second active agent") or method of to conventional chemotherapy. The methods comprise treating, managing, or preventing cancer. Second active administering to a patient in need of such treatment or pre­ agents include small molecules and large molecules (e.g., vention a therapeutically or prophylactically effective proteins and antibodies), examples of which are provided amount of an immunomodulatory compound, or a pharma­ herein, as well as stem cells. Methods, or therapies, that can ceutically acceptable salt, solvate, hydrate, stereoisomer, 55 be used in combination with the administration of the immu- clathrate, or prodrug thereof. The invention also encompasses nomodulatory compound include, but are not limited to, sur­ methods of managing certain cancers (e.g., preventing or gery, blood transfusions, immunotherapy, biological therapy, prolonging their recurrence, or lengthening the time of remis­ radiation therapy, and other non-drug based therapies pres­ sion) which comprise administering to a patient in need of ently used to treat, prevent or manage cancer. such management a prophylactically effective amount of an 60 Another embodiment of the invention encompasses meth­ immunomodulatory compound of the invention, or a pharma­ ods of treating, managing or preventing diseases and disor­ ceutically acceptable salt, solvate, hydrate, stereoisomer, ders other than cancer that are characterized by undesired clathrate, or prodrug thereof. angiogenesis. These methods comprise the administration of In particular methods of the invention, an immunomodu­ a therapeutically or prophylactically effective amount of an latory compound is administered in combination with a 65 immunomodulatory compound, or a pharmaceutically therapy conventionally used to treat, prevent or manage can­ acceptable salt, solvate, hydrate, stereoisomer, clathrate, or cer. Examples of such conventional therapies include, but are prodrug thereof. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 60 of 148 PageID: 60

US 8,673,939 B2 5 6 Examples of diseases and disorders associated with, or closed in U.S. Pat. No. 5,929,117; l-oxo-2-(2,6-dioxo-3- characterized by, undesired angiogenesis include, but are not fluoropiperidin-3yl) isoindolines and 1,3-dioxo-2-(2,6- limited to, inflammatory diseases, autoimmune diseases, dioxo-3-fluoropiperidine-3-yl) isoindolines such as those viral diseases, genetic diseases, allergic diseases, bacterial described in U.S. Pat. No. 5,874,448; the tetra substituted diseases, ocular neovascular diseases, choroidal neovascular 5 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in diseases, retina neovascular diseases, and rubeosis (neovas­ U.S. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-diox- cularization of the angle). opiperidin-3-yl) isoindolines (e.g., 4-methyl derivatives of In particular methods encompassed by this embodiment, thalidomide and EM-12), including, but not limited to, those the immunomodulatory compound is administer in combina­ 10 disclosed in U.S. Pat. No. 5,635,517; and a class of non­ tion with a second active agent or method of treating, man­ polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698, aging, or preventing the disease or condition. Second active 579 and 5,877,200; analogs and derivatives of thalidomide, agents include small molecules and large molecules ( e.g., including hydrolysis products, metabolites, derivatives and proteins and antibodies), examples of which are provided precursors of thalidomide, such as those described in U.S. herein, as well as stem cells. Methods, or therapies, that can 15 Pat. Nos. 5,593,990, 5,629,327, and 6,071,948 to D' Amato; be used in combination with the administration of the immu- aminothalidomide, as well as analogs, hydrolysis products, nomodulatory compound include, but are not limited to, sur­ metabolites, derivatives and precursors of aminothalidomide, gery, blood transfusions, immunotherapy, biological therapy, and substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles radiation therapy, and other non-drug based therapies pres­ 20 ently used to treat, prevent or manage disease and conditions such as those described in U.S. Pat. Nos. 6,281,230 and associated with, or characterized by, undesired angiogenesis. 6,316,471; isoindole-imide compounds such as those The invention also encompasses pharmaceutical composi­ described in U.S. patent application Ser. No. 09/972,487 filed tions (e.g., single unit dosage forms) that can be used in on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 filed on Dec. 21, 2001, and International Application No. methods disclosed herein. Particular pharmaceutical compo­ 25 sitions comprise an immunomodulatory compound of the PCT/USOl/50401 (International Publication No. WO invention, or a pharmaceutically acceptable salt, solvate, 02/059106). The entireties of each of the patents and patent hydrate, stereoisomer, clathrate, or prodrug thereof, and a applications identified herein are incorporated herein by ref­ second active agent. erence. Immunomodulatory compounds of the invention do 5.1 Immunomodulatory Compounds 30 not include thalidomide. Compounds used in the invention include immunomodu­ Other specific immunomodulatory compounds of the latory compounds that are racemic, stereomerically enriched invention include, but are not limited to, 1-oxo- and 1,3 or stereomerically pure, and pharmaceutically acceptable dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines substituted salts, solvates, hydrates, stereoisomers, clathrates, and pro- with amino in the benzo ring as described in U.S. Pat. No. 35 drugs thereof. Preferred compounds used in the invention are 5,635,517 which is incorporated herein by reference. These small organic molecules having a molecular weight less than compounds have the structure I: about 1,000 g/mol, and are not proteins, peptides, oligonucle­ otides, oligosaccharides or other macromolecules.

As used herein and unless otherwise indicated, the terms 40 0 "immunomodulatory compounds" and "IMiDs™" (Celgene Corporation) encompasses small organic molecules that markedly inhibit TNF-a, LPS induced monocyte ILi ~ and IL12, and partially inhibit IL6 production. Specific immuno­ modulatory compounds are discussed below. 45 JX>-\:( TNF -a is an inflammatory cytokine produced by macroph­ ages and monocytes during acute inflammation. TNF-a is in which one ofX andY is C=O, the otherofX andY is C=O 2 responsible for a diverse range of signaling events within or CH2 , and R is hydrogen or lower alkyl, in particular cells. TNF-a may play a pathological role in cancer. Without methyl. Specific immunomodulatory compounds include, but being limited by theory, one of the biological effects exerted 50 are not limited to: by the immunomodulatory compounds of the invention is the l -oxo-2-(2,6-dioxopiperidin-3-yl )-4-aminoisoindoline; reduction of synthesis of TNF-a. Immunomodulatory com­ l -oxo-2-(2,6-dioxopiperidin-3-yl )-5-aminoisoindoline; pounds of the invention enhance the degradation of TNF-a l -oxo-2-(2,6-dioxopiperidin-3-yl )-6-aminoisoindoline; mRNA. l-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; Further, without being limited by theory, immunomodula­ 55 1,3-dioxo-2-(2, 6-dioxopiperidin-3-yl )-4-aminoisoindoline; tory compounds used in the invention may also be potent and co-stimulators of T cells and increase cell proliferation dra­ 1,3-dioxo-2-(2, 6-dioxopiperidin-3-yl )-5-aminoisoindoline. matically in a dose dependent manner. Immunomodulatory Other specific immunomodulatory compounds of the compounds of the invention may also have a greater co- 60 invention belong to a class of substituted 2-(2,6-dioxopiperi­ stimulatory effect on the CDS+ T cell subset than on the din-3-yl) phthalimides and substituted 2-(2,6-dioxopiperi­ CD4+ T cell subset. In addition, the compounds preferably din-3-yl)-1-oxoisoindoles, such as those described in U.S. have anti-inflammatory properties, and efficiently co-stimu­ Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, late T cells. and International Patent Application No. PCT/US97/13375 Specific examples of immunomodulatory compounds of 65 (International Publication No. WO 98/03502), each of which the invention, include, but are not limited to, cyano and car­ is incorporated herein by reference. Compounds representa­ boxy derivatives of substituted styrenes such as those dis- tive of this class are of the formulas: Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 61 of 148 PageID: 61

US 8,673,939 B2 7 8

C4 )alkyl-(C1 -C 6 )heterocycloalkyl, (C0 -C4 )alkyl-(C2-Cs)het­ 6 eroaryl, (C0 -Cs)alkyl-N(R ) 2, (C 1 -Cs)alkyl-ORs, (C 1 -Cs) alkyl-C(O)ORs, (C 1 -Cs)alkyl-O(CO)Rs, or C(O)ORs; 4 R is (C 1 -Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, (C 1 - 5 C4 )alkyl-0Rs, benzyl, aryl, (C0 -C4 )alkyl-(C1-C6 )heterocy­ cloalkyl, or (C0 -C4 )alkyl-(C2-Cs)heteroaryl; Rs is (C 1 -Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, ben­ zyl, aryl, or (C2-Cs)heteroaryl; 6 each occurrence of R is independently H, (C 1 -Cs)alkyl, 10 (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C2-Cs)het­ 6 eroaryl, or (C0 -Cs)alkyl-C(O)O-Rs or the R groups can join to form a heterocycloalkyl group; n is O or 1; and * represents a chiral-carbon center. 15 In specific compounds of formula II, when n is Othen R 1 is

(C3 -C7 )cycloalkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C0 -C4 )alkyl-(C1 -C 6 )heterocycloalkyl, (C0 -C4 )alkyl­ 3 4 6 (C2-Cs)heteroaryl, C(O)R , C(O)OR , (C 1 -Cs)alkyl-N(R ) 2, 3 20 (C 1 -Cs)alkyl-0Rs, (C 1-Cs)alkyl-C(O)ORs, C(S)NHR , or (C -Cs)alkyl-O(CO)Rs; 1 2 R is Hor (C 1 -Cs)alkyl; and 3 R is (C 1-Cs)alkyl, (C3 -C7 )cycloalkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C0 -C4 )alkyl-(C1 -C 6 )heterocy- 25 cloalkyl, (C0 -C4 )alkyl-(C2-Cs)heteroaryl, (Cs-Cs)alkyl-N 6 (R ) 2; (C0 -Cs)alkyl-NH-C(O)O-Rs; (C 1-Cs)alkyl-0Rs, (C 1 -Cs)alkyl-C(O)ORs, (C 1 -Cs)alkyl-O(CO)Rs, or C(O) ORs; and the other variables have the same definitions. In other specific compounds of formula II, R2 is H or 1 30 wherein R is hydrogen or methyl. In a separate embodiment, (C 1 -C4 )alkyl. 1 the invention encompasses the use of enantiomerically pure In other specific compounds of formula II, R is (C 1 -Cs) forms ( e.g. optically pure (R) or (S) enantiomers) of these alkyl or benzyl. 1 compounds. In other specific compounds of formula II, R is H, (C 1 - Still other specific immunomodulatory compounds of the Cs)alkyl, benzyl, CH 0CH , CH CH 0CH , or 35 2 3 2 2 3 invention belong to a class of isoindole-imides disclosed in U.S. patent application Ser. Nos. 10/032,286 and 09/972,487, and International Application No. PCT/USOl/50401 (Inter­ national Publication No. WO 02/059106), each of which are incorporated herein by reference. Representative compounds 40 are of formula II: In another embodiment of the compounds of formula II, R 1 IS II

45

50

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mix- 55 tures of stereoisomers thereof, wherein: wherein Q is O or S, and each occurrence ofR7 is indepen­

one of X and Y is C=O and the other is CH2 or C=O; dently H, (C 1 -Cs)alkyl, benzyl, CH20CH3 , or 1 R is H, (C 1 -Cs)alkyl, (C3 -C7 )cycloalkyl, (C2-Cs)alkenyl, CH2CH20CH3 • 1 3 (C2-Cs)alkynyl, benzyl, aryl, (C0 -C4 )alkyl-(C1-C6)heterocy­ In other specific compounds of formula II, R is C(O)R . 3 3 3 cloalkyl, (C0 -C4 )alkyl-(C2-Cs)heteroaryl, C(O)R , C(S)R , 60 In other specific compounds of formula II, R is (C0 -C4 ) 4 6 C(O)OR , (C 1-Cs)alkyl-N(R ) 2, (C 1-Cs)alkyl-0Rs, (C 1 -Cs) alkyl-(C2-Cs)heteroaryl, (C 1-Cs)alkyl, aryl, or (C0 -C4 )alkyl- 3 3 3 3 alkyl-C(O)ORs, C(O)NHR , C(S)NHR , C(O)NR R ', C(S) 0Rs. 3 3 NR R ' or (C -Cs)alkyl-C(CO)Rs; In other specific compounds of formula II, heteroaryl is 2 1 R is H, F, benzyl, (C 1 -Cs)alkyl, (C2-Cs)alkenyl, or (C2- pyridyl, fury!, or thienyl. 1 4 Cs)alkynyl; 65 In other specific compounds of formula II, R is C(O)OR . 3 3 R and R ' are independently (C 1 -Cs)alkyl, (C3 -C7 )cy­ In other specific compounds of formula II, the H of C(O) cloalkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C 0 - NHC(O) can be replaced with (C 1 -C4 )alkyl, aryl, or benzyl. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 62 of 148 PageID: 62

US 8,673,939 B2 9 10 Still other specific immunomodulatory compounds of the invention belong to a class of isoindole-imides disclosed in U.S. patent application Ser. No. 09/781,179, International Publication No. WO 98/54170, and U.S. Pat. No. 6,395,754, each of which are incorporated herein by reference. Repre- 5 sentative compounds are of formula III:

III 10 Compounds of the invention can either be commercially purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically synthesized or resolved using known resolving agents or chiral colunms 15 as well as other standard synthetic organic chemistry tech­ niques. As used herein and unless otherwise indicated, the term and pharmaceutically acceptable salts, hydrates, solvates, "pharmaceutically acceptable salt" encompasses non-toxic clathrates, enantiomers, diastereomers, racemates, and mix­ 20 acid and base addition salts of the compound to which the tures of stereoisomers thereof, wherein: term refers. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases know one of X and Y is C=O and the other is CH or C=O; 2 in the art, which include, for example, hydrochloric acid,

R is H or CH2 0COR'; hydrobromic acid, phosphoric acid, sulfuric acid, methane- 2 3 4 (i) eachofR1, R , R , or R , independently of the others, is 25 sulphonic acid, acetic acid, tartaric acid, lactic acid, succinic halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic 2 3 4 5 acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, atoms or (ii) one ofR1, R , R , or R is nitro or-NHR and 2 3 4 and the like. the remaining ofR1, R , R , or R are hydrogen; Compounds that are acidic in nature are capable of forming 5 R is hydrogen or alkyl of 1 to 8 carbons 30 salts with various pharmaceutically acceptable bases. The R6 hydrogen, alkyl ofl to 8 carbon atoms, benzo, chloro, or bases that can be used to prepare pharmaceutically acceptable fluoro; base addition salts of such acidic compounds are those that 7 10 8 9 form non-toxic base addition salts, i.e., salts containing phar- R' is R -CHR -N(R R ); macologically acceptable cations such as, but not limited to, 7 R is m-phenylene or p-phenylene or -(CnH2n)- in 35 alkali metal or alkaline earth metal salts and the calcium, which n has a value of O to 4; magnesium, sodium or potassium salts in particular. Suitable each of R8 and R9 taken independently of the other is organic bases include, but are not limited to, N,N-dibenzyl­ hydrogen or alky 1 of 1 to 8 carbon atoms, or R 8 and R9 taken ethylenediamine, chloroprocaine, choline, diethanolamine, together are tetramethylene, pentamethylene, hexamethyl­ ethylenediamine, meglumaine (N-methylglucamine), lysine, 40 and procaine. ene, or ----CH CH [X]X CH CH - in which [X]X is 2 2 1 2 2 1 As used herein and unless otherwise indicated, the term -0-, -S-, or -NH-; "prodrug" means a derivative of a compound that can hydro­ 10 R is hydrogen, alkyl ofto 8 carbon atoms, or phenyl; and lyze, oxidize, or otherwise react under biological conditions * represents a chiral-carbon center. (in vitro or in vivo) to provide the compound. Examples of 45 prodrugs include, but are not limited to, derivatives of immu­ The most preferred immunomodulatory compounds of the nomodulatory compounds of the invention that comprise bio­ invention are 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindo­ hydrolyzable moieties such as biohydrolyzable amides, bio­ line-l,3-dione and 3-(4-amino-l-oxo-l ,3-dihydro-isoindol- hydrolyzable esters, biohydrolyzable carbamates, 2-yl)-piperidine-2,6-dione. The compounds can be obtained biohydrolyzable carbonates, biohydrolyzable ureides, and via standard, synthetic methods (see e.g., U.S. Pat. No. 5,635, 50 biohydrolyzable phosphate analogues. Other examples of 51 7, incorporated herein by reference). The compounds are prodrugs include derivatives of immunomodulatory com­ available from Celgene Corporation, Warren, N.J. pounds of the invention that comprise -NO, -N0 , 4-(Amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1,3-dione 2 -ONO, or---ON0 moieties. Prodrugs can typically be pre­ (ACTIMID™) has the following chemical structure: 2 pared using well-known methods, such as those described in 55 1 Burger's Medicinal Chemistry and Drug Discovery, 172- 178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, N.Y. 1985). As used herein and unless otherwise indicated, the terms "biohydrolyzable amide," "biohydrolyzable ester," "biohy- 60 drolyzable carbamate," "biohydrolyzable carbonate," "bio­ hydrolyzable ureide," "biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate, ureide, or phosphate, respectively, of a compound that either: 1) does not interfere with the biological activity of the compound but can confer The compound 3-(4-amino-l-oxo-1,3-dihydro-isoindol-2- 65 upon that compound advantageous properties in vivo, such as yl)-piperidine-2,6-dione (REVIMID™) has the following uptake, duration of action, or onset of action; or 2) is biologi- chemical structure: cally inactive but is converted in vivo to the biologically Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 63 of 148 PageID: 63

US 8,673,939 B2 11 12 active compound. Examples of biohydrolyzable esters It should be noted that if there is a discrepancy between a include, but are not limited to, lower alkyl esters, lower acy­ depicted structure and a name given that structure, the loxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, ami­ depicted structure is to be accorded more weight. In addition, nocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxy­ if the stereochemistry of a structure or a portion of a structure ethyl esters), lactonyl esters (such as phthalidyl and 5 is not indicated with, for example, bold or dashed lines, the thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such structure or portion of the structure is to be interpreted as as methoxycarbony1-oxymethy I, ethoxycarbony loxyethy I encompassing all stereoisomers of it. and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, 5 .2 Second Active Agents choline esters, and acylamino alkyl esters (such as acetami­ Immunomodulatory compounds can be combined with 10 other pharmacologically active compounds ("second active domethyl esters). Examples of biohydrolyzable amides agents") in methods and compositions of the invention. It is include, but are not limited to, lower alkyl amides, a-amino believed that certain combinations work synergistically in the acid amides, alkoxyacyl amides, and alkylaminoalkylcarbo­ treatment of particular types of cancer and certain diseases nyl amides. Examples of biohydrolyzable carbamates and conditions associated with, or characterized by, undes- include, but are not limited to, lower alkylamines, substituted 15 ired angiogenesis. Immunomodulatory compounds can also ethylenediamines, amino acids, hydroxyalkylamines, hetero­ work to alleviate adverse effects associated with certain sec- cyclic and heteroaromatic amines, and polyether amines. ond active agents, and some second active agents can be used Various immunomodulatory compounds of the invention to alleviate adverse effects associated with immunomodula­ contain one or more chiral centers, and can exist as racemic tory compounds. mixtures of enantiomers or mixtures of diastereomers. This 20 One or more second active ingredients or agents can be invention encompasses the use of stereomerically pure forms used in the methods and compositions of the invention of such compounds, as well as the use of mixtures of those together with an immunomodulatory compound. Second forms. For example, mixtures comprising equal or unequal active agents can be large molecules (e.g., proteins) or small amounts of the enantiomers of a particular immunomodula­ molecules (e.g., synthetic inorganic, organometallic, or tory compounds of the invention may be used in methods and 25 organic molecules). compositions of the invention. These isomers may be asym­ Examples of large molecule active agents include, but are metrically synthesized or resolved using standard techniques not limited to, hematopoietic growth factors, cytokines, and such as chiral colunms or chiral resolving agents. See, e.g., monoclonal and polyclonal antibodies. Typical large mol­ Jacques, J., et al., Enantiomers, Racemates and Resolutions ecule active agents are biological molecules, such as naturally (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., 30 occurring or artificially made proteins. Proteins that are par­ Tetrahedron 33:2725 (1977); Elie!, E. L., Stereochemistry of ticularly useful in this invention include proteins that stimu­ Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. late the survival and/or proliferation ofhematopoietic precur­ H., Tables ofResolving Agents and Optical Resolutions p. 268 sor cells and immunologically active poietic cells in vitro or (E. L. Elie!, Ed., Univ. of Notre Dame Press, Notre Dame, in vivo. Others stimulate the division and differentiation of Ind., 1972). 35 committed erythroid progenitors in cells in vitro or in vivo. As used herein and unless otherwise indicated, the term Particular proteins include, but are not limited to: interleu­ "stereomerically pure" means a composition that comprises kins, such as IL-2 (including recombinant IL-II ("rIL2") and one stereoisomer of a compound and is substantially free of canarypox TL-2), IL-10, IL-12, and IL-18; interferons, such other stereoisomers of that compound. For example, a stereo­ as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, merically pure composition of a compound having one chiral 40 interferon alfa-n3, interferon beta-I a, and interferon center will be substantially free of the opposite enantiomer of gamma-I b; GM-CF and GM-CSF; and EPO. the compound. A stereomerically pure composition of a com­ Particular proteins that can be used in the methods and pound having two chiral centers will be substantially free of compositions of the invention include, but are not limited to: other diastereomers of the compound. A typical stereomeri­ filgrastim, which is sold in the United States under the trade cally pure compound comprises greater than about 80% by 45 name Neupogen® (Amgen, Thousand Oaks, Calif.); sargra­ weight of one stereoisomer of the compound and less than mostim, which is sold in the United States under the trade about 20% by weight of other stereoisomers of the com­ name Leukine® (Immunex, Seattle, Wash.); and recombinant pound, more preferably greater than about 90% by weight of EPO, which is sold in the United States under the trade name one stereoisomer of the compound and less than about 10% Epogen® (Amgen, Thousand Oaks, Calif.). by weight of the other stereoisomers of the compound, even 50 Recombinant and mutated forms of GM-CSF can be pre­ more preferably greater than about 95% by weight of one pared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; stereoisomer of the compound and less than about 5% by and 5,229,496; all of which are incorporated herein by refer­ weight of the other stereoisomers of the compound, and most ence. Recombinant and mutated forms of G-CSF can be preferably greater than about 97% by weight of one stereoi­ prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; somer of the compound and less than about 3% by weight of 55 5,528,823; and 5,580,755; all of which are incorporated the other stereoisomers of the compound. As used herein and herein by reference. unless otherwise indicated, the term "stereomerically This invention encompasses the use of native, naturally enriched" means a composition that comprises greater than occurring, and recombinant proteins. The invention further about 60% by weight of one stereoisomer of a compound, encompasses mutants and derivatives (e.g., modified forms) preferably greater than about 70% by weight, more preferably 60 of naturally occurring proteins that exhibit, in vivo, at least greater than about 80% by weight of one stereoisomer of a some of the pharmacological activity of the proteins upon compound. As used herein and unless otherwise indicated, which they are based. Examples of mutants include, but are the term "enantiomerically pure" means a stereomerically not limited to, proteins that have one or more amino acid pure composition of a compound having one chiral center. residues that differ from the corresponding residues in the Similarly, the term "stereomerically enriched" means a ste- 65 naturally occurring forms of the proteins. Also encompassed reomerically enriched composition of a compound having by the term "mutants" are proteins that lack carbohydrate one chiral center. moieties normally present in their naturally occurring forms Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 64 of 148 PageID: 64

US 8,673,939 B2 13 14 ( e.g., nonglycosylated forms). Examples of derivatives hydrochloride; lanreotide acetate; letrozole; leuprolide include, but are not limited to, pegylated derivatives and acetate; liarozole hydrochloride; lometrexol sodium; lomus­ fusion proteins, such as proteins formed by fusing IgG 1 or tine; losoxantrone hydrochloride; masoprocol; maytansine; IgG3 to the protein or active portion of the protein of interest. mechlorethamine hydrochloride; megestrol acetate; See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. 5 melengestrol acetate; melphalan; menogaril; mercaptopu­ Methods 248:91-101 (2001). rine; methotrexate; methotrexate sodium; metoprine; meture­ Antibodies that can be used in combination with com­ depa; mitindomide; mitocarcin; mitocromin; mitogillin; pounds of the invention include monoclonal and polyclonal mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone antibodies. Examples of antibodies include, but are not lim­ hydrochloride; mycophenolic acid; nocodazole; nogalamy- ited to, trastuzumab (Herceptin®), rituximab (Rituxae®), 10 cin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomy­ bevacizumab (Avastin™), pertuzumab (Onmitarg™), tositu­ cin; pentamustine; peplomycin sulfate; perfosfamide; pipo­ momab (Bcxxar®), edrecolomab (Panorex®), and G250. broman; piposulfan; piroxantrone hydrochloride; Compounds of the invention can also be combined with, or plicamycin; plomestane; porfimer sodium; porfiromycin; used in combination with, anti-TNF-a antibodies. prednimustine; procarbazine hydrochloride; puromycin; Large molecule active agents may be administered in the 15 puromycin hydrochloride; pyrazofurin; riboprine; safingol; form of anti-cancer vaccines. For example, vaccines that safingol hydrochloride; semustine; simtrazene; sparfosate secrete, or cause the secretion of, cytokines such as IL-2, sodium; sparsomycin; spirogermaniumhydrochloride; spiro­ G-CSF, and GM-CSF can be used in the methods, pharma­ mustine; spiroplatin; streptonigrin; streptozocin; sulofenur; ceutical compositions, and kits of the invention. See, e.g., talisomycin; tecogalan sodium; taxotere; tegafur; telox- Emens, L.A., et al., Curr. Opinion Mal. Ther. 3(1):77-84 20 antrone hydrochloride; temoporfin; teniposide; teroxirone; (2001). testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; In one embodiment of the invention, the large molecule tirapazamine; toremifene citrate; trestolone acetate; tricirib­ active agent reduces, eliminates, or prevents an adverse effect ine phosphate; trimetrexate; trimetrexate glucuronate; trip­ associated with the administration of an immunomodulatory torelin; tubulozole hydrochloride; uracil mustard; uredepa; compound. Depending on the particular immunomodulatory 25 vapreotide; verteporfin; vinblastine sulfate; vincristine sul­ compound and the disease or disorder begin treated, adverse fate; vindesine; vindesine sulfate; vinepidine sulfate; vingly­ effects can include, but are not limited to, drowsiness and cinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vin­ sonmolence, dizziness and orthostatic hypotension, neutro­ rosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; penia, infections that result from neutropenia, increased HIV­ zinostatin; and zorubicin hydrochloride. viral load, bradycardia, Stevens-Johnson Syndrome and toxic 30 Other anti-cancer drugs include, but are not limited to: epidermal necrolysis, and seizures (e.g., grand ma! convul­ 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater­ sions). A specific adverse effect is neutropenia. one; aclarubicin; acylfulvene; adecypenol; adozelesin; Second active agents that are small molecules can also be aldesleukin; ALL-TK antagonists; altretamine; ambamus­ used to alleviate adverse effects associated with the adminis­ tine; amidox; amifostine; aminolevulinic acid; amrubicin; tration of an immunomodulatory compound. However, like 35 amsacrine; anagrelide; anastrozole; andrographolide; angio­ some large molecules, many are believed to be capable of genesis inhibitors; antagonist D; antagonist G; antarelix; anti­ providing a synergistic effect when administered with ( e.g., dorsalizing morphogenetic protein-I; antiandrogen, prostatic before, after or simultaneously) an immunomodulatory com­ carcinoma; antiestrogen; antineoplaston; antisense oligo­ pound. Examples of small molecule second active agents nucleotides; aphidicolin glycinate; apoptosis gene modula- include, but are not limited to, anti-cancer agents, antibiotics, 40 tors; apoptosis regulators; apurinic acid; ara-CDP-DL­ immunosuppressive agents, and steroids. PTBA; argmme deaminase; asulacrine; atamestane; Examples of anti-cancer agents include, but are not limited atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; aza­ to: acivicin; aclarubicin; acodazole hydrochloride; acronine; setron; azatoxin; azatyrosine; baccatin III derivatives; bal­ adozelesin; aldesleukin; altretamine; ambomycin; amet­ anol; batimastat; BCR/ABL antagonists; benzochlorins; ben- antrone acetate; amsacrine; anastrozole; anthramycin; 45 zoylstaurosporine; beta lactam derivatives; beta-alethine; asparaginase; asperlin; azacitidine; azetepa; azotomycin; betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta­ batimastat; benzodepa; bicalutamide; bisantrene hydrochlo­ mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene ride; bisnafide dimesylate; bizelesin; bleomycin sulfate; bre­ A; bizelesin; breflate; bropirimine; budotitane; buthionine quinar sodium; bropirimine; busulfan; cactinomycin; calus­ sulfoximine; calcipotriol; calphostin C; camptothecin deriva- terone; caracemide; carbetimer; carboplatin; carmustine; 50 tives; capecitabine; carboxamide-amino-triazole; carboxya­ carubicin hydrochloride; carzelesin; cedefingol; celecoxib midotriazole; CaRest M3; CARN 700; cartilage derived (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; inhibitor; carzelesin; casein kinase inhibitors (ICOS); cladribine; crisnatol mesylate; cyclophosphamide; cytara­ castanospermine; cecropinB; cetrorelix; chlorins; chloroqui­ bine; dacarbazine; dactinomycin; daunorubicin hydrochlo­ noxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; ride; decitabine; dexormaplatin; dezaguanine; dezaguanine 55 clomifene analogues; clotrimazole; collismycinA; collismy­ mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin cin B; combretastatin A4; combretastatin analogue; conage­ hydrochloride; droloxifene; droloxifene citrate; dromo­ nin; crambescidin 816; crisnatol; cryptophycin 8; cryptophy­ stanolone propionate; duazomycin; edatrexate; eflomithine cin A derivatives; curacin A; cyclopentanthraquinones; hydrochloride; elsamitrucin; enloplatin; enpromate; epipro­ cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic fac- pidine; epirubicin hydrochloride; erbulozole; esorubicin 60 tor; cytostatin; dacliximab; decitabine; dehydrodidenmin B; hydrochloride; estramustine; estramustine phosphate deslorelin; dexamethasone; dexifosfamide; dexrazoxane; sodium; etanidazole; etoposide; etoposide phosphate; eto­ dexverapamil; diaziquone; didenmin B; didox; diethylnor­ prine; fadrozole hydrochloride; fazarabine; fenretinide; spermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamy­ floxuridine; fludarabine phosphate; fluorouracil; fluorocitab­ cin; diphenyl spiromustine; docetaxel; docosanol; dolas- ine; fosquidone; fostriecin sodium; gemcitabine; gemcitab­ 65 etron; doxifluridine; doxorubicin; droloxifene; dronabinol; ine hydrochloride; hydroxyurea; idarubicin hydrochloride; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolo­ ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan mab; eflornithine; elemene; emitefur; epirubicin; epristeride; Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 65 of 148 PageID: 65

US 8,673,939 B2 15 16 estramustine analogue; estrogen agonists; estrogen antago­ 1; squalamine; stipiamide; stromelysin inhibitors; sulfi­ nists; etanidazole; etoposide phosphate; exemestane; fadro­ nosine; superactive vasoactive intestinal peptide antagonist; zole; fazarabine; fenretinide; filgrastim; finasteride; fla­ suradista; suramin; swainsonine; tallimustine; tamoxifen vopiridol; flezelastine; fluasterone; fludarabine; methiodide; tauromustine; tazarotene; tecogalan sodium; fluorodaunorunicin hydrochloride; forfenimex; formestane; 5 tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; fostriecin; fotemustine; gadolinium texaphyrin; gallium teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit­ thiocoraline; thrombopoietin; thrombopoietin mimetic; thy­ abine; glutathione inhibitors; hepsulfam; heregulin; hexam­ malfasin; thymopoietin receptor agonist; thymotrinan; thy­ ethylene bisacetamide; hypericin; ibandronic acid; idarubi­ roid stimulating hormone; tin ethyl etiopurpurin; tira- cin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib 10 pazamine; titanocene bichloride; topsentin; toremifene; (e.g., Gleevec®), imiquimod; immunostimulant peptides; translation inhibitors; tretinoin; triacetyluridine; triciribine; insulin-like growth factor-I receptor inhibitor; interferon trimetrexate; triptorelin; tropisetron; turosteride; tyrosine agonists; interferons; interleukins; iobenguane; iododoxoru­ kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; bicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; iso­ urogenital sinus-derived growth inhibitory factor; urokinase homohalicondrin B; itasetron; jasplakinolide; kahalalide F; 15 receptor antagonists; vapreotide; variolin B; velaresol; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; veramine; verdins; verteporfin; vinorelbine; vinxaltine; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and factor; leukocyte alpha interferon; leuprolide+estrogen+ zinostatin stimalamer. progesterone; leuprorelin; levamisole; liarozole; linear Specific second active agents include, but are not limited polyamine analogue; lipophilic disaccharide peptide; lipo­ 20 to, oblimersen (Genasense®), remicade, docetaxel, cele­ philic platinum compounds; lissoclinamide 7; lobaplatin; coxib, melphalan, dexamethasone (Decadron®), steroids, lombricine; lometrexol; lonidamine; losoxantrone; loxorib­ gemcitabine, cisplatinum, temozolomide, etoposide, cyclo­ ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep­ phosphamide, temodar, carboplatin, procarbazine, gliadel, tides; maitansine; mannostatin A; marimastat; masoprocol; tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, maspin; matrilysin inhibitors; matrix metalloproteinase 25 fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, inter­ inhibitors; menogaril; merbarone; meterelin; methioninase; feron alpha, pegy lated interferon alpha (e.g., PEG INTRON­ metoclopramide; MIF inhibitor; mifepristone; miltefosine; A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, mirimostim; mitoguazone; mitolactol; mitomycin analogues; liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, mitonafide; mitotoxin fibroblast growth factor-saporin; vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, mitoxantrone; mofarotene; molgramostim; Erbitux, human 30 zoledronic acid, palmitronate, biaxin, busulphan, prednisone, chorionic gonadotrophin; monophosphoryl lipidA+myobac­ bisphosphonate, arsenic trioxide, vincristine, doxorubicin terium cell wall sk; mopidamol; mustard anticancer agent; (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine mycaperoxide B; mycobacterial cell wall extract; myriapor­ sodium phosphate (Emcyt®), sulindac, and etoposide. one; N-acetyldinaline; N-substituted benzamides; nafarelin; 5.3 Methods of Treatments and Prevention nagrestip; naloxone+pentazocine; napavin; naphterpin; nar- 35 Methods of this invention encompass methods of treating, tograstim; nedaplatin; nemorubicin; neridronic acid; niluta­ preventing and/or managing various types of cancer and dis­ mide; nisamycin; nitric oxide modulators; nitroxide antioxi­ eases and disorders associated with, or characterized by, dant; nitrullyn; oblimersen (Genasense®); undesired angiogenesis. As used herein, unless otherwise 0 6 -benzylguanine; octreotide; okicenone; oligonucleotides; specified, the term "treating" refers to the administration of a onapristone; ondansetron; ondansetron; oracin; oral cytokine 40 compound of the invention or other additional active agent inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; after the onset of symptoms of the particular disease or dis- paclitaxel; paclitaxel analogues; paclitaxel derivatives; order. As used herein, unless otherwise specified, the term palauamine; palmitoylrhizoxin; pamidronic acid; panax­ "preventing" refers to the administration prior to the onset of ytriol; panomifene; parabactin; pazelliptine; pegaspargase; symptoms, particularly to patients at risk of cancer, and other peldesine; pentosan polysulfate sodium; pentostatin; pentro- 45 diseases and disorders associated with, or characterized by, zole; perflubron; perfosfamide; perillyl alcohol; phenazino­ undesired angiogenesis. The term "prevention" includes the mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo­ inhibition of a symptom of the particular disease or disorder. carpine hydrochloride; pirarubicin; piritrexim; placetin A; Patients with familial history of cancer and diseases and placetin B; plasminogen activator inhibitor; platinum com­ disorders associated with, or characterized by, undesired plex; platinum compounds; platinum-triamine complex; por- 50 angiogenesis are preferred candidates for preventive regi­ fimer sodium; porfiromycin; prednisone; propyl bis-acri­ mens. As used herein and unless otherwise indicated, the term done; prostaglandin 12; proteasome inhibitors; protein "managing" encompasses preventing the recurrence of the A-based immune modulator; protein kinase C inhibitor; pro­ particular disease or disorder in a patient who had suffered tein kinase C inhibitors, microalgal; protein tyrosine phos­ from it, and/or lengthening the time a patient who had suf­ phatase inhibitors; purine nucleoside phosphorylase inhibi- 55 fered from the disease or disorder remains in remission. tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin As used herein, the term "cancer" includes, but is not polyoxyethylene conjugate; raf antagonists; raltitrexed; limited to, solid tumors and blood born tumors. The term ramosetron; ras farnesyl protein transferase inhibitors; ras "cancer" refers to disease of skin tissues, organs, blood, and inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe­ vessels, including, but not limited to, cancers of the bladder, nium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; 60 bone or blood, brain, breast, cervix, chest, colon, rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; endrometrium, esophagus, eye, head, kidney, liver, lymph safingol; saintopin; SarCNU; sarcophytol A; sargramostim; nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, Sdi 1 mimetics; semustine; senescence derived inhibitor 1; stomach, testis, throat, and uterus. Specific cancers include, sense oligonucleotides; signal transduction inhibitors; sizofi­ but are not limited to, advanced malignancy, amyloidosis, ran; sobuzoxane; sodium borocaptate; sodium phenylacetate; 65 neuroblastoma, meningioma, hemangiopericytoma, multiple solverol; somatomedin binding protein; sonermin; sparfosic brain metastase, glioblastoma multiforms, glioblastoma, acid; spicamycin D; spiromustine; splenopentin; spongistatin brain stem glioma, poor prognosis malignant brain tumor, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 66 of 148 PageID: 66

US 8,673,939 B2 17 18 malignant glioma, recurrent malignant giolma, anaplastic monary inflammatory disease, dermatitis, cystic fibrosis, sep­ astrocytoma, anaplastic oligodendroglioma, neuroendocrine tic shock, sepsis, endotoxic shock, hemodynamic shock, sep­ tumor, rectal adenocarcinoma, Dukes C & D colorectal can­ sis syndrome, post ischemic reperfusion injury, meningitis, cer, unresectable colorectal carcinoma, metastatic hepatocel­ psoriasis, fibrotic disease, cachexia, graft rejection, rheuma- lular carcinoma, Kaposi's sarcoma, karotype acute myelo­ 5 toid spondylitis, osteoporosis, Crohn's disease, ulcerative blastic leukemia, Hodgkin's lymphoma, non-Hodgkin's colitis, inflammatory-bowel disease, multiple sclerosis, sys­ lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell temic lupus erythrematosus, erythema nodosum leprosum in lymphoma, diffuse large B-Cell lymphoma, low grade folli­ leprosy, radiation damage, asthma, hyperoxic alveolar injury, cular lymphoma, malignant melanoma, malignant mesothe­ malaria, mycobacterial infection, and opportunistic infec- lioma, malignant pleural effusion mesothelioma syndrome, 10 tions resulting from HIV. peritoneal carcinoma, papillary serous carcinoma, gyneco­ This invention encompasses methods of treating patients logic sarcoma, soft tissue sarcoma, scleroderma, cutaneous who have been previously treated for cancer or diseases or vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, disorders associated with, or characterized by, undesired fibrodysplasia ossificans progressive, hormone refractory angiogenesis, but are non-responsive to standard therapies, as prostate cancer, resected high-risk soft tissue sarcoma, unre­ 15 well as those who have not previously been treated. The sectable hepatocellular carcinoma, Waldenstrom's macro­ invention also encompasses methods of treating patients globulinemia, smoldering myeloma, indolent myeloma, fal­ regardless of patient's age, although some diseases or disor­ lopian tube cancer, androgen independent prostate cancer, ders are more common in certain age groups. The invention androgen dependent stage IV non-metastatic prostate cancer, further encompasses methods of treating patients who have hormone-insensitive prostate cancer, chemotherapy-insensi­ 20 undergone surgery in an attempt to treat the disease or con­ tive prostate cancer, papillary thyroid carcinoma, follicular dition at issue, as well as those who have not. Because patients thyroid carcinoma, medullary thyroid carcinoma, and lei­ with cancer and diseases and disorders characterized by omyoma. In a specific embodiment, the cancer is metastatic. undesired angiogenesis have heterogenous clinical manifes­ In another embodiment, the cancer is refractory or resistance tations and varying clinical outcomes, the treatment given to to chemotherapy or radiation; in particular, refractory to tha­ 25 a patient may vary, depending on his/her prognosis. The lidomide. skilled clinician will be able to readily determine without As used herein to refer to diseases and conditions other undue experimentation specific secondary agents, types of than cancer, the terms "diseases or disorders associated with, surgery, and types of non-drug based standard therapy that or characterized by, undesired angiogenesis," "diseases or can be effectively used to treat an individual patient with disorders associated with undesired angiogenesis," and "dis­ 30 cancer and other diseases or disorders. eases or disorders characterized by undesired angiogenesis" Methods encompassed by this invention comprise admin­ refer to diseases, disorders and conditions that are caused, istering one or more immunomodulatory compound of the mediated or attended by undesired, unwanted or uncontrolled invention, or a pharmaceutically acceptable salt, solvate, angiogenesis, including, but not limited to, inflammatory dis­ hydrate, stereoisomer, clathrate, or prodrug thereof, to a eases, autoimmune diseases, genetic diseases, allergic dis­ 35 patient (e.g., a human) suffering, or likely to suffer, from eases, bacterial diseases, ocular neovascular diseases, chor­ cancer or a disease or disorder mediated by undesired angio- oidal neovascular diseases, and retina neovascular diseases. genesis. Examples of such diseases or disorders associated with In one embodiment of the invention, an immunomodula­ undesired angiogenesis include, but are not limited to, dia­ tory compound of the invention can be administered orally betic retinopathy, retinopathy of prematurity, corneal graft 40 and in single or divided daily doses in an amount of from rejection, neovascular glaucoma, retrolental fibroplasia, pro­ about 0.10 to about 150 mg/day. In a particular embodiment, liferative vitreoretinopathy, trachoma, myopia, optic pits, 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione epidemic keratoconjunctivitis, atopic keratitis, superior lim­ (Actimid™) may be administered in an amount of from about bic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, 0.1 to about 1 mg per day, or alternatively from about 0.1 to phylectenulosis, syphilis, lipid degeneration, bacterial ulcer, 45 about 5 mg every other day. In a preferred embodiment, fungal ulcer, Herpes simplex infection, Herpes zoster infec­ 3-(4-amino- l-oxo-l ,3-dihydro-isoindol-2-yl-piperidine-2,6- tion, protozoan infection, Kaposi sarcoma, Mooren ulcer, dione (Revimid™) may be administered in an amount of from Terrien's marginal degeneration, mariginal keratolysis, rheu­ about 5 to 25 mg per day, or alternatively from about 10 to matoid arthritis, systemic lupus, polyarteritis, trauma, Wege­ about 50 mg every other day. ners sarcoidosis, Scleritis, Steven's Johnson disease, periph- 50 In a specific embodiment, 4-(amino)-2-(2,6-dioxo(3-pip­ igoid radial keratotomy, sickle cell anemia, sarcoid, eridyl))-isoindoline-l,3-dione (Actimid™) may be adminis­ pseudoxanthoma elasticum, Pagets disease, vein occlusion, tered in an amount of about 1, 2, or 5 mg per day to patients artery occlusion, carotid obstructive disease, chronic uveitis, with relapsed multiple myeloma. In a particular embodiment, chronic vitritis, Lyme's disease, Eales disease, Behcet's dis­ 3-(4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2, ease, retinitis, choroiditis, presumed ocular histoplasmosis, 55 6-dione (Revimid™) may be administered initially in an Bests disease, Stargarts disease, pars planitis, chronic retinal amount of 5 mg/day and the dose can be escalated every week detachment, hyperviscosity syndromes, toxoplasmosis, to 10, 20, 25, 30 and 50 mg/day. In a specific embodiment, rubeosis, sarcodisis, sclerosis, soriatis, psoriasis, primary Revimid™ can be administered in an amount ofup to about sclerosing cholangitis, proctitis, primary biliary srosis, idio­ 30 mg/day to patients with solid tumor. In a particular pathic pulmonary fibrosis, and alcoholic hepatitis. 60 embodiment, Revimid™ can be administered in an amount of In specific embodiments of the invention, diseases or dis­ up to about 40 mg/day to patients with glioma. orders associated with undesired angiogenesis do not include 5 .3 .1 Combination Therapy with a Second Active Agent congestive heart failure, cardiomyopathy, pulmonary edema, Specific methods of the invention comprise administering endotoxin-mediated septic shock, acute viral myocarditis, an immunomodulatory compound of the invention, or a phar­ cardiac allograft rejection, myocardial infarction, HIV, hepa- 65 maceutically acceptable salt, solvate, hydrate, stereoisomer, titis, adult respiratory distress syndrome, bone-resorption clathrate, or prodrug thereof, in combination with one or disease, chronic obstructive pulmonary diseases, chronic pul- more second active agents, and/ or in combination with radia- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 67 of 148 PageID: 67

US 8,673,939 B2 19 20 tion therapy, blood transfusions, or surgery. Examples of In another embodiment, an immunomodulatory compound immunomodulatory compounds of the invention are dis­ is administered with gemcitabine and cisplatinum to patients closed herein (see, e.g., section 5.1). Examples of second with locally advanced or metastatic transitional cell bladder active agents are also disclosed herein (see, e.g., section 5.2). cancer. Administration of the immunomodulatory compounds and 5 In another embodiment, an immunomodulatory compound the second active agents to a patient can occur simultaneously is administered in combination with a second active ingredi­ or sequentially by the same or different routes of administra­ ent as follows: temozolomide to pediatric patients with tion. The suitability of a particular route of administration relapsed or progressive brain tumors or recurrent neuroblas­ employed for a particular active agent will depend on the toma; celecoxib, etoposide and cyclophosphamide for active agent itself (e.g., whether it can be administered orally 10 relapsed or progressive CNS cancer; temodar to patients with without decomposing prior to entering the blood stream) and recurrent or progressive meningioma, malignant menin­ the disease being treated. A preferred route of administration gioma, hemangiopericytoma, multiple brain metastases, for an immunomodulatory compound of the invention is relapsed brain tumors, or newly diagnosed glioblastoma mul­ orally. Preferred routes of administration for the second active tiforms; irinotecan to patients with recurrent glioblastoma; agents or ingredients of the invention are known to those of 15 carboplatin to pediatric patients with brain stem glioma; pro­ ordinary skill in the art. See, e.g., Physicians' Desk Refer­ carbazine to pediatric patients with progressive malignant ence, 1755-1760 (56'h ed., 2002). gliomas; cyclophosphamide to patients with poor prognosis In one embodiment of the invention, the second active malignant brain tumors, newly diagnosed or recurrent glio­ agent is administered intravenously or subcutaneously and blastoma multiforms; Gliadel® for high grade recurrent once or twice daily in an amount of from about 1 to about 20 malignant gliomas; temozolomide and tamoxifen for ana­ 1000 mg, from about 5 to about 500 mg, from about 10 to plastic astrocytoma; or topotecan for gliomas, glioblastoma, about 350 mg, or from about 50 to about 200 mg. The specific anaplastic astrocytoma or anaplastic oligodendroglioma. amount of the second active agent will depend on the specific In another embodiment, an immunomodulatory compound agent used, the type of disease being treated or managed, the is administered with methotrexate and cyclophosphamide to severity and stage of disease, and the amount( s) of immuno- 25 patients with metastatic breast cancer. modulatory compounds of the invention and any optional In another embodiment, an immunomodulatory compound additional active agents concurrently administered to the is administered with temozolomide to patients with neuroen­ patient. In a particular embodiment, the second active agent is docrine tumors. oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, In another embodiment, an immunomodulatory compound irinotecan, dacarbazine, transretinoic acid, topotecan, pen- 30 is administered with gemcitabine to patients with recurrent or toxifylline, ciprofloxacin, dexamethasone, vincristine, doxo­ metastatic head or neck cancer. In another embodiment, an rubicin, COX-2 inhibitor, IL2, ILS, IL18, IFN, Ara-C, immunomodulatory compound is administered with gemcit­ vinorelbine, or a combination thereof. abine to patients with pancreatic cancer. In a particular embodiment, GM-CSF, G-CSF or EPO is In another embodiment, an immunomodulatory compound administered subcutaneously during about five days in a four 35 is administered to patients with colon cancer in combination or six week cycle in an amount of from about 1 to about 750 with Arisa®, taxol and/or taxotere. mg/m2 /day, preferably in an amount of from about 25 to about In another embodiment, an immunomodulatory compound 500 mg/m2/day, more preferably in an amount of from about is administered with capecitabine to patients with refractory 50 to about 250 mg/m2 /day, and most preferably in an amount colorectal cancer or patients who fail first line therapy or have 2 of from about 50 to about 200 mg/m /day. In a certain 40 poor performance in colon or rectal adenocarcinoma. embodiment, GM-CSF may be administered in an amount of In another embodiment, an immunomodulatory compound from about 60 to about 500 mcg/m2 intravenously over 2 is administered in combination with fluorouracil, leucovorin, hours, or from about 5 to about 12 mcg/m2/day subcutane­ and irinotecan to patients with Dukes C & D colorectal cancer ously. In a specific embodiment, G-CSF may be administered or to patients who have been previously treated for metastatic subcutaneously in an amount of about 1 mcg/kg/day initially 45 colorectal cancer. and can be adjusted depending on rise of total granulocyte In another embodiment, an immunomodulatory compound counts. The maintenance dose ofG-CSF may be administered is administered to patients with refractory colorectal cancer in in an amount of about 300 (in smaller patients) or 480 mcg combination with capecitabine, xeloda, and/or CPT-11. subcutaneously. In a certain embodiment, EPO may be In another embodiment, an immunomodulatory compound administered subcutaneously in an amount of 10,000 Unit 3 50 of the invention is administered with capecitabine and irino­ times per week. tecan to patients with refractory colorectal cancer or to In another embodiment, Revimid™ in an amount of about patients with unresectable or metastatic colorectal carci­ 25 mg/d and dacarbazine in an amount of about from 200 to noma. 1,000 mg/m2 /d are administered to patients with metastatic In another embodiment, an immunomodulatory compound malignant melanoma. In a specific embodiment, Revimid™ 55 is administered alone or in combination with interferon alpha is administered in an amount of from about 5 to about 25 mg/d or capecitabine to patients with unresectable or metastatic to patients with metastatic malignant melanoma whose dis­ hepatocellular carcinoma; or with cisplatin and thiotepa to ease has progressed on treatment with dacarbazine, IL-2 or patients with primary or metastatic liver cancer. IFN. In a specific embodiment, Revimid™ is administered to In another embodiment, an immunomodulatory compound patients with relapsed or refractory multiple myeloma in an 60 is administered in combination with pegylated interferon amount of about 15 mg/d twice a day or about 30 mg/d four alpha to patients with Kaposi's sarcoma. times a day in a combination with dexamethasone. In another embodiment, an immunomodulatory compound In another embodiment, an immunomodulatory compound is administered in combination with fludarabine, carboplatin, is administered with melphalan and dexamethasone to and/or topotecan to patients with refractory or relapsed or patients with amyloidosis. In a specific embodiment, an 65 high-risk acute myelogenous leukemia. immunomodulatory compound of the invention and steroids In another embodiment, an immunomodulatory compound can be administered to patients with amyloidosis. is administered in combination with liposomal daunorubicin, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 68 of 148 PageID: 68

US 8,673,939 B2 21 22 topotecan and/or cytarabine to patients with unfavorable renal cell cancer, in combination with capecitabine, IFN, karotype acute myeloblastic leukemia. tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination In another embodiment, an immunomodulatory compound thereof. is administered in combination with gemcitabine and irino­ In another embodiment, an immunomodulatory compound tecan to patients with non-small cell lung cancer. In one 5 is administered to patients with various types or stages of embodiment, an immunomodulatory compound is adminis­ gynecologic, uterus or soft tissue sarcoma cancer in combi­ tered in combination with carboplatin and irinotecan to nation with IFN, a COX-2 inhibitor such as Celebrex®, and/ patients with non-small cell lung cancer. In one embodiment, or sulindac. an immunomodulatory compound is administered with dox­ In another embodiment, an immunomodulatory compound 10 is administered to patients with various types or stages of etaxol to patients with non-small cell lung cancer who have solid tumors in combination with celebrex, etoposide, cyclo­ been previously treated with carboNP 16 and radiotherapy. phosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, In another embodiment, an immunomodulatory compound GM-CSF, or a combination thereof. is administered in combination with carboplatin and/or taxo­ In another embodiment, an immunomodulatory compound tere, or in combination with carboplatin, pacilitaxel and/or 15 is administered to patients with scleroderma or cutaneous thoracic radiotherapy to patients with non-small cell lung vasculitis in combination with celebrex, etoposide, cyclo­ cancer. In a specific embodiment, an immunomodulatory phosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, compound is administered in combination with taxotere to GM-CSF, or a combination thereof. patients with stage IIIB or TV non-small cell lung cancer. This invention also encompasses a method of increasing In another embodiment, an immunomodulatory compound 20 the dosage of an anti-cancer drug or agent that can be safely of the invention is administered in combination with and effectively administered to a patient, which comprises oblimersen (Genasense®) to patients with small cell lung administering to a patient (e.g., a human) an immunomodu­ cancer. latory compound of the invention, or a pharmaceutically In another embodiment, an immunomodulatory compound acceptable derivative, salt, solvate, clathrate, hydrate, or pro- is administered alone or in combination with a second active 25 drug thereof. Patients that can benefit by this method are those ingredient such as vinblastine or fludarabine to patients with likely to suffer from an adverse effect associated with anti­ various types of lymphoma, including, but not limited to, cancer drugs for treating a specific cancer of the skin, subcu­ Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous taneous tissue, lymph nodes, brain, lung, liver, bone, intes­ T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large tine, colon, heart, pancreas, adrenal, kidney, prostate, breast, B-Cell lymphoma or relapsed or refractory low grade folli­ 30 colorectal, or combinations thereof. The administration of an cular lymphoma. immunomodulatory compound of the invention alleviates or In another embodiment, an immunomodulatory compound reduces adverse effects which are of such severity that it is administered in combination with taxotere, IL-2, IFN, GM­ would otherwise limit the amount of anti-cancer drug. CSF, and/or dacarbazine to patients with various types or In one embodiment, an immunomodulatory compound of stages of melanoma. 35 the invention can be administered orally and daily in an In another embodiment, an immunomodulatory compound amount of from about 0.1 to about 150 mg, and preferably is administered alone or in combination with vinorelbine to from about 1 to about 50 mg, more preferably from about 2 to patients with malignant mesothelioma, or stage IIIB non­ about 25 mg prior to, during, or after the occurrence of the small cell lung cancer with pleural implants or malignant adverse effect associated with the administration of an anti- pleural effusion mesothelioma syndrome. 40 cancer drug to a patient. In a particular embodiment, an In another embodiment, an immunomodulatory compound immunomodulatory compound of the invention is adminis­ is administered to patients with various types or stages of tered in combination with specific agents such as heparin, multiple myeloma in combination with dexamethasone, aspirin, coumadin, or G-CSF to avoid adverse effects that are zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, associated with anti-cancer drugs such as but not limited to melphalan, busulphan, cyclophosphamide, IFN, palmidr- 45 neutropenia or thrombocytopenia. onate, prednisone, bisphosphonate, celecoxib, arsenic triox­ In one embodiment, an immunomodulatory compound of ide, PEG INTRON-A, vincristine, or a combination thereof. the invention can be administered to patients with diseases In another embodiment, an immunomodulatory compound and disorders associated with, or characterized by, undesired is administered to patients with relapsed or refractory mul­ angiogenesis in combination with additional active ingredi­ tiple myeloma in combination with doxorubicin (Doxil®), 50 ents including but not limited to anti-cancer drugs, anti-in­ vincristine and/or dexamethasone (Decadron®). flanimatories, antihistamines, antibiotics, and steroids. In another embodiment, an immunomodulatory compound In another embodiment, this invention encompasses a is administered to patients with various types or stages of method of treating, preventing and/or managing cancer, ovarian cancer such as peritoneal carcinoma, papillary serous which comprises administering an immunomodulatory com­ carcinoma, refractory ovarian cancer or recurrent ovarian 55 pound of the invention, or a pharmaceutically acceptable salt, cancer, in combination with taxol, carboplatin, doxorubicin, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or in conjunction with (e.g. before, during, or after) conven­ a combination thereof. tional therapy including, but not limited to, surgery, immu­ In another embodiment, an immunomodulatory compound notherapy, biological therapy, radiation therapy, or other non­ is administered to patients with various types or stages of 60 drug based therapy presently used to treat, prevent or manage prostate cancer, in combination with xeloda, 5 FU/LVi, gem­ cancer. The combined use of the immunomodulatory com- citabine, irinotecan plus gemcitabine, cyclophosphamide, pounds of the invention and conventional therapy may pro­ vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, vide a unique treatment regimen that is unexpectedly effec­ ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, tive in certain patients. Without being limited by theory, it is Emcyt, or a combination thereof. 65 believed that immunomodulatory compounds of the inven­ In another embodiment, an immunomodulatory compound tion may provide additive or synergistic effects when given is administered to patients with various types or stages of concurrently with conventional therapy. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 69 of 148 PageID: 69

US 8,673,939 B2 23 24 As discussed elsewhere herein, the invention encompasses In another embodiment, an immunomodulatory compound a method of reducing, treating and/or preventing adverse or and prednisone are administered as maintenance therapy to undesired effects associated with conventional therapy patients with multiple myeloma following the transplantation including, but not limited to, surgery, chemotherapy, radia­ of autologous stem cell. tion therapy, hormonal therapy, biological therapy and immu- 5 In another embodiment, an immunomodulatory compound notherapy. One or more immunomodulatory compounds of and dexamethasone are administered as salvage therapy for the invention and other active ingredient can be administered low risk post transplantation to patients with multiple to a patient prior to, during, or after the occurrence of the myeloma. adverse effect associated with conventional therapy. In another embodiment, an immunomodulatory compound In one embodiment, an immunomodulatory compound of 10 and dexamethasone are administered as maintenance therapy the invention can be administered in an amount of from about to patients with multiple myeloma following the transplanta­ 0.1 to about 150 mg, and preferably from about 1 to about 25 tion of autologous bone marrow. mg, more preferably from about 2 to about 10 mg orally and In another embodiment, an immunomodulatory compound daily alone, or in combination with a second active agent 15 is administered following the administration of high dose of disclosed herein (see, e.g., section 5.2), prior to, during, or melphalan and the transplantation of autologous stem cell to after the use of conventional therapy. patients with chemotherapy responsive multiple myeloma. In a specific embodiment ofthis method, an immunomodu­ In another embodiment, an immunomodulatory compound latory compound of the invention and doxetaxol are admin­ and PEG INTRO-A are administered as maintenance therapy istered to patients with non-small cell lung cancer who were 20 to patients with multiple myeloma following the transplanta­ previously treated with carboNP 16 and radiotherapy. tion of autologous CD34-selected peripheral stem cell. 5.3.2 Use with Transplantation Therapy In another embodiment, an immunomodulatory compound Compounds of the invention can be used to reduce the risk is administered with post transplant consolidation chemo­ of Graft Versus Host Disease (GVHD). Therefore, the inven­ therapy to patients with newly diagnosed multiple myeloma tion encompasses a method of treating, preventing and/or 25 to evaluate anti-angiogenesis. managing cancer, which comprises administering the immu­ In another embodiment, an immunomodulatory compound nomodulatory compound of the invention, or a pharmaceuti­ and dexamethasone are administered as maintenance therapy cally acceptable salt, solvate, hydrate, stereoisomer, clath­ after DCEP consolidation, following the treatment with high rate, or prodrug thereof, in conjunction with transplantation dose of melphalan and the transplantation of peripheral blood therapy. 30 stem cell to 65 years of age or older patients with multiple myeloma. As those of ordinary skill in the art are aware, the treatment 5 .3 .3 Cycling Therapy of cancer is often based on the stages and mechanism of the In certain embodiments, the prophylactic or therapeutic disease. For example, as inevitable leukemic transformation agents of the invention are cyclically administered to a develops in certain stages of cancer, transplantation ofperiph­ 35 patient. Cycling therapy involves the administration of an eral blood stem cells, hematopoietic stem cell preparation or active agent for a period of time, followed by a rest for a bone marrow may be necessary. The combined use of the period of time, and repeating this sequential administration. immunomodulatory compound of the invention and trans­ Cycling therapy can reduce the development of resistance to plantation therapy provides a unique and unexpected syner­ one or more of the therapies, avoid or reduce the side effects gism. In particular, an immunomodulatory compound of the 40 of one of the therapies, and/or improves the efficacy of the invention exhibits immunomodulatory activity that may pro­ treatment. vide additive or synergistic effects when given concurrently Consequently, in one specific embodiment of the inven- with transplantation therapy in patients with cancer. tion, an immunomodulatory compound of the invention is An immunomodulatory compound of the invention can administered daily in a single or divided doses in a four to six work in combination with transplantation therapy reducing 45 week cycle with a rest period of about a week or two weeks. complications associated with the invasive procedure of The invention further allows the frequency, number, and transplantation and risk of GVHD. This invention encom­ length of dosing cycles to be increased. Thus, another specific passes a method of treating, preventing and/or managing embodiment of the invention encompasses the administration cancer which comprises administering to a patient (e.g., a of an immunomodulatory compound of the invention for human) an immunomodulatory compound of the invention, 50 more cycles than are typical when it is administered alone. In or a pharmaceutically acceptable salt, solvate, hydrate, stere­ yet another specific embodiment of the invention, an immu- nomodulatory compound of the invention is administered for oisomer, clathrate, or prodrug thereof, before, during, or after a greater number of cycles that would typically cause dose­ the transplantation of umbilical cord blood, placental blood, limiting toxicity in a patient to whom a second active ingre­ peripheral blood stem cell, hematopoietic stem cell prepara- 55 dient is not also being administered. tion or bone marrow. Examples of stem cells suitable for use In one embodiment, an immunomodulatory compound of in the methods of the invention are disclosed in U.S. provi­ the invention is administered daily and continuously for three sional patent application No. 60/372,348, filed Apr. 12, 2002 or four weeks at a dose of from about 0.1 to about 150 mg/d by R. Hariri et al., the entirety of which is incorporated herein followed by a break of one or two weeks. Actimid™ is pref- by reference. 60 erably administered daily and continuously at an initial dose In one embodiment of this method, an immunomodulatory of0.1 to 5 mg/d with dose escalation (every week) by 1 to 10 compound of the invention is administered to patients with mg/d to a maximum dose of 50 mg/d for as long as therapy is multiple myeloma before, during, or after the transplantation tolerated. In a particular embodiment, Revimid™ is admin- of autologous peripheral blood progenitor cell. istered in an amount of about 5, 10, or 25 mg/day, preferably In another embodiment, an immunomodulatory compound 65 in an amount of about 10 mg/day for three to four weeks, is administered to patients with relapsing multiple myeloma followed by one week or two weeks of rest in a four or six after the stem cell transplantation. week cycle. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 70 of 148 PageID: 70

US 8,673,939 B2 25 26 In one embodiment of the invention, an immunomodula­ specific dosage forms encompassed by this invention will tory compound of the invention and a second active ingredi­ vary from one another will be readily apparent to those skilled ent are administered orally, with administration of an immu­ in the art. See, e.g., Remington's Pharmaceutical Sciences, nomodulatory compound of the invention occurring 30 to 60 18th ed., Mack Publishing, Easton Pa. (1990). minutes prior to a second active ingredient, during a cycle of 5 Typical pharmaceutical compositions and dosage forms four to six weeks. In another embodiment ofthe invention, the comprise one or more excipients. Suitable excipients are well combination of an immunomodulatory compound of the known to those skilled in the art of pharmacy, and non­ invention and a second active ingredient is administered by limiting examples of suitable excipients are provided herein. intravenous infusion over about 90 minutes every cycle. In a Whether a particular excipient is suitable for incorporation specific embodiment, one cycle comprises the administration 10 into a pharmaceutical composition or dosage form depends of from about 10 to about 25 mg/day ofRevimid™ and from on a variety of factors well known in the art including, but not about 50 to about 200 mg/m2/day of a second active ingredi­ limited to, the way in which the dosage form will be admin­ ent daily for three to four weeks and then one or two weeks of rest. In another specific embodiment, each cycle comprises istered to a patient. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral the administration of from about 5 to about 10 mg/day of 15 Actimid™ and from about 50 to about 200 mg/m2/day of a dosage forms. The suitability of a particular excipient may second active ingredient for 3 to 4 weeks followed by one or also depend on the specific active ingredients in the dosage two weeks of rest. Typically, the number of cycles during form. For example, the decomposition of some active ingre­ which the combinatorial treatment is administered to a patient dients may be accelerated by some excipients such as lactose, will be from about one to about 24 cycles, more typically from 20 or when exposed to water. Active ingredients that comprise about two to about 16 cycles, and even more typically from primary or secondary amines are particularly susceptible to about four to about three cycles. such accelerated decomposition. Consequently, this inven­ 5.4 Pharmaceutical Compositions and Dosage Forms tion encompasses pharmaceutical compositions and dosage Pharmaceutical compositions can be used in the prepara­ forms that contain little, if any, lactose other mono- or di- tion of individual, single unit dosage forms. Pharmaceutical 25 saccharides. As used herein, the term "lactose-free" means compositions and dosage forms of the invention comprise an that the amount of lactose present, if any, is insufficient to immunomodulatory compound of the invention, or a pharma­ substantially increase the degradation rate of an active ingre­ ceutically acceptable salt, solvate, hydrate, stereoisomer, dient. clathrate, or prodrug thereof. Pharmaceutical compositions Lactose-free compositions of the invention can comprise and dosage forms of the invention can further comprise one or 30 excipients that are well known in the art and are listed, for more excipients. example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). Pharmaceutical compositions and dosage forms of the In general, lactose-free compositions comprise active ingre­ invention can also comprise one or more additional active dients, a binder/filler, and a lubricant in pharmaceutically ingredients. Consequently, pharmaceutical compositions and compatible and pharmaceutically acceptable amounts. Pre­ dosage forms of the invention comprise the active ingredients 35 disclosed herein (e.g., an immunomodulatory compound and ferred lactose-free dosage forms comprise active ingredients, a second active agent). Examples of optional second, or addi­ microcrystalline cellulose, pre-gelatinized starch, and mag­ tional, active ingredients are disclosed herein (see, e.g., sec­ nesium stearate. tion 5.2). This invention further encompasses anhydrous pharma­ Single unit dosage forms of the invention are suitable for 40 ceutical compositions and dosage forms comprising active oral, mucosa! ( e.g., nasal, sub lingual, vaginal, buccal, or rec­ ingredients, since water can facilitate the degradation of some tal), parenteral (e.g., subcutaneous, intravenous, bolus injec­ compounds. For example, the addition of water (e.g., 5%) is tion, intramuscular, or intraarterial), topical (e.g., eye drops or widely accepted in the pharmaceutical arts as a means of other ophthalmic preparations), transdermal or transcutane­ simulating long-term storage in order to determine character- ous administration to a patient. Examples of dosage forms 45 istics such as shelf-life or the stability of formulations over include, but are not limited to: tablets; caplets; capsules, such time. See, e.g., Jens T. Carstensen, Drug Stability: Principles as soft elastic gelatin capsules; cachets; troches; lozenges; & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. dispersions; suppositories; powders; aerosols (e.g., nasal 379-80. In effect, water and heat accelerate the decomposi­ sprays or inhalers); gels; liquid dosage forms suitable for oral tion of some compounds. Thus, the effect of water on a or mucosa! administration to a patient, including suspensions 50 formulation can be of great significance since moisture and/or (e.g., aqueous or non-aqueous liquid suspensions, oil-in-wa- humidity are commonly encountered during manufacture, ter emulsions, or a water-in-oil liquid emulsions), solutions, handling, packaging, storage, shipment, and use of formula­ and elixirs; liquid dosage forms suitable for parenteral admin­ tions. istration to a patient; eye drops or other ophthalmic prepara­ Anhydrous pharmaceutical compositions and dosage tions suitable for topical administration; and sterile solids 55 forms of the invention can be prepared using anhydrous or (e.g., crystalline or amorphous solids) that can be reconsti­ low moisture containing ingredients and low moisture or low tuted to provide liquid dosage forms suitable for parenteral humidity conditions. Pharmaceutical compositions and dos­ administration to a patient. age forms that comprise lactose and at least one active ingre­ The composition, shape, and type of dosage forms of the dient that comprises a primary or secondary amine are pref- invention will typically vary depending on their use. For 60 erably anhydrous if substantial contact with moisture and/or example, a dosage form used in the acute treatment of a humidity during manufacturing, packaging, and/or storage is disease may contain larger amounts of one or more of the expected. active ingredients it comprises than a dosage form used in the An anhydrous pharmaceutical composition should be pre­ chronic treatment of the same disease. Similarly, a parenteral pared and stored such that its anhydrous nature is maintained. dosage form may contain smaller amounts of one or more of 65 Accordingly, anhydrous compositions are preferably pack­ the active ingredients it comprises than an oral dosage form aged using materials known to prevent exposure to water such used to treat the same disease. These and other ways in which that they can be included in suitable formulary kits. Examples Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 71 of 148 PageID: 71

US 8,673,939 B2 27 28 of suitable packaging include, but are not limited to, hermeti­ mately admixing the active ingredients with liquid carriers, cally sealed foils, plastics, unit dose containers (e.g., vials), finely divided solid carriers, or both, and then shaping the blister packs, and strip packs. product into the desired presentation if necessary. The invention further encompasses pharmaceutical com­ For example, a tablet can be prepared by compression or positions and dosage forms that comprise one or more com­ 5 molding. Compressed tablets can be prepared by compress­ pounds that reduce the rate by which an active ingredient will ing in a suitable machine the active ingredients in a free­ decompose. Such compounds, which are referred to herein as flowing form such as powder or granules, optionally mixed "stabilizers," include, but are not limited to, antioxidants such with an excipient. Molded tablets can be made by molding in as ascorbic acid, pH buffers, or salt buffers. a suitable machine a mixture of the powdered compound Like the amounts and types of excipients, the amounts and 10 moistened with an inert liquid diluent. specific types of active ingredients in a dosage form may Examples of excipients that can be used in oral dosage differ depending on factors such as, but not limited to, the forms of the invention include, but are not limited to, binders, route by which it is to be administered to patients. However, fillers, disintegrants, and lubricants. Binders suitable for use typical dosage forms of the invention comprise an immuno­ in pharmaceutical compositions and dosage forms include, modulatory compound of the invention or a pharmaceutically 15 but are not limited to, corn starch, potato starch, or other acceptable salt, solvate, hydrate, stereoisomer, clathrate, or starches, gelatin, natural and synthetic gums such as acacia, prodrug thereof in an amount of from about 0.10 to about 150 sodium alginate, alginic acid, other alginates, powdered mg. Typical dosage forms comprise an immunomodulatory tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl compound of the invention or a pharmaceutically acceptable cellulose, cellulose acetate, carboxymethyl cellulose cal- salt, solvate, hydrate, stereoisomer, clathrate, or prodrug 20 cium, sodium carboxymethyl cellulose), polyvinyl pyrroli­ thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, done, methyl cellulose, pre-gelatinized starch, hydroxypro­ 17.5, 20, 25, 50, 100, 150 or 200 mg. Ina particular embodi­ pyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), ment, a preferred dosage form comprises 4-(amino )-2-(2,6- microcrystalline cellulose, and mixtures thereof. dioxo(3-piperidyl))-isoindoline-l,3-dione (Actimid™) in an Suitable forms of microcrystalline cellulose include, but amount of about 1, 2, 5, 10, 25 or 50 mg. In a specific 25 are not limited to, the materials sold as AVICEL-PH-101, embodiment, a preferred dosage form comprises 3-(4-amino­ AVICEL-PH-103AVICELRC-581,AVICEL-PH-105 (avail­ l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Re­ able from FMC Corporation, American Viscose Division, vimid™) in an amount of about 5, 10, 25 or 50 mg. Typical Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. An dosage forms comprise the second active ingredient in an specific binder is a mixture of microcrystalline cellulose and amount of 1 to about 1000 mg, from about 5 to about 500 mg, 30 sodium carboxymethyl cellulose sold as AVICEL RC-581. from about 10 to about 350 mg, or from about 50 to about 200 Suitable anhydrous or low moisture excipients or additives mg. Of course, the specific amount of the anti-cancer drug includeAVICEL-PH-103™ and Starch 1500 LM. will depend on the specific agent used, the type of cancer Examples of fillers suitable for use in the pharmaceutical being treated or managed, and the amount(s) of an immuno­ compositions and dosage forms disclosed herein include, but modulatory compound of the invention and any optional 35 are not limited to, talc, calcium carbonate (e.g., granules or additional active agents concurrently administered to the powder), microcrystalline cellulose, powdered cellulose, patient. dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre­ 5.4.1 Oral Dosage Forms gelatinized starch, and mixtures thereof. The binder or filler in Pharmaceutical compositions of the invention that are suit­ pharmaceutical compositions of the invention is typically able for oral administration can be presented as discrete dos- 40 present in from about 50 to about 99 weight percent of the age forms, such as, but are not limited to, tablets (e.g., chew­ pharmaceutical composition or dosage form. able tablets), caplets, capsules, and liquids (e.g., flavored Disintegrants are used in the compositions of the invention syrups). Such dosage forms contain predetermined amounts to provide tablets that disintegrate when exposed to an aque­ of active ingredients, and may be prepared by methods of ous environment. Tablets that contain too much disintegrant pharmacy well known to those skilled in the art. See gener- 45 may disintegrate in storage, while those that contain too little ally, Remington's Pharmaceutical Sciences, 18th ed., Mack may not disintegrate at a desired rate or under the desired Publishing, Easton Pa. (1990). conditions. Thus, a sufficient amount of disintegrant that is Typical oral dosage forms of the invention are prepared by neither too much nor too little to detrimentally alter the combining the active ingredients in an intimate admixture release of the active ingredients should be used to form solid with at least one excipient according to conventional pharma- 50 oral dosage forms of the invention. The amount of disinte­ ceutical compounding techniques. Excipients can take a wide grant used varies based upon the type of formulation, and is variety of forms depending on the form of preparation desired readily discernible to those of ordinary skill in the art. Typical for administration. For example, excipients suitable for use in pharmaceutical compositions comprise from about 0.5 to oral liquid or aerosol dosage forms include, but are not limited about 15 weight percent of disintegrant, preferably from to, water, glycols, oils, alcohols, flavoring agents, preserva- 55 about 1 to about 5 weight percent of disintegrant. tives, and coloring agents. Examples of excipients suitable for Disintegrants that can be used in pharmaceutical compo­ use in solid oral dosage forms (e.g., powders, tablets, cap­ sitions and dosage forms of the invention include, but are not sules, and caplets) include, but are not limited to, starches, limited to, agar-agar, alginic acid, calcium carbonate, micro­ sugars, micro-crystalline cellulose, diluents, granulating crystalline cellulose, croscarmellose sodium, crospovidone, agents, lubricants, binders, and disintegrating agents. 60 polacrilin potassium, sodium starch glycolate, potato or tapi­ Because of their ease of administration, tablets and cap­ oca starch, other starches, pre-gelatinized starch, other sules represent the most advantageous oral dosage unit forms, starches, clays, other al gins, other celluloses, gums, and mix­ in which case solid excipients are employed. If desired, tab­ tures thereof. lets can be coated by standard aqueous or nonaqueous tech­ Lubricants that can be used in pharmaceutical composi­ niques. Such dosage forms can be prepared by any of the 65 tions and dosage forms of the invention include, but are not methods of pharmacy. In general, pharmaceutical composi­ limited to, calcium stearate, magnesium stearate, mineral oil, tions and dosage forms are prepared by uniformly and inti- light mineral oil, glycerin, sorbitol, mannitol, polyethylene Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 72 of 148 PageID: 72

US 8,673,939 B2 29 30 glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, 5.4.3 Parenteral Dosage Forms hydrogenated vegetable oil ( e.g., peanut oil, cottonseed oil, Parenteral dosage forms can be administered to patients by sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), various routes including, but not limited to, subcutaneous, zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures intravenous (including bolus injection), intramuscular, and thereof. Additional lubricants include, for example, a syloid 5 intraarterial. Because their administration typically bypasses silica gel (AEROSIL200, manufactured by W.R. Grace Co. of patients' natural defenses against contaminants, parenteral Baltimore, Md.), a coagulated aerosol of synthetic silica dosage forms are preferably sterile or capable of being ster­ (marketed by Degussa Co. of Plano, Tex.), CAB-0-SIL (a ilized prior to administration to a patient. Examples of pyrogenic silicon dioxide product sold by Cabot Co. of Bos­ parenteral dosage forms include, but are not limited to, solu­ 10 tions ready for injection, dry products ready to be dissolved or ton, Mass.), and mixtures thereof. If used at all, lubricants are suspended in a pharmaceutically acceptable vehicle for injec- typically used in an amount of less than about 1 weight tion, suspensions ready for injection, and emulsions. percent of the pharmaceutical compositions or dosage forms Suitable vehicles that can be used to provide parenteral into which they are incorporated. dosage forms of the invention are well known to those skilled A preferred solid oral dosage form of the invention com- 15 in the art. Examples include, but are not limited to: Water for prises an immunomodulatory compound of the invention, Injection USP; aqueous vehicles such as, but not limited to, anhydrous lactose, microcrystalline cellulose, polyvinylpyr­ Sodium Chloride Injection, Ringer's Injection, Dextrose rolidone, stearic acid, colloidal anhydrous silica, and gelatin. Injection, Dextrose and Sodium Chloride Injection, and Lac­ 5.4.2 Delayed Release Dosage Forms tated Ringer's Injection; water-miscible vehicles such as, but Active ingredients of the invention can be administered by 20 not limited to, ethyl alcohol, polyethylene glycol, and controlled release means or by delivery devices that are well polypropylene glycol; and non-aqueous vehicles such as, but known to those of ordinary skill in the art. Examples include, not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, but are not limited to, those described in U.S. Pat. Nos. 3,845, ethyl oleate, isopropyl myristate, and benzyl benzoate. 770; 3,916,899; 3,536,809; 3,598,123; and4,008,719, 5,674, Compounds that increase the solubility of one or more of 533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 25 the active ingredients disclosed herein can also be incorpo­ 5,354,556, and 5,733,566, each of which is incorporated rated into the parenteral dosage forms of the invention. For herein by reference. Such dosage forms can be used to pro­ example, cyclodextrin and its derivatives can be used to vide slow or controlled-release of one or more active ingre­ increase the solubility of an immunomodulatory compound dients using, for example, hydropropylmethyl cellulose, of the invention and its derivatives. See, e.g., U.S. Pat. No. otherpolymermatrices, gels, permeable membranes, osmotic 30 5,134,127, which is incorporated herein by reference. 5.4.4 Topical and Mucosa! Dosage Forms systems, multilayer coatings, microparticles, liposomes, Topical and mucosa! dosage forms of the invention microspheres, or a combination thereof to provide the desired include, but are not limited to, sprays, aerosols, solutions, release profile in varying proportions. Suitable controlled­ emulsions, suspensions, eye drops or other ophthalmic prepa- release formulations known to those of ordinary skill in the 35 rations, or other forms known to one of skill in the art. See, art, including those described herein, can be readily selected e.g., Remington's Pharmaceutical Sciences, 16th and 18th for use with the active ingredients ofthe invention. The inven­ eds., Mack Publishing, Easton Pa. (1980 & 1990); and Intro­ tion thus encompasses single unit dosage forms suitable for duction to Pharmaceutical Dosage Forms, 4th ed., Lea & oral administration such as, but not limited to, tablets, cap­ Febiger, Philadelphia (1985). Dosage forms suitable fortreat- sules, gelcaps, and caplets that are adapted for controlled­ 40 ing mucosa! tissues within the oral cavity can be formulated release. as mouthwashes or as oral gels. All controlled-release pharmaceutical products have a Suitable excipients (e.g., carriers and diluents) and other common goal of improving drug therapy over that achieved materials that can be used to provide topical and mucosa! by their non-controlled counterparts. Ideally, the use of an dosage forms encompassed by this invention are well known optimally designed controlled-release preparation in medical 45 to those skilled in the pharmaceutical arts, and depend on the treatment is characterized by a minimum of drug substance particular tissue to which a given pharmaceutical composi­ being employed to cure or control the condition in a minimum tion or dosage form will be applied. With that fact in mind, amount of time. Advantages of controlled-release formula­ typical excipients include, but are not limited to, water, tions include extended activity of the drug, reduced dosage acetone, ethanol, ethylene glycol, propylene glycol, butane- frequency, and increased patient compliance. In addition, 50 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral controlled-release formulations can be used to affect the time oil, and mixtures thereof to form solutions, emulsions or gels, of onset of action or other characteristics, such as blood levels which are non-toxic and pharmaceutically acceptable. Mois­ of the drug, and can thus affect the occurrence of side ( e.g., turizers or humectants can also be added to pharmaceutical adverse) effects. compositions and dosage forms if desired. Examples of such Most controlled-release formulations are designed to ini­ 55 additional ingredients are well known in the art. See, e.g., tially release an amount of drug (active ingredient) that Remington's Pharmaceutical Sciences, 16th and 18th eds., promptly produces the desired therapeutic effect, and gradu­ Mack Publishing, Easton Pa. (1980 & 1990). ally and continually release of other amounts of drug to main­ The pH of a pharmaceutical composition or dosage form tain this level of therapeutic or prophylactic effect over an may also be adjusted to improve delivery of one or more extended period of time. In order to maintain this constant 60 active ingredients. Similarly, the polarity of a solvent carrier, level of drug in the body, the drug must be released from the its ionic strength, or tonicity can be adjusted to improve dosage form at a rate that will replace the amount of drug delivery. Compounds such as stearates can also be added to being metabolized and excreted from the body. Controlled­ pharmaceutical compositions or dosage forms to advanta­ release of an active ingredient can be stimulated by various geously alter the hydrophilicity or lipophilicity of one or conditions including, but not limited to, pH, temperature, 65 more active ingredients so as to improve delivery. In this enzymes, water, or other physiological conditions or com­ regard, stearates can serve as a lipid vehicle for the formula­ pounds. tion, as an emulsifying agent or surfactant, and as a delivery- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 73 of 148 PageID: 73

US 8,673,939 B2 31 32 enhancing or penetration-enhancing agent. Different salts, human whole blood were -24 nM (6.55 ng/mL) and-25 nM hydrates or solvates of the active ingredients can be used to (6.83 ng/mL), respectively. In vitro studies suggest a pharma­ further adjust the properties of the resulting composition. cological activity profile for 3-(4-amino-l-oxo-l ,3-dihydro­ 5.4.5 Kits isoindol-2-yl)-piperidine-2,6-dione that is similar to, but at Typically, active ingredients of the invention are preferably 5 least 200 times more potent than, thalidomide. In vitro studies not administered to a patient at the same time or by the same have also demonstrated that concentrations of 4-(amino )-2- route of administration. This invention therefore encom­ (2,6-dioxo(3-piperidyl))-isoindoline-l,3-dione of 2.73 to passes kits which, when used by the medical practitioner, can 27.3 ng/mL (0.01 to 0.1 µM) achieved 50% inhibition of the simplify the administration of appropriate amounts of active proliferation of MM.IS and Hs Sultan cells. ingredients to a patient. 10 The IC50's of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2- A typical kit of the invention comprises a dosage form of an yl)-piperidine-2,6-dione for inhibiting production of TNF­ immunomodulatory compound of the invention, or a pharma­ afollowing LPS-stimulation of PBMC and human whole ceutically acceptable salt, solvate, hydrate, stereoisomer, pro­ blood were -100 nM (25.9 ng/mL) and -480 nM (103.6 drug, or clathrate thereof. Kits encompassed by this invention ng/mL ), respectively. Thalidomide, in contrast, had an IC50 of can further comprise additional active ingredients such as 15 -194 µM (50.2 µg/mL) for inhibiting production ofTNF-a oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, following LPS-stimulation of PBMC. In vitro studies suggest EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, a pharmacological activity profile for 3-(4-amino-l-oxo-l ,3- COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexametha­ dihydro-isoindol-2-yl)-piperidine-2,6-dione that is similar sone, IL2, IL8, IL 18, Ara-C, vinorelbine, isotretinoin, 13 to, but 50 to 2000 times more potent than, thalidomide. It has cis-retinoic acid, or a pharmacologically active mutant or 20 been shown that the compound is approximately 50-100 derivative thereof, or a combination thereof. Examples of the times more potent than thalidomide in stimulating the prolif­ additional active ingredients include, but are not limited to, eration of T-cells following primary induction by T-cell those disclosed herein (see, e.g., section 5.2). receptor (TCR) activation. 3-(4-amino-l-oxo-l ,3-dihydro­ Kits of the invention can further comprise devices that are isoindol-2-yl)-piperidine-2,6-dione is also approximately 50 used to administer the active ingredients. Examples of such 25 to 100 times more potent than thalidomide in augmenting the devices include, but are not limited to, syringes, drip bags, production of IL-2 and IFN-y following TCR activation of patches, and inhalers. PBMC (IL-2) or T-cells (IFN-y). In addition, 3-(4-amino-l­ Kits of the invention can further comprise cells or blood for oxo-l,3-dihydro-isoindol-2-yl )-piperidine-2,6-dione exhib­ transplantation as well as pharmaceutically acceptable ited dose-dependent inhibition ofLPS-stimulated production vehicles that can be used to administer one or more active 30 of the pro-inflanmiatory cytokines TNF-a, IL-1 ~' and IL-6 ingredients. For example, if an active ingredient is provided in by PBMC while it increased production of the anti-inflam­ a solid form that must be reconstituted for parenteral admin­ matory cytokine IL-10. istration, the kit can comprise a sealed container of a suitable 6.2 Inhibition of Mm Cell Proliferation vehicle in which the active ingredient can be dissolved to The ability of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2- form a particulate-free sterile solution that is suitable for 35 yl)-piperidine-2,6-dione (Revimid™) and thalidomide for parenteral administration. Examples of pharmaceutically comparison to effect the proliferation of MM cell lines has acceptable vehicles include, but are not limited to: Water for been investigated in an in vitro study. Uptake [3 H]-thymidine Injection USP; aqueous vehicles such as, but not limited to, by different MM cell lines (MM.IS, Hs Sultan, U266 and Sodium Chloride Injection, Ringer's Injection, Dextrose RPMI-8226) was measured as an indicator of cell prolifera- Injection, Dextrose and Sodium Chloride Injection, and Lac- 40 tion. Cells were incubated in the presence of compounds for tated Ringer's Injection; water-miscible vehicles such as, but 48 hours; [3 H]-thymidine was included for the last 8 hours of not limited to, ethyl alcohol, polyethylene glycol, and the incubation period. Addition of 3-(4-amino-l-oxo-l ,3-di­ polypropylene glycol; and non-aqueous vehicles such as, but hydro-isoindol-2-yl)-piperidine-2,6-dione to MM.IS and Hs not limited to, com oil, cottonseed oil, peanut oil, sesame oil, Sultan cells resulted in 50% inhibition of cell proliferation at ethyl oleate, isopropyl myristate, and benzyl benzoate. 45 concentrations of0.4 µm and 1 µm, respectively. In contrast, addition of thalidomide at concentrations up to 100 µm 6. EXAMPLES resulted in only 15% and 20% inhibition of cell proliferation in MM.IS and Hs Sultan cells, respectively. These data are Certain embodiments of the invention are illustrated by the sUlllillarized in FIG. 1. following non-limiting examples. 50 6.3 Toxicology Studies 6.1 Modulation of Cytokine Production The effects of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2- A series of non-clinical pharmacology and toxicology yl)-piperidine-2,6-dione (Revimid™) on cardiovascular and studies have been performed to support the clinical evaluation respiratory function are investigated in anesthetized dogs. of an immunomodulatory compound of the invention in Two groups ofBeagle dogs (2/sex/group) are used. One group human subjects. These studies were performed in accordance 55 receives three doses of vehicle only and the other receives with internationally recognized guidelines for study design three ascending doses of 3-(4-amino-l-oxo-l ,3-dihydro­ and in compliance with the requirements of Good Laboratory isoindol-2-yl)-piperidine-2,6-dione (2, 10, and 20 mg/kg). In Practice (GLP), unless otherwise noted. all cases, doses of3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2- Inhibition of TNF-a production following LPS-stimula­ yl)-piperidine-2,6-dione or vehicle are successively adminis- tion of human PBMC and human whole blood by 4-( amino)- 60 tered via infusion through the jugular vein separated by inter­ 2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione (Ac­ vals of at least 30 minutes. timid™), 3-(4-amino- l-oxo-l ,3-dihydro-isoindol-2-yl)­ The cardiovascular and respiratory changes induced by piperidine-2,6-dione and thalidomide (Revimid™) was 3-( 4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2, investigated in vitro (Muller et al., Bioorg. Med. Chem. Lett. 6-dione are minimal at all doses when compared to the

9:1625-1630, 1999). The IC50's of 4-(amino)-2-(2,6-dioxo 65 vehicle control group. The only statistically significant dif­ (3-piperidyl))-isoindoline-1,3-dione for inhibiting produc­ ference between the vehicle and treatment groups is a small tion of TNF-afollowing LPS-stimulation of PBMC and increase in arterial blood pressure (from 94 mmHg to 101 Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 74 of 148 PageID: 74

US 8,673,939 B2 33 34 mmHg) following administration of the low dose of 3-(4- fashion until the MTD is established or the maximum daily amino-l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-di­ dose (10 mg/day) is attained. However, if one of the three one. This effect lasts approximately 15 minutes and is not additional patients enrolled experiences DLT, the MTD has seen at higher doses. Deviations in femoral blood flow, res­ been reached. If two or more of the three additional patients piratory parameters, and Qtc interval are common to both the 5 enrolled experience DLT, the MTD is judged to have been control and treated groups and are not considered treatment­ exceeded and three additional patients are enrolled at the related. preceding dose level to confirm the MTD. Once the MTD has 6.4 Cycling Therapy in Patients been identified, four additional patients are enrolled at that In a specific embodiment, an immunomodulatory com­ dose level so that a total of 10 patients is treated at the MTD. pound of the invention are cyclically administered to patients 10 with cancer. Cycling therapy involves the administration of a Blood sampling for analysis of pharmacokinctic param­ first agent for a period of time, followed by a rest for a period eters is performed on Days 1 and 28 according to the follow­ of time and repeating this sequential administration. Cycling ing sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, therapy can reduce the development of resistance to one or 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. An additional more of the therapies, avoid or reduce the side effects of one 15 blood sample is collected at each weekly visit for the deter­ ofthe therapies, and/or improves the efficacy ofthe treatment. mination of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindo­ In a specific embodiment, prophylactic or therapeutic line-l,3-dione levels. Total urine collections are also made agents are administered in a cycle of about 4 to 6 weeks, about with urine pooled according to the following time intervals once or twice every day. One cycle can comprise the admin­ post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours. Safety istration of a therapeutic on prophylactic agent for three to 20 assessments are made by monitoring adverse events, vital four weeks and at least a week or two weeks of rest. The signs, ECGs, clinical laboratory evaluations (blood chemis­ number of cycles administered is from about one to about 24 try, hematology, lymphocyte phenotyping, and urinalysis), cycles, more typically from about two to about 16 cycles, and and physical examination at specific times during the study. more typically from about four to about eight cycles. For example, ina cycle of four weeks, on day 1, theadmin- 25 Results of interim pharmacokinetic analyses obtained fol- istration of 25 mg/d of 3-(4-amino-l-oxo-l ,3-dihydro-isoin­ lowing single- and multiple-dose administration of dol-2-yl)-piperidine-2,6-dione is started. On day 22, the 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione administration of the compound is stopped for a week of rest. to multiple myeloma patients are presented below in Tables 1 On day 29, the administration of25 mg/d 3-(4-amino-l-oxo- and 2. These data show that 4-(amino)-2-(2,6-dioxo(3-pip- 1,3-dihydro-isoindol-2-yl)-piperidin-2,6-dione is begun. 30 eridyl))-isoindoline-1,3-dione was steadily absorbed at all 6.5 Clinical Studies in Patients dose levels in relapsed multiple myeloma patients. Maximum 6.5.1 Treatment of Relapsed Multiple Myeloma plasma concentrations occurred at a median T max of between 4-(amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1,3-di- 2.5 and 2.8 hours post-dose at Day 1 and between 3 and 4 one (Actimid™) was administered to patients with relapsed/ hours post-dose at Week 4. At all doses, plasma concentra­ refractory multiple myeloma. The study was conducted in 35 tions declined in a monophasic manner after reaching C. The compliance with Good Clinical Practices. Patients were at start of the elimination phase occurred between 3 and 10 least 18 years old, had been diagnosed with multiple hours post-dose at Day 1 and Week 4, respectively. myeloma (with paraprotein in seruni and/or urine), and were considered refractory to treatment after at least two cycles of These data also showed that after 4 weeks of dosing, treatment, or have relapsed after two cycles of treatment. 40 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione Patients who have progressive disease, according to the accumulated to a small extent (mean accumulation ratios Southwest Oncology Group (SWOG) criteria, on their prior -1.02 to 1.52 and-0.94 to 1.62 forCmax andAUCco-,;), respec­ regimen are considered treatment refractory. Relapse follow­ tively). There was almost a dose proportional increase in ing remission is defined as >25% increase in M component AUCco-,;) and Cmax values with increasing dose. A five-fold from baseline levels; reappearance of the M paraprotein that 45 higher dose of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoin­ had previously disappeared; or a definite increase in the size doline-l,3-dione produced a 3.2- and 2.2-fold increase in and number oflytic bone lesions recognized on radiographs. Cmax at Day 1 and Week 4, respectively. Similarly, a 5-fold Patients may have had prior therapy with thalidomide, pro­ increase in dose resulted in a 3.6- and 2.3-fold increase in vided they were able to tolerate the treatment. A Zubrod AUCco-,;), at Day 1 and Week 4, respectively. performance status ofO to 2 is required for all patients. 50 4-(amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1,3-di­ TABLE 1 one is administered to patients at doses of!, 2, 5, or lOmg/day Pharmacokinetic parameters of Actimid TM for up to four weeks; at each dose level, three patients are in relapsed multiple myeloma patients initially enrolled. Dosing occurs at approximately the same time each morning; all doses are administered in the fasted 55 1mg 2mg 5mg state (no eating for at least two hours prior to dosing and two Parameter (N- 6) (N-2) (N-3) hours after dosing). 4-(amino)-2-(2,6-dioxo(3-piperidyl))­ Day 1 isoindoline-l,3-dione doses are administered in an ascending fashion such that patients in the first cohort receive the lowest cm= ng/mL 15.03 (4.04) 24.4* (12.1) 48.56 (14.03) dose of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l, 60 Im= h 3.3 (2.6) 2.7* (0.3) 2.3 3-dione (1 mg/day) and escalation to the next higher dose (0.3) level occurs only following the establishment of safety and AUC(O-oo) ng ·h/mL 152.90 (36.62) 279.18 (51.10) 593.10 tolerability at the current dose. If one out of three patients at (335.23) any dose level experience dose limiting toxicity (DLT), three AUC(O-c) 134.21 (27.14) 249.57 (29.26) 520.94 (267.32) additional patients are enrolled at that dose. If none of the 65 !1/2 h 7.3 (3.4) 6.3 (1.4) 6.5 three additional patients experience DLT, escalation to the (2.2) next dose level occurs; dose escalations continue in a similar Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 75 of 148 PageID: 75

US 8,673,939 B2 35 36 TABLE I-continued schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. In addition, a blood sample Pharmacokinetic parameters of Actimid TM was collected at each weekly clinic visit for 3-( 4-amino-l­ in relapsed multiple myeloma patients oxo-1,3-dihydro-isoindol-2-yl )-piperidine-2,6-dione deter- 1mg 2mg 5mg 5 mination. Total urine was collected and pooled according to Parameter (N- 6) (N-2) (N-3) the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours. Response to treatment was assessed by CL/F mL/min 114.75 (29.20) 121.43 (22.22) 182.31 (117.06) M-protein quantification (by immunoelectrophoresis) from Vz/f L 69.55 (44.97) 65.31 (2.80) 87.24 serum and a 24-hour urine collection, with creatinine clear- (22.61) 10 ance and 24-hour protein calculations undertaken at screen­ ing, baseline, Weeks 2 and 4, and monthly thereafter (or upon t = 24hours NIA= not available early termination). Bone marrow aspirations and/or tissue biopsy are also performed at Months 3, 6 and 12 if a patient's paraprotein serum concentration or 24-hour urine protein TABLE2 15 excretion declined to the next lower level, based on best response criteria. Preliminary results for the 28-day treatment Pharmacokinetic parameters of Actimid TM following multiple period are summarized below. oral doses (1, 2, and 5 mg/day) in relapsed multiple myeloma patients Preliminary pharmacokinetic analyses based on these two 1mg 2mg 5mg studies indicated that AUC and Cmax values increase propor- Parameter (N-5) (N-2) (N-3) 20 tionally with dose following single and multiple doses in Week4 multiple myeloma patients (as was seen in healthy volun­ teers). Further, there was no evidence of accumulation with cm= ng/mL 23.20 (7.48) 30.05* (15.64) 58.07 multiple dosing as single dose AUCco-=) was comparable to (38.08) multiple doseAUC _.,, following the same dose of3-(4-amino- tm= h 3.6 (1.5) 2.8* (0.3) 5.0 0 (2.6) 25 l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. AUC(O-oo) ng · h/mL NIA NIA NIA Similar to healthy volunteer studies, double peaks were AUC(O-c) 239.31 (122.59) 269.36 (186.34) 597.24 observed. Exposure inmultiplemyeloma patients appeared to (354.23) be slightly higher based on Cmax andAUC values as compared t1/2 h 6.2* (0.6) 7.7 (2.8) 7.8 (4.0) to healthy male volunteers while clearance in multiple CL/F mL/min 87.85 (48.48) 162.68 (112.54) 207.50 30 myeloma patients was lower than it was in healthy volunteers, (175.41) consistent with their poorer renal function (both as a conse­ Vz/f L 41.35* (8.84) 95.04 (35.39) 103.95 quence of their age and their disease). Finally, 3-( 4-amino-l­ (27.25) oxo-1,3-dihydro-isoindol-2-yl )-piperidine-2,6-dione half­ -r = 24hours live in patients was shorter than in healthy volunteers (mean 8 NIA= not available 35 hours, ranging up to 17 hours). *N = 3 patients In this study, the first cohort of3 patients was treated for 28 6.5.2 Treatment of Relapsed Multiple Myeloma days at 5 mg/day without any dose limiting toxicity (DLT). Two Phase 1 clinical studies of3-(4-amino-l-oxo-l,3-di­ The second cohort of 3 patients subsequently commenced therapy at 10 mg/day. Patients in the second 10 mg/day of hydro-isoindol-2-y l)-piperidine-2,6-dione (Revimid™) have 40 3-( 4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2, been conducted to identify the maximum tolerated dose 6-dione cohort tolerated treatment well. (MTD) in patients with refractory or relapsed multiple 6.5.3 Treatment of Solid Tumors myeloma. These studies have also characterized the safety Study with 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)­ profile of 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)-pip­ piperidine-2,6-dione (Revimid™) was conducted in patients eridine-2,6-dione when ascending doses of 3-( 4-amino-l­ 45 with varying types of solid tumors, including malignant mela­ oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione were noma (13), carcinoma of the pancreas (2), carcinoid-un­ given orally for up to 4 weeks. Patients started 3-(4-amino­ known primary (1 ), renal carcinoma (1 ), breast carcinoma (1) l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione treat­ and NSCLC (2). Patients received 5 mg/day 3-( 4-amino-l­ ment at 5 mg/day with subsequent escalation to 10, 25, and 50 oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for mg/day. Patients were enrolled for 28 days at their assigned 50 seven days and are subsequently escalated every seven days to dose, with the option of extended treatment for those who did 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks not exhibit disease progression or experience dose limiting of treatment. Patients who, experienced clinical benefit were toxicity (DLT). Patients were evaluated for adverse events at permitted to continue on treatment as Named Patients. each visit and the severity of these events was graded accord­ The study initially enrolled 20 patients and was subse- ing to the National Cancer Institute (NCI) Common Toxicity 55 quently amended to enroll 16 additional patients (adrenal Criteria. Patients were discontinued if they experienced DLT carcinoma, NSCLC, malignant mesothelioma, breast cancer, (Grade 3 or greater non-hematological, or Grade 4 hemato­ malignant melanoma (8), renal cell cancer (4)) at a higher logical toxicity). dose. The 16 additional patients were given weekly escalating In this study, 27 patients were enrolled. All patients had doses of25 mg/day, 50 mg/day, 75 mg/day, lOOmg/day, 125 relapsed multiple myeloma and 18 (72%) were refractory to 60 mg/day, and 150 mg/day over a 6-week period with continu­ salvage therapy. Among these patients, 15 had undergone ing treatment for an additional six weeks. prior autologous stem cell transplantation and 16 patients had The study of Phase 1 study was designed to determine a received prior thalidomide treatment. The median number of maximum tolerated dose (MTD) of 3-(4-amino-l-oxo-l,3- prior regimens was 3 (range 2 to 6). dihydro-isoindol-2-yl)-piperidine-2,6-dione in patients with Blood and urine samples were collected for analysis of 65 refractory solid tumors and/or lymphoma, as well as to char­ pharmacokinetic parameters on Days 1 and 28. Blood acterize the pharmacokinetic and side effect profiles of3-(4- samples were collected according to the following sampling amino-l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-di- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 76 of 148 PageID: 76

US 8,673,939 B2 37 38 one in this patient population. The study design dictates that at that particular dose level. If two DLTs occur, the MTD, at least 3 patients must be enrolled at a dose level and have defined as the dose at which fewer than one-third of patients completed 28 days oftreatment prior to enrollment ofpatients at each dose level experiences DLT has been exceeded and at the next higher dose level. Patients in the first cohort began four more patients are treated at the previous dose. dosing at 5 mg/day of3-(4-amino-l-oxo-l,3-dihydro-isoin- 5 Patients who experience DLT during the first 4-week cycle dol-2-yl)-piperidine-2,6-dione. Patients will be escalated to are removed from the study, except if they have a response to 10, 20, 25, and 30 mg/day provided there is no toxicity. therapy. For patients who have completed their first 4-week In this study, the MTD is defined as the highest dose level cycle of without DLT, but who subsequently experience in which fewer than two of six patients treated did not expe­ Grade 3 or 4 hematological and/or nonhematological toxicity, rience Grade 3 or greater non-hematological toxicity or 10 treatment is suspended for a minimum of a week. If the Grade 4 or greater hematological toxicity. If, at any given toxicity resolves to

US 8,673,939 B2 39 40 myeloma, from about 1 mg to about 5 mg per day of a 20. The method of claim 1, wherein the compound is orally compound having the formula: administered 4 mg per day on days 1 through 21 of repeated 28-day cycles until disease progression. 21. The method of claim 1, which further comprises admin- 5 istering a therapeutically effective amount of an additional active agent. 22. The method of claim 21, wherein the additional active agent is dexamethasone. 23. The method of claim 22, wherein 40 mg dexametha- 10 sane is administered. 24. The method of claim 22, wherein the dexamethasone is orally administered once daily on days 1, 8, 15 and 22 of a 28 day cycle. or a pharmaceutically acceptable salt, solvate or stereoiso­ 25. The method of claim 22, wherein the dexamethasone is mer thereof, wherein the compound is administered in orally administered once a week of a 28 day cycle. one or more cycles, each of which comprises adminis­ 15 26. A method of treating multiple myeloma, which com- tering the compound for a period of time followed by a prises administering to a patient having multiple myeloma, period of rest, wherein the multiple myeloma is and which patient has received previous therapy for multiple relapsed, refractory, or relapsed and refractory multiple myeloma and has demonstrated disease progression on the myeloma. previous therapy, from about 1 mg to about 5 mg per day of a 20 2. The method of claim 1, wherein the patient has demon­ compound having the formula: strated disease progression on the previous therapy. 3. The method of claim 1, wherein the previous therapy is treatment with thalidomide, a proteasome inhibitor, or a com­ bination thereof. 25 4. The method of claim 1, wherein the previous therapy is treatment with stem cell transplantation. 5. The method of claim 2, wherein the previous therapy is treatment with a proteasome inhibitor. 6. The method of claim 1, wherein the patient is 65 years or 30 younger. 7. The method of claim 1, wherein the patient is older than or a solvate thereof, wherein the compound is administered 65 years. in one or more cycles, each of which comprises admin­ istering the compound for a period of time followed by a 8. The method of claim 1, wherein the compound is admin­ period ofrest. istered in an amount of about 4 mg per day. 35 27. The method of claim 26, wherein the previous therapy 9. The method of claim 1, wherein the compound is admin­ istered in an amount of about 3 mg per day. is treatment with a proteasome inhibitor. 28. The method of claim 26, wherein the compound is 10. The method of claim 1, wherein the compound is administered in an amount of about 2 mg per day. administered in an amount of about 4 mg, 3 mg, 2 mg or 1 mg per day. 11. The method of claim 1, wherein the compound is 40 administered in an amount of about 1 mg per day. 29. The method of claim 26, wherein the compound is 12. The method of claim 1, wherein the compound is administered as a free base. administered as a free base. 30. The method of claim 26, wherein the compound is 13. The method of claim 1, wherein the compound is administered orally. 31. The method of claim 26, wherein the compound is administered orally. 45 14. The method of claim 1, wherein the compound is administered in a capsule. administered in a capsule. 32. The method claim 26, wherein the compound is admin­ 15. The method of claim 1, wherein the compound is istered for 21 consecutive days followed by seven consecutive administered in a tablet. days of rest in a 28 day cycle. 33. The method of claim 26, which further comprises 16. The method of claim 14, wherein the capsule comprises 50 the compound, mannitol and pre-gelatinized starch. administering a therapeutically effective amount of dexam­ 17. The method of claim 1, wherein the compound is ethasone. administered orally in a capsule of 1 mg, 2 mg, 3 mg, or 4 mg. 34. The method of claim 33, wherein 40 mg dexametha­ 18. The method of claim 1, wherein one cycle comprises sone is administered. 35. The method of claim 33, wherein the dexamethasone is four to six weeks. 55 19. The method of claim 1, wherein the compound is orally administered once daily on days 1, 8, 15 and 22 of a 28 administered for 21 consecutive days followed by seven con­ day cycle. secutive days of rest in a 28 day cycle. * * * * * Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 78 of 148 PageID: 78

EXHIBIT C Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 79 of 148 PageID: 79 IIIIII IIIIIIII Ill lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111 US008735428B2 c12) United States Patent (IO) Patent No.: US 8,735,428 B2 Zeldis (45) Date of Patent: *May 27, 2014

(54) METHODS FOR TREATING MULTIPLE 5,580,755 A 12/1996 Souza MYELOMA WITH 5,591,767 A 1/ 1997 Mohr et al. 4-(AMIN0)-2-(2,6-DIOX0(3- 5,593,990 A 1/1997 D' Amato 5,629,327 A 5/1997 D' Amato PIPERIDYL))-ISOINDOLINE-1,3-DIONE 5,635,517 A 6/1997 Muller et al. 5,639,476 A 6/ 1997 Oshlack et al. (71) Applicant: Celgene Corporation, Summit, NJ (US) 5,674,533 A 10/ 1997 Santus et al. 5,698,579 A 12/1997 Muller (72) Inventor: Jerome B. Zeldis, Princeton, NJ (US) 5,712,291 A 1/1998 D' Amato 5,731,325 A 3/1998 Andrulis, Jr. et al. 5,733,566 A 3/ 1998 Lewis (73) Assignee: Celgene Corporation, Summit, NJ (US) 5,798,368 A 8/1998 Muller et al. 5,874,448 A 2/1999 Muller et al. ( *) Notice: Subject to any disclaimer, the term ofthis 5,877,200 A 3/1999 Muller patent is extended or adjusted under 35 5,929,117 A 7/1999 Muller et al. U.S.C. 154(b) by O days. 5,955,476 A 9/1999 Muller et al. 6,020,358 A 2/2000 Muller et al. This patent is subject to a terminal dis­ 6,071,948 A 6/2000 D' Amato claimer. 6,114,355 A 9/2000 D' Amato 6,140,346 A 10/2000 Andrulis, Jr. et al. 6,228,879 Bl 5/2001 Green et al. (21) Appl. No.: 13/782,612 6,235,756 Bl 5/2001 D' Amato 6,281,230 Bl 8/2001 Muller et al. (22) Filed: Mar.1, 2013 6,316,471 Bl 11/2001 Muller et al. 6,326,388 Bl 12/2001 Man et al. (65) Prior Publication Data (Continued) US 2013/0177644 Al Jul. 11, 2013 FOREIGN PATENT DOCUMENTS

Related U.S. Application Data WO WO 92/14455 9/1992 WO WO 94/20085 9/1994 (63) Continuation of application No. 13/488,888, filed on WO WO 98/03502 1/1998 Jun. 5, 2012, which is acontinuationofapplicationNo. WO WO 98/54170 12/1998 WO WO 01/70275 9/2001 12/640,702, filed on Dec. 17, 2009, now Pat. No. WO WO 01/87307 11/2001 8,198,306, which is a continuation of application No. WO WO 02/15926 2/2002 10/438,213, filed on May 15, 2003, now Pat. No. WO WO 02/059106 8/2002 7,968,569. WO WO 02/064083 8/2002 WO PCT/US03/11578 4/2003 (60) Provisional application No. 60/380,842, filed on May WO WO 03/086373 10/2003 17, 2002, provisional application No. 60/424,600, filed on Nov. 6, 2002. OTHER PUBLICATIONS

(51) Int. Cl. Siegel et al. ( J Clin Oncol 31, 2013 (suppl; abstr 8588). Published at AOJN 43/40 (2006.01) http://meetinglibrary.asco.org/content/l 12890-132. 2013. * (52) U.S. Cl. (Continued) USPC ...... 514/321; 514/323; 514/329; 514/330 ( 58) Field of Classification Search USPC ...... 514/323, 329, 330 Primary Examiner - Jeffrey S. Lundgren See application file for complete search history. Assistant Examiner - Chris Simmons (74) Attorney, Agent, or Firm - Jones Day (56) References Cited

U.S. PATENT DOCUMENTS (57) ABSTRACT

3,536,809 A 10/1970 Applezweig Methods of treating, preventing and/or managing cancer as 3,598,123 A 8/1971 Zaffaroni et al. well as and diseases and disorders associated with, or char­ 3,845,770 A 11/1974 Theeuwes et al. 3,916,899 A 11/1975 Theeuwes et al. acterized by, undesired angiogenesis are disclosed. Specific 4,008,719 A 2/1977 Theeuwes et al. methods encompass the administration of an immunomodu­ 4,551,177 A * 11/1985 Trubiano et al. 106/206.1 latory compound alone or in combination with a second 4,810,643 A 3/ 1989 Souza active ingredient. The invention further relates to methods of 4,999,291 A 3/ 1991 Souza 5,059,595 A 10/1991 Le Grazie reducing or avoiding adverse side effects associated with 5,073,543 A 12/1991 Marshall et al. chemotherapy, radiation therapy, hormonal therapy, biologi­ 5,120,548 A 6/ 1992 McClelland et al. cal therapy or immunotherapy which comprise the adminis­ 5,134,127 A 7/1992 Stella et al. tration of an immunomodulatory compound. Pharmaceutical 5,229,496 A 7I 1993 Deeley et al. compositions, single unit dosage forms, and kits suitable for 5,354,556 A 10/ 1994 Sparks et al. 5,385,901 A 1/1995 Kaplan et al. use in methods of the invention are also disclosed. 5,391,485 A 2/1995 Deeley et al. 5,393,870 A 2/1995 Deeley et al. 5,528,823 A 6/ 1996 Rudy, Jr. et al. 27 Claims, 1 Drawing Sheet Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 80 of 148 PageID: 80

US 8,735,428 B2 Page 2

(56) References Cited Jagannath, S. et al., "Pomalidomide (POM) with or without low-dose dexamethasone (Lo DEX) in patients (Pts) with relapsed and refrac­ U.S. PATENT DOCUMENTS tory multiple myeloma (RRMM): MM-002 phase II age subgroup analysis," J Clin Oncol 31, 2013 (suppl; abstr 8532). 6,335,349 Bl 1/2002 Muller et al. Siegel, D. et al, "Long-term safety and efficacy of pomalidomide 6,380,239 Bl 4/2002 Muller et al. (POM) with or without low-dose dexamethasone (LoDEX) in 6,395,754 Bl 5/2002 Muller et al. 6,403,613 Bl 6/2002 Man et al. relapsed and refractory multiple myeloma (RRMM) patients enrolled 6,420,414 Bl 7/2002 D'Amato in the MM-002 phase II trial," J Clin Oncol 31, 2013 (suppl; abstr 6,458,810 Bl 10/2002 Muller et al. 8588). 6,469,045 Bl 10/2002 D'Amato Richardson, P.G. et al., A Phase 1/2 Multi-Center, Randomized, Open 6,476,052 Bl 11/2002 Muller et al. Label Dose Escalation Study to Determine the Maximum Tolerated 6,518,298 B2 2/2003 Green et al. 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TNF-a production inhibitor," Drugs of the Treatment ofCancer; Principles & Practice of Oncology, vol. 15, No. Future, 2003, 28(5):425-431. 2, 2001. Streetly et al., "Thalidomide analogue CC-4047 is effective in the Thomas, Melodie; Doss, Deborah, Thalidomide Nursing Roundtable treatment of patients with relapsed and refractory multiple mycloma Update, Monograph, Sep. 2002. (MM) and induces T-cell activation and IL-12 production," Abstract Richardson, Paul, Hideshima, Teru; Anderson, Kenneth, #367, International Multiple Myeloma Workshop, May 23-27, 2003. Thalidomide: Emerging Role in Cancer Medicine; Annual Review of Streetly et al., "Changes in neutrophil phenotype following the Medicine, 2002. administration of CC-4047 (Actimid) to patients with multiple Berenson, J.R.; Bergsagel, P. L.; Munshi, N.; Initiation and Mainte­ myeloma," Abstract# 2543, American Society ofHematology, Dec. nance ofMultiple Myeloma; Seminars in Hematology, vol. 36, No. 1, 6-9, 2003. Supp.3,Jan. 1999,pp.9-13. Streetly et al., "An update of the use and outcomes of the new Gollob, J.A.; Schinpper, C.P.; Orsini, E.; Murphy, E.; Daley, J.F.; immunomodulatory agent CC-4047 (Actimid) in patients with Lazo, S.B.; Frank. D.A.; Characterization ofa Novel Subset ofCD8 relapsed/refractory myeloma," Abstract #829, American Society of T Cells That Expands in patients Receiving Interleukin-I 2, 02, Am. Hematology, Dec. 6-9, 2003. Soc. For Clin. 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Kantarjian, H.M., Thalidomide as anti-angiogenesis therapy (rx) in Tiiertulien et al., "Hybrid MEL/DT PACE autotransplant regimen for refractory or relapsed leukemia. Abstract #2269, American Society Multiple Myeloma (MM)-safety and efficacy data in pilot study of of Hematology, Dec. 3-7, 1999. 15 patients," Blood, Abstract# 2869, American Society ofHematol­ Barlogie, B., Desikan, R., Munshi, N., Siegel, D., Mehta, J., Singha!, ogy, Dec. 7-11, 2001. S., Anaissie, E., Single Course D.T. Pace Anti-Angiochemotherapy Tohnya et al., "A phase I study of oral CC-5013 (lenalidomide, Effects CR in Plasma Cell Leukemia and Fulminant Multiple Revlimid™), a thalidomide derivative, in patients with refractory Myeloma (MM). Abstract #4180. American Society of Hematology, metastatic cancer," Clinical Prostate Cancer, 2004, 2:241-243. Dec. 4-9, 1998. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 85 of 148 PageID: 85

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American Society of Hema­ tolerated by patients with end stage cancer and shows evidence of tology, Dec. 7-11, 2001. clinical responses and extensive immune activation," Br. J Cancer, Lentsch, S., Rogers, M., Leblanc, R., Birsner, A., Shah, J., Anderson 2002, 86(Supp. l):Abst 6.4. K., D' Amato R., 3-Amino-Phthalimido-Glutarimide (S-3APG) Kast, R.E., "Evidence of a mechanism by which etanercept increased Inhibits Angiogenesis and Growth in Drug Resistant Multiple TNF-alpha in multiple myeloma: New insights into the biology of Mycloma (MM) in vivo. Abstract# 1976, American Society of Hema­ TNF-alpha giving new treatment opportunities-the role of tology, Dec. 7-11, 2001. burproion," Leukemia Research, 2005, 29:1459-1463. Park, Y., Kim, S.A., Kim, C.J., Chung, J.H., Mechanism of the Effect of Thalidomide on Human Multiple Mycloma Cells. Abstract #2685. 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Anderson, K.C., Apoptotic Signaling Induced by Immunomodula­ Hideshima, T., et al., "A review oflenalidomide in combination with tory Thalidomide Analogs (Imids) in Human Multiple Myeloma dexathasone for the treatment of multiple myeloma," Therapeutics Cells; Therapeutic Implications. Abstract #3224. American Society and Clinical Risk Management, 2008, 4( 1): 129-136. of Hematology, Dec. 7-11, 2001. Wang, M., et al., "Lenalidomide plus dexamethasone is more effec­ Richardson, P.G., Schlossman, R.L., Hideshima, T., Davies, F., tive than dexamethasone alone in patients with relapsed or refractory Leblanc, R., Catley, L., Doss, D., Kelly, K.A., McKenney, M., multiple myeloma regardless of prior thalidomide exposure," Blood, Mechlowicz, J., Freeman, A,. Deocampo, R., Rich, R., Ryoo, J., 2008, l 12(12).4445-4451. Chauhan, D., Munshi, N., Weller, E., Zeldis, J., Anderson, K.C., A Gandhi, A., et al., "Dexamethasone Synergizes with Lenalidomide to Phase 1 Study of Oral CC5013, an Immunomodulatory Thalidomide Inhibit Multiple Myeloma Tumor Growth, But Reduces (Thal) Derivative, in Patients With Relapsed and Refractory Multiple Lenalidomide-Induced Immunomodulation ofT and NK Cell Func­ Myeloma (MM). Abstract #3225. American Society of Hematology, tion," Current Cancer Drug Targets, 2010, 10(1):1-13. Dec. 7-11, 2001. Gay, F. et al., "Lenalidomide plus dexamethasone versus thalidomide "Celgene drug promises activity in solid tumors," Marketletter, Jun. plus dexamethasone in newly diagnosed multiple myeloma: a com­ 18,2001. parative analysis of 411 patients," Blood, 2010, 115(97): 1343-150. 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(56) References Cited Gamberi et al., "Overall Safety and Treatment Duration in Lenalidomide (LEN)-, Thalidomide (THAL)-, and Bortezomib OTHER PUBLICATIONS (BORT)-Treated Patients (Pts) within the European Post-Approval Safety Study (EU PASS) of Relapsed/Refractory Multiple Myeloma Notification letter dated Aug. 30,2010 from Natco Pharma Limited to (RRMM)", presented at 54th ASH Annual Meeting and Exposition, Celgene Corporation re: Notification purusant to § 505(j)(2)(B) of Atlanta, Georgia, Dec. 8-11, 2012, Abstract #4068. the Federal Food, Drug and Cosmetic Act. Kor de et al., "Phase II Clinical and Correlative Study of Carfilzomib, Complaint for Patent Infringement filed on Oct. 8, 2010 by Celgene Lenalidomide, andDexamethasone (CRd) in Newly Diagnosed Mul­ Corporation in the U.S. District Court, District of New Jersey against tiple Myeloma (MM) Patients", presented at 54th ASH Annual Meet­ Natco Pharma Limited. ing and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract Answer to Complaint filed on Nov. 18, 2010 byNatco Pharma Lim­ #732. ited in the U.S. District Court, District of New Jersey. Kumar et al., "A Phase 1/2 Study of Weekly MLN9708, an Investi­ Grosshans, E. and Illy, G., "Thalidomide Therapy for Inflammatory gational Oral Proteasome Inhibitor, in Combination with Dermatoses," International Journal of Dermatology, 1984, Lenalidomide and Dexamethasone in Patients with Previously 23(9):598-602. Untreated Multiple Myeloma (MM)", presened at 54th ASH Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract Krenn, M. et al., "Improvements in Solubility and Stability of #332. Thalidomide upon Complexation with Hydropropyl-13- Palumbo et al., "Pomalidomide Cyclophosphamide and Prednisone Cyclodextrin," Journal of Pharmaceutical Sciences, 1992, (PCP) Treatment for Relapsed/Refractory Multiple Myeloma", pre­ 81(7):685-689. sented at 54th ASH Annual Meeting and Exposition, Atlanta, Geor­ Schmahl, H. J. et al., "Pharmacokinetics of the Teratogenic and gia, Dec. 8-11, 2012, Abstract #446. Nonteratogenic Thalidomide Analogs EM 12 and Supidimide in the Richardson et al., "A Phase 2 Study ofElotuzumab (Elo) in Combi­ Rat and Marmoset Monkey", in Pharmacokinetics in Teratogenesis, nation with Lenalidomide and Low-Dose Dexamethasone (Ld) in CRC Press, 1987, vol. I, Ch. 12, pp. 181-192. Patients (pts) with Relapsed/Refractory Multiple Myeloma (R/R Schumacher, H. et al., "The Teratogenic Activity of a Thalidomide MM): Updated Results", presented at 54th ASH Annual Meeting and Analogue, EMw in Rabbits, Rats, and Monkeys," Teratology, 1971, Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract #202. 5:233-240. Sacchi et al., "A Phase I/II Study of Bendamustine, Low-Dose Smith, R. et al., "Studies on the Relationship Between the Chemical Dexamethasone, and Lenalidomide (BdL) for the Treatment of Structure and Embryotoxic Activity of Thalidomide and Related Patients with Relapsed Multiple Myeloma", presented at 54th ASH Compounds," in A Symposium on Embryopathie Activity ofDrugs, J. Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, & A. Churchill Ltd., 1965, Session 6, pp. 194-209. Abstract #1851. 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Lenalidomide with Melphalan and Autologous Transplant for Mul­ Med., 2002, 6(2):160-174. tiple Myeloma: A Report of the Phase I Dose-Finding Study", pre­ Singha!, S. And Mehta, J., "Thalidomide in Cancer,"BioDrugs, 2001, sented at 54th ASH Annual Meeting and Exposition, Atlanta, Geor­ 15(3):163-172. gia, Dec. 8-11, 2012,Abstract#3146. Notice of Opposition to EP 1 505 973 filed by Synthon B.V. on Nov. Mark et al., "ClaPD (Clarithromycin, Pomalidomide, 30, 2010. Dexamethasone) Therapy in Relapsed or Refractory Multiple Notice of Opposition to EP 1505973 filed by Strawman Limited on Myeloma", presented at 54th ASH Annual Meeting and Exposition, Dec. 1, 2010. Atlanta, Georgia, Dec. 8-11, 2012, Abstract #77. Samson, D. et al., "Infusion ofVincristine and Doxorubicin with Oral Lacy et al., "Pomalidomide Plus Low-Dose Dexamethasone (Porn/ Dexamethasone as First-Line Therapy for Multiple Myeloma," The Dex) in Relapsed Myeloma: Long Term Follow up and Factors Lancet, 1989, 334(8668):882-885. Predicing Outcome in 345 Patients," presented at 54th ASH Annual Barlogie, B. et al., "Effective Treatment of Advanced Multiple Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract Myeloma Refractory to Alkylating Agents," N. Engl. J Med., 1984, #201. 310(21): 1353-1356. Jagannath et al., "Pomalidomide (POM) with Low-Dose Dimopoulos, M. et al., "Thalidomide and dexamethasone combina­ Dexamethasone (LoDex) in Patients (Pts) with Relapsed and Refrac­ tion for refractory multiple myeloma," Annals of Oncology, 2001, tory Multiple Myeloma Who Have Received Prior Therapy with 12:991-995. Lenalidomide (LEN) and Bortezomib (BORT): Updated Phase 2 Zangari, M., et al., "Thrombogenic activity of doxorubicin in Results and Age Subgroup Analysis," presented at 54th ASH Annual myeloma patients receiving thalidomide: implications for therapy," Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract Blood, 2002, 100: 1168-1171. #450. List, A. et al., "High Erythropoietic Remitting Activity of the Richardson et al., "MM-005: A Phase 1, Multicenter, Open-Label, Immunomodulatory Thalidomide Analog, CC5013, in Patients with Dose-Escalation Study to Determine the Maximum Tolerated Dose Myelodysplastic Syndrome (MDS)," Abstract #353, Blood, 2002, for the Combination of Pomalidomide, Bortezomib, and Low-Dose 100(1 l):96a. Dexamethasone in Subjects with Relapsed or Refractory Multiple Mufti, G. et al., "Myelodysplastic Syndrome," American Society of Myeloma," presented at 54th ASH Annual Meeting and Exposition, Hematology, 2003, pp. 176-199. Atlanta, Georgia, Dec. 8-11, 2012, Abstract #727. Extracts from drug databases: retrieved from http://www.nextbio. 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(56) References Cited Bortezomib (BORT)", presented at 54th ASH Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, Abstract #4053. OTHER PUBLICATIONS Dimopoulos et al., "Pomalidomide in Combination with Low-Dose Dexamethasone: Demonstrates a Significant Progression Free Sur­ Lonial et al., "Improvement in Clinical Benefit Parameters with vival and Overall Survival Advantage, in Relapsed/Refractory MM: Pomalidomide (POM) in Combination with Low-Dose A Phase 3, Multicenter, Randomized, Open-Label Study," presented Dexamethasone (LoDex) in Patients with Relapsed and Refractory at 54th ASH Annual Meeting and Exposition, Atlanta, Georgia, Dec. Multiple Myeloma (RRMM): Results From a Phase 2 Study," pre­ 8-11, 2012, Abstract #LBA-6. sented at 54th ASH Annual Meeting and Exposition, Atlanta, Geor­ Shastri et al., "A Phase II Study of Low-Dose Pornalidomide (0.5mg/ gia, Dec. 8-11, 2012, Abstract #4052. day) and Prednisone Combination Therapy in Patients with Vij et al., "Pomalidomie (POM) with Low-Dose Dexamethasone Myelofibrosis and Significant Anemia," presented at 54th ASH (Lo Dex) in Patients with Relapsed and Refractory Multiple Myelorna Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, (RRMM): Outcomes Based on Prior Treatment Exposure," presented Abstract # 1728. at 54th ASH Annual Meeting and Exposition, Atlanta, Georgia, Dec. Shah et al., "A Multi-Center Phase I/II Trial of Carfilzomib and 8-11, 2012, Abstract #4070. Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Richardson et al., "Treatment Outcomes with Pomalidomide (POM) Relapsed/Refractory Multiple Myeloma," presented at 54th ASH in Combination with Low-Dose Dexamethasone (LoDex) in Patients Annual Meeting and Exposition, Atlanta, Georgia, Dec. 8-11, 2012, with Relapsed and Refractory Multiple Myeloma (RRMM) and Abstract #74. Del(l 7p13) and/or t(4;14) (pl6;q32) Cytogenic Abnormalities Who Have Received Prior Therapy with Lenalidomide (LEN) and * cited by examiner Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 88 of 148 PageID: 88

U.S. Patent May 27, 2014 US 8,735,428 B2

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US 8,735,428 B2 1 2 METHODS FOR TREATING MULTIPLE (e.g., b-FGF). Angiogenesis can also be induced indirectly MYELOMA WITH through the recruitment of inflammatory cells (particularly 4-(AMIN0)-2-(2,6-DIOX0(3- macrophages) and their subsequent release of angiogenic PIPERIDYL))-ISOINDOLINE-1,3-DIONE cytokines (e.g., TNF-a, bFGF). 5 A variety of other diseases and disorders are also associ- This application is a continuation of U.S. patent applica­ ated with, or characterized by, undesired angiogenesis. For tion Ser. No. 13/488,888, filed Jun. 5, 2012, which is a con­ example, enhanced or unregulated angiogenesis has been tinuation ofU. S. patent application Ser. No. 12/640, 702, filed implicated in a number of diseases and medical conditions Dec. 17, 2009, now U.S. Pat. No. 8,198,306, which is a including, but not limited to, ocular neovascular diseases, continuation application of U.S. patent application Ser. No. 10 choroidal neovascular diseases, retina neovascular diseases, 10/438,213, filed May 15, 2003,nowU.S. Pat. No. 7,968,569, rubeosis (neovascularization of the angle), viral diseases, which claims the benefit of U.S. provisional application Nos. genetic diseases, inflammatory diseases, allergic diseases, 60/380,842, filed May 17, 2002, and 60/424,600, filed Nov. 6, and autoimmune diseases. Examples of such diseases and 2002, the entireties of which are incorporated herein by ref­ conditions include, but are not limited to: diabetic retinopa­ erence. 15 thy; retinopathy of prematurity; corneal graft rejection; 1. FIELD OF THE INVENTION neovascular glaucoma; retrolental fibroplasia; and prolifera­ tive vitreoretinopathy. This invention relates to methods of treating, preventing Accordingly, compounds that can control angiogenesis or and/or managing specific cancers, and other diseases includ­ 20 inhibit the production of certain cytokines, including TNF-a, ing, but not limited to, those associated with, or characterized may be useful in the treatment and prevention of various by, undesired angiogenesis, by the administration of one or diseases and conditions. more immunomodulatory compounds alone or in combina­ 2.2 Methods of Treating Cancer tion with other therapeutics. In particular, the invention Current cancer therapy may involve surgery, chemo- encompasses the use of specific combinations, or "cocktails," 25 therapy, hormonal therapy and/or radiation treatment to of drugs and other therapy, e.g., radiation to treat these spe­ eradicate neoplastic cells in a patient (see, for example, cific cancers, including those refractory to conventional Stockdale, 1998, Medicine, vol. 3, Rubenstein and Federman, therapy. The invention also relates to pharmaceutical compo­ eds., Chapter 12, Section IV). Recently, cancer therapy could sitions and dosing regimens. also involve biological therapy or immunotherapy. All of 30 these approaches pose significant drawbacks for the patient. 2. BACKGROUND OF THE INVENTION Surgery, for example, may be contraindicated due to the health of a patient or may be unacceptable to the patient. 2.1 Pathobiology of Cancer and Other Diseases Additionally, surgery may not completely remove neoplastic Cancer is characterized primarily by an increase in the tissue. Radiation therapy is only effective when the neoplastic number of abnormal cells derived from a given normal tissue, 35 invasion of adjacent tissues by these abnormal cells, or lym­ tissue exhibits a higher sensitivity to radiation than normal phatic or blood-borne spread of malignant cells to regional tissue. Radiation therapy can also often elicit serious side lymph nodes and to distant sites (metastasis). Clinical data effects. Hormonal therapy is rarely given as a single agent. and molecular biologic studies indicate that cancer is a mul­ Although hormonal therapy can be effective, it is often used tistep process that begins with minor preneoplastic changes, 40 to prevent or delay recurrence of cancer after other treatments which may under certain conditions progress to neoplasia. have removed the majority of cancer cells. Biological thera­ The neoplastic lesion may evolve clonally and develop an pies and immunotherapies are limited in number and may increasing capacity for invasion, growth, metastasis, and het­ produce side effects such as rashes or swellings, flu-like erogeneity, especially under conditions in which the neoplas­ symptoms, including fever, chills and fatigue, digestive tract tic cells escape the host's immune surveillance. Raitt, I., 45 problems or allergic reactions. Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed., With respect to chemotherapy, there are a variety of che­ Mosby, St. Louis, Mo., 1993). motherapeutic agents available for treatment of cancer. A There is an enormous variety of cancers which are majority of cancer chemotherapeutics act by inhibiting DNA described in detail in the medical literature. Examples synthesis, either directly, or indirectly by inhibiting the bio- includes cancer of the lung, colon, rectum, prostate, breast, 50 synthesis of deoxyribonucleotide triphosphate precursors, to brain, and intestine. The incidence of cancer continues to prevent DNA replication and concomitant cell division. Gil­ climb as the general population ages, as new cancers develop, man et al., Goodman and Gilman 's: The Pharmacological and as susceptible populations (e.g., people infected with Basis of Therapeutics, Tenth Ed. (McGraw Hill, New York). AIDS or excessively exposed to sunlight) grow. A tremen­ Despite availability of a variety of chemotherapeutic dous demand therefore exists for new methods and composi­ 55 agents, chemotherapy has many drawbacks. Stockdale, Medi­ tions that can be used to treat patients with cancer. cine, vol. 3, Rubenstein and Federman, eds., ch. 12, sect. 10, Many types of cancers are associated with new blood ves­ 1998. Almost all chemotherapeutic agents are toxic, and che­ sel formation, a process known as angiogenesis. Several of motherapy causes significant, and often dangerous side the mechanisms involved in tumor-induced angiogenesis effects including severe nausea, bone marrow depression, and have been elucidated. The most direct of these mechanisms is 60 immunosuppression. Additionally, even with administration the secretion by the tumor cells of cytokines with angiogenic of combinations of chemotherapeutic agents, many tumor properties. Examples of these cytokines include acidic and cells are resistant or develop resistance to the chemothera­ basic fibroblastic growth factor (a,b-FGF), angiogenin, vas­ peutic agents. In fact, those cells resistant to the particular cular endothelial growth factor (VEGF), and TNF-a. Alter­ chemotherapeutic agents used in the treatment protocol often natively, tumor cells can release angiogenic peptides through 65 prove to be resistant to other drugs, even if those agents act by the production of proteases and the subsequent breakdown of different mechanism from those of the drugs used in the the extracellular matrix where some cytokines are stored specific treatment. This phenomenon is referred to as pleio- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 90 of 148 PageID: 90

US 8,735,428 B2 3 4 tropic drug or multi drug resistance. Because of the drug resis­ not limited to, surgery, chemotherapy, radiation therapy, hor­ tance, many cancers prove refractory to standard chemothera­ monal therapy, biological therapy and immunotherapy. peutic treatment protocols. This invention also encompasses methods of treating, man­ Other diseases or conditions associated with, or character­ aging or preventing diseases and disorders other than cancer ized by, undesired angiogenesis are also difficult to treat. 5 that are associated with, or characterized by, undesired angio­ However, some compounds such as protamine, hepain and genesis, which comprise administering to a patient in need of steroids have been proposed to be useful in the treatment of such treatment, management or prevention a therapeutically certain specific diseases. Tayloretal.,Nature 297:307 (1982); or prophylactically effective amount of an immunomodula­ Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos. tory compound, or a pharmaceutically acceptable salt, sol- 5,001,116 and 4,994,443. Thalidomide and certain deriva­ IO vate, hydrate, stereoisomer, clathrate, or prodrug thereof. tives of it have also been proposed for the treatment of such In other methods of the invention, an immunomodulatory diseases and conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, compound is administered in combination with a therapy 5,712,291, 6,071,948 and 6,114,355 to D' Amato. conventionally used to treat, prevent or manage diseases or

Still, there is a significant need for safe and effective meth­ 15 disorders associated with, or characterized by, undesired ods of treating, preventing and managing cancer and other angiogenesis. Examples of such conventional therapies diseases and conditions, particularly for diseases that are include, but are not limited to, surgery, chemotherapy, radia­ refractory to standard treatments, such as surgery, radiation tion therapy, hormonal therapy, biological therapy and immu- therapy, chemotherapy and hormonal therapy, while reducing notherapy. or avoiding the toxicities and/or side effects associated with 20 This invention encompasses pharmaceutical composi- the conventional therapies. tions, single unit dosage forms, dosing regimens and kits 2.3 IMiDs™ which comprise an immunomodulatory compound, or a phar­ A number of studies have been conducted with the aim of maceutically acceptable salt, solvate, hydrate, stereoisomer, providing compounds that can safely and effectively be used clathrate, or prodrug thereof, and a second, or additional, to treat diseases associated with abnormal production of 25 active agent. Second active agents include specific combina­ TNF-a. See, e.g., Marriott, J. B., et al., Expert Opin. Biol. tions, or "cocktails," of drugs. Ther. 1(4): 1-8 (2001); G. W. Muller, et al., Journal of Medici­ nal Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, 4. BRIEF DESCRIPTION OF FIGURE et al., Bioorganic & Medicinal Chemistry Letters 8: 2669- 2674 (1998). Some studies have focused on a group of com- 30 FIG. 1 shows a comparison of the effects of3-(4-amino-l­ pounds selected for their capacity to potently inhibit TNF -a oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Re­ production by LPS stimulated PBMC. L. G. Corral, et al., vimid™) and thalidomide in inhibiting the proliferation of Ann. Rheum. Dis. 58:(Suppl I) 1107-1113 (1999). These multiple mycloma (MM) cell lines in an in vitro study. The compounds, which are referred to as IMiDs™ (Celgene Cor­ uptake of [3 H]-thymidine by different MM cell lines poration) or Immunomodulatory Drugs, show not only potent 35 (MM. IS, Hs Sultan, U266 and RPMI-8226) was measured as inhibition of TNF-a but also marked inhibition of LPS an indicator of the cell proliferation. induced monocyte ILi~ and IL12 production. LPS induced IL6 is also inhibited by immunomodulatory compounds, 5. DETAILED DESCRIPTION OF THE albeit partially. These compounds are potent stimulators of INVENTION LPS induced ILlO. Id. Particular examples of IMiD™s 40 include, but are not limited to, the substituted 2-(2,6-dioxopi­ A first embodiment of the invention encompasses methods peridin-3-yl)phthalimides and substituted 2-(2,6-dioxopip­ of treating, managing, or preventing cancer which comprises eridin-3-yl)-1-oxoisoindoles described in U.S. Pat. Nos. administering to a patient in need of such treatment or pre­ 6,281,230 and 6,316,471, both to G. W. Muller, et al. vention a therapeutically or prophylactically effective 45 amount of an immunomodulatory compound of the inven­ 3. SUMMARY OF THE INVENTION tion, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. This invention encompasses methods of treating and pre­ In particular methods encompassed by this embodiment, venting certain types of cancer, including primary and meta­ the immunomodulatory compound is administered in combi- static cancer, as well as cancers that are refractory or resistant 50 nation with another drug ("second active agent") or method of to conventional chemotherapy. The methods comprise treating, managing, or preventing cancer. Second active administering to a patient in need of such treatment or pre­ agents include small molecules and large molecules (e.g., vention a therapeutically or prophylactically effective proteins and antibodies), examples of which are provided amount of an immunomodulatory compound, or a pharma­ herein, as well as stem cells. Methods, or therapies, that can ceutically acceptable salt, solvate, hydrate, stereoisomer, 55 be used in combination with the administration of the immu- clathrate, or prodrug thereof. The invention also encompasses nomodulatory compound include, but are not limited to, sur­ methods of managing certain cancers (e.g., preventing or gery, blood transfusions, immunotherapy, biological therapy, prolonging their recurrence, or lengthening the time of remis­ radiation therapy, and other non-drug based therapies pres­ sion) which comprise administering to a patient in need of ently used to treat, prevent or manage cancer. such management a prophylactically effective amount of an 60 Another embodiment of the invention encompasses meth­ immunomodulatory compound of the invention, or a pharma­ ods of treating, managing or preventing diseases and disor­ ceutically acceptable salt, solvate, hydrate, stereoisomer, ders other than cancer that are characterized by undesired clathrate, or prodrug thereof. angiogenesis. These methods comprise the administration of In particular methods of the invention, an immunomodu­ a therapeutically or prophylactically effective amount of an latory compound is administered in combination with a 65 immunomodulatory compound, or a pharmaceutically therapy conventionally used to treat, prevent or manage can­ acceptable salt, solvate, hydrate, stereoisomer, clathrate, or cer. Examples of such conventional therapies include, but are prodrug thereof. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 91 of 148 PageID: 91

US 8,735,428 B2 5 6 Examples of diseases and disorders associated with, or thalidomide and EM-12), including, but not limited to, those characterized by, undesired angiogenesis include, but are not disclosed in U.S. Pat. No. 5,635,517; and a class of non­ limited to, inflammatory diseases, autoimmune diseases, polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698, viral diseases, genetic diseases, allergic diseases, bacterial 579 and 5,877,200; analogs and derivatives of thalidomide, diseases, ocular neovascular diseases, choroidal neovascular 5 including hydrolysis products, metabolites, derivatives and diseases, retina neovascular diseases, and rubeosis (neovas­ precursors of thalidomide, such as those described in U.S. cularization of the angle). Pat. Nos. 5,593,990, 5,629,327, and 6,071,948 to D' Amato; In particular methods encompassed by this embodiment, aminothalidomide, as well as analogs, hydrolysis products, the immunomodulatory compound is administer in combina­ metabolites, derivatives and precursors of aminothalidomide, tion with a second active agent or method of treating, man­ 10 and substituted 2-(2,6-dioxopiperidin-3-yl)phthalimides and aging, or preventing the disease or condition. Second active substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles agents include small molecules and large molecules ( e.g., such as those described in U.S. Pat. Nos. 6,281,230 and proteins and antibodies), examples of which are provided 6,316,471; isoindole-imide compounds such as those herein, as well as stem cells. Methods, or therapies, that can described in U.S. patent application Ser. No. 09/972,487 filed be used in combination with the administration of the immu­ 15 on Oct. 5, 2001, U.S. patent application Ser. No. 10/032,286 nomodulatory compound include, but are not limited to, sur­ filed on Dec. 21, 2001, and International Application No. gery, blood transfusions, immunotherapy, biological therapy, PCT/USOl/50401 (International Publication No. WO radiation therapy, and other non-drug based therapies pres­ 02/059106). The entireties of each of the patents and patent ently used to treat, prevent or manage disease and conditions applications identified herein are incorporated herein by ref- associated with, or characterized by, undesired angiogenesis. 20 erence. Immunomodulatory compounds of the invention do The invention also encompasses pharmaceutical composi­ tions (e.g., single unit dosage forms) that can be used in not include thalidomide. methods disclosed herein. Particular pharmaceutical compo­ Other specific immunomodulatory compounds of the sitions comprise an immunomodulatory compound of the invention include, but are not limited to, 1-oxo- and 1,3 invention, or a pharmaceutically acceptable salt, solvate, dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolines substituted hydrate, stereoisomer, clathrate, or prodrug thereof, and a 25 with amino in the benzo ring as described in U.S. Pat. No. second active agent. 5,635,517 which is incorporated herein by reference. These 5.1 Immunomodulatory Compounds compounds have the structure I: Compounds used in the invention include immunomodu­ latory compounds that are racemic, stereomerically enriched or stereomerically pure, and pharmaceutically acceptable 30 salts, solvates, hydrates, stereoisomers, clathrates, and pro­ drugs thereof. Preferred compounds used in the invention are small organic molecules having a molecular weight less than about 1,000 g/mol, and are not proteins, peptides, oligonucle­ otides, oligosaccharides or other macromolecules. 35 As used herein and unless otherwise indicated, the terms "immunomodulatory compounds" and "IMiDs™" (Celgene Corporation) encompasses small organic molecules that in which one ofX andY is C=O, the otherofX andY is C=O markedly inhibit TNF-a, LPS induced monocyte ILi ~ and 2 or CH , and R is hydrogen or lower alkyl, in particular IL12, and partially inhibit IL6 production. Specific immuno- 2 methyl. Specific immunomodulatory compounds include, but modulatory compounds are discussed below. 40 TNF -a is an inflammatory cytokine produced by macroph­ are not limited to: ages and monocytes during acute inflammation. TNF-a is l -oxo-2-(2,6-dioxopiperidin-3-yl )-4-aminoisoindoline; responsible for a diverse range of signaling events within l -oxo-2-(2,6-dioxopiperidin-3-yl )-5-aminoisoindoline; cells. TNF-a may play a pathological role in cancer. Without l -oxo-2-(2,6-dioxopiperidin-3-yl )-6-aminoisoindoline; being limited by theory, one of the biological effects exerted 45 l-oxo-2-(2,6-dioxopiperidin-3-yl)-7-aminoisoindoline; by the immunomodulatory compounds of the invention is the 1,3-dioxo-2-(2, 6-dioxopiperidin-3-yl )-4-aminoisoindoline; reduction of synthesis of TNF-a. Immunomodulatory com­ and pounds of the invention enhance the degradation of TNF-a 1,3-dioxo-2-(2, 6-dioxopiperidin-3-yl )-5-aminoisoindoline. mRNA. Other specific immunomodulatory compounds of the Further, without being limited by theory, immunomodula­ 50 invention belong to a class of substituted 2-(2,6-dioxopiperi­ tory compounds used in the invention may also be potent co-stimulators of T cells and increase cell proliferation dra­ din-3-yl)phthalimides and substituted 2-(2,6-dioxopiperidin- matically in a dose dependent manner. Immunomodulatory 3-yl)-1-oxoisoindoles, such as those described in U.S. Pat. compounds of the invention may also have a greater co­ Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, and International Patent Application No. PCT/US97/13375 (In­ stimulatory effect on the CDS+ T cell subset than on the 55 CD4+ T cell subset. In addition, the compounds preferably ternational Publication No. WO 98/03502), each of which is have anti-inflammatory properties, and efficiently co-stimu­ incorporated herein by reference. Compounds representative late T cells. of this class are of the formulas: Specific examples of immunomodulatory compounds of the invention, include, but are not limited to, cyano and car­ boxy derivatives of substituted styrenes such as those dis- 60 closed in U.S. Pat. No. 5,929,117; l-oxo-2-(2,6-dioxo-3- fluoropiperidin-3yl)isoindolines and 1,3-dioxo-2-(2,6- dioxo-3-fluoropiperidine-3-yl)isoindolines such as those described in U.S. Pat. No. 5,874,448; the tetra substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolines described in 65 U.S. Pat. No. 5,798,368; 1-oxo and 1,3-dioxo-2-(2,6-diox­ opiperidin-3-yl)isoindolines (e.g., 4-methyl derivatives of Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 92 of 148 PageID: 92

US 8,735,428 B2 7 8 Rs is (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, ben­ zyl, aryl, or (C2-Cs)heteroaryl; 6 each occurrence of R is independently H, (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C2-Cs)het- 6 5 eroaryl, or (C0 -Cs)alkyl-C(O)O-Rs or the R groups can join to form a heterocycloalkyl group; n is O or 1; and * represents a chiral-carbon center. In specific compounds of formula II, when n is Othen R 1 is 10 (C3 -C7 )cycloalkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C0 -C4)alkyl-(C1-C 6 )heterocycloalkyl, (C0 -C4)alkyl­ 3 4 6 (C2-Cs)heteroaryl, C(O)R , C(O)OR , (C1-Cs)alkyl-N(R ) 2, 3 (C1-Cs)alkyl-ORs, (C1-Cs)alkyl-C(O)ORs, C(S)NHR , or (C1-Cs)alkyl-O(CO)Rs; 15 2 R is Hor (C1-Cs)alkyl; and 3 R is (C1-Cs)alkyl, (C3 -C7 )cycloalkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C0 -C4)alkyl-(C1-C 6 )heterocy­ cloalkyl, (C0 -C4)alkyl-(C2-Cs)heteroaryl, (Cs-Cs)alkyl-N 6 20 (R ) 2; (C0 -Cs)alkyl-NH-C(O)O-Rs; (C1-Cs)alkyl-0Rs, (C1-Cs)alkyl-C(O)ORs, (C1-Cs)alkyl-O(CO)Rs, or C(O) ORs; and the other variables have the same definitions. In other specific compounds of formula II, R2 is H or wherein R 1 is hydrogen or methyl. In a separate embodiment, (C1-C 4)alkyl. the invention encompasses the use of enantiomerically pure 1 25 In other specific compounds of formula II, R is (C -Cs) forms ( e.g. optically pure (R) or (S) enantiomers) of these 1 alkyl or benzyl. compounds. In other specific compounds of formula II, R 1 is H, (C - Still other specific immunomodulatory compounds of the 1 Cs)alkyl, benzyl, CH 0CH , CH CH 0CH , or invention belong to a class of isoindole-imides disclosed in 2 3 2 2 3 U.S. patent application Ser. Nos. 10/032,286 and 09/972,487, 30 and International Application No. PCT/USOl/50401 (Inter­ national Publication No. WO 02/059106), each of which are incorporated herein by reference. Representative compounds are of formula II: 35 In another embodiment of the compounds of formula II, R 1 II IS

40

45

and pharmaceutically acceptable salts, hydrates, solvates, clathrates, enantiomers, diastereomers, racemates, and mix­ tures of stereoisomers thereof, wherein: 7 50 wherein Q is O or S, and each occurrence ofR is indepen- one of X and Y is C=O and the other is CH2 or C=O; dently H, (C1-Cs)alkyl, benzyl, CH20CH3 , or 1 R is H, (C1-Cs)alkyl, (C3 -C7 )cycloalkyl, (C2-Cs)alkenyl, CH2CH20CH3 • 1 3 (C2-Cs)alkynyl, benzyl, aryl, (C0 -C4)alkyl-(C1-C6)heterocy­ In other specific compounds of formula II, R is C(O)R • 3 3 3 cloalkyl, (C0 -C4)alkyl-(C2-Cs)heteroaryl, C(O)R , C(S)R , In other specific compounds of formula II, R is (C0 -C4) 4 6 ) 55 C(O)OR , (C1-Cs)alkyl-N(R 2, (C1-Cs)alkyl-0Rs, (C1-Cs) alkyl-(C2-Cs)heteroaryl, (C1-Cs)alkyl, aryl, or (C0 -C4)alkyl- 3 3 3 3 alkyl-C(O)ORs, C(O)NHR , C(S)NHR , C(O)NR R ', C(S) 0Rs. 3 30 NR R or (C1-Cs)alkyl-O(CO)Rs; In other specific compounds of formula II, heteroaryl is 2 R is H, F, benzyl, (C1-Cs)alkyl, (C2-Cs)alkenyl, or (C2- pyridyl, fury!, or thienyl. Cs)alkynyl; In other specific compounds of formula II, R1 is C(O)OR4. 3 3 R and R ' are independently (C1-Cs)alkyl, (C3 -C7 )cy- 60 In other specific compounds of formula II, the H of C(O) cloalkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, benzyl, aryl, (C 0 - NHC(O) can be replaced with (C1-C 4)alkyl, aryl, or benzyl. C4)alkyl-(C1 -C 6 )heterocycloalkyl, (C0 -C4)alkyl-(C2-Cs)het­ Still other specific immunomodulatory compounds of the 6 eroaryl, (C0 -Cs)alkyl-N(R ) 2, (C1-Cs)alkyl-ORs, (C1-Cs) invention belong to a class of isoindole-imides disclosed in alkyl-C(O)ORs, (C1-Cs)alkyl-O(CO)Rs, or C(O)ORs; U.S. patent application Ser. No. 09/781,179, International 4 R is (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, (C1- 65 Publication No. WO 98/54170, and U.S. Pat. No. 6,395,754, C4)alkyl-0Rs, benzyl, aryl, (C0 -C4)alkyl-(C1-C6)heterocy­ each of which are incorporated herein by reference. Repre- cloalkyl, or (C0 -C4)alkyl-(C2-Cs)heteroaryl; sentative compounds are of formula III: Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 93 of 148 PageID: 93

US 8,735,428 B2 9 10 Compounds of the invention can either be commercially III purchased or prepared according to the methods described in the patents or patent publications disclosed herein. Further, optically pure compounds can be asymmetrically synthesized 5 or resolved using known resolving agents or chiral colunms as well as other standard synthetic organic chemistry tech­ niques. As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" encompasses non-toxic 10 acid and base addition salts of the compound to which the term refers. Acceptable non-toxic acid addition salts include and pharmaceutically acceptable salts, hydrates, solvates, those derived from organic and inorganic acids or bases know clathrates, enantiomers, diastereomers, racemates, and mix­ in the art, which include, for example, hydrochloric acid, tures of stereoisomers thereof, wherein: hydrobromic acid, phosphoric acid, sulfuric acid, methane-

one of X and Y is C=O and the other is CH2 or C=O; 15 sulphonic acid, acetic acid, tartaric acid, lactic acid, succinic

R is H or CH2 0COR'; acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic 2 3 4 (i) eachofR1, R , R , or R , independently of the others, is acid, salicylic acid, phthalic acid, embolic acid, enanthic acid, halo, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon and the like. 2 3 4 5 atoms or (ii) one ofR1, R , R , or R is nitro or-NHR and Compounds that are acidic in nature are capable of forming 2 3 4 the remaining ofR1, R , R , or R are hydrogen; 20 salts with various pharmaceutically acceptable bases. The R5 is hydrogen or alkyl of 1 to 8 carbons bases that can be used to prepare pharmaceutically acceptable R6 hydrogen, alkyl ofl to 8 carbon atoms, benzo, chloro, or base addition salts of such acidic compounds are those that fluoro; form non-toxic base addition salts, i.e., salts containing phar- 7 10 8 9 macologically acceptable cations such as, but not limited to, R' is R -CHR -N(R R ); R7 is m-phenylene or p-phenylene or -(CnH n)- in 25 alkali metal or alkaline earth metal salts and the calcium, 2 magnesium, sodium or potassium salts in particular. Suitable which n has a value of O to 4; organic bases include, but are not limited to, N,N-dibenzyl­ each of R8 and R9 taken independently of the other is ethylenediamine, chloroprocaine, choline, diethanolamine, hydrogen or alky 1 of 1 to 8 carbon atoms, or R 8 and R9 taken ethylenediamine, meglumaine (N-methylglucamine), lysine, together are tetramethylene, pentamethylene, hexamethyl- 30 and procaine. [X]X - [X]X ene, or ----CH2 CH2 1 CH2 CH2 in which 1 is As used herein and unless otherwise indicated, the term -0-, -S-, or -NH-; "prodrug" means a derivative of a compound that can hydro­ 10 R is hydrogen, alkyl ofto 8 carbon atoms, or phenyl; and lyze, oxidize, or otherwise react under biological conditions * represents a chiral-carbon center. (in vitro or in vivo) to provide the compound. Examples of The most preferred immunomodulatory compounds of the 35 prodrugs include, but are not limited to, derivatives of immu­ invention are 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindo­ nomodulatory compounds of the invention that comprise bio- line-l,3-dione and 3-(4-amino-l-oxo-l ,3-dihydro-isoindol- hydrolyzable moieties such as biohydrolyzable amides, bio­ 2-yl)-piperidine-2,6-dione. The compounds can be obtained hydrolyzable esters, biohydrolyzable carbamates, via standard, synthetic methods (see e.g., U.S. Pat. No. 5,635, biohydrolyzable carbonates, biohydrolyzable ureides, and 51 7, incorporated herein by reference). The compounds are 40 biohydrolyzable phosphate analogues. Other examples of available from Celgene Corporation, Warren, N.J. prodrugs include derivatives of immunomodulatory com- 4-(Amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1,3-dione pounds of the invention that comprise -NO, -N02 , (ACTIMID™) has the following chemical structure: -ONO, or---ON02 moieties. Prodrugs can typically be pre­ pared using well-known methods, such as those described in 45 1 Burger's Medicinal Chemistry and Drug Discovery, 172- 178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, New York 1985). As used herein and unless otherwise indicated, the terms 50 "biohydrolyzable amide," "biohydrolyzable ester," "biohy­ drolyzable carbamate," "biohydrolyzable carbonate," "bio­ hydrolyzable ureide," "biohydrolyzable phosphate" mean an amide, ester, carbamate, carbonate, ureide, or phosphate, The compound 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2- respectively, of a compound that either: 1) does not interfere yl)-piperidine-2,6-dione (REVIMID™) has the following 55 with the biological activity of the compound but can confer chemical structure: upon that compound advantageous properties in vivo, such as uptake, duration of action, or onset of action; or 2) is biologi­ cally inactive but is converted in vivo to the biologically active compound. Examples of biohydrolyzable esters 60 include, but are not limited to, lower alkyl esters, lower acy­ loxyalkyl esters (such as acetoxylmethyl, acetoxyethyl, ami­ nocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxy­ ethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such 65 as methoxycarbony1-oxymethy 1, ethoxycarbony loxyethy1 and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such as acetami- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 94 of 148 PageID: 94

US 8,735,428 B2 11 12 domethyl esters). Examples of biohydrolyzable amides agents") in methods and compositions of the invention. It is include, but are not limited to, lower alkyl amides, a-amino believed that certain combinations work synergistically in the acid amides, alkoxyacyl amides, and alkylaminoalkylcarbo­ treatment of particular types of cancer and certain diseases nyl amides. Examples of biohydrolyzable carbamates and conditions associated with, or characterized by, undes­ include, but are not limited to, lower alkylamines, substituted 5 ired angiogenesis. Immunomodulatory compounds can also ethylenediamines, amino acids, hydroxyalkylamines, hetero­ work to alleviate adverse effects associated with certain sec­ cyclic and heteroaromatic amines, and polyether amines. ond active agents, and some second active agents can be used Various immunomodulatory compounds of the invention to alleviate adverse effects associated with immunomodula­ contain one or more chiral centers, and can exist as racemic tory compounds. mixtures of enantiomers or mixtures of diastereomers. This 10 One or more second active ingredients or agents can be invention encompasses the use of stereomerically pure forms used in the methods and compositions of the invention of such compounds, as well as the use of mixtures of those together with an immunomodulatory compound. Second forms. For example, mixtures comprising equal or unequal active agents can be large molecules (e.g., proteins) or small amounts of the enantiomers of a particular immunomodula­ molecules (e.g., synthetic inorganic, organometallic, or tory compounds of the invention may be used in methods and 15 organic molecules). compositions of the invention. These isomers may be asym­ Examples of large molecule active agents include, but are metrically synthesized or resolved using standard techniques not limited to, hematopoietic growth factors, cytokines, and such as chiral colunms or chiral resolving agents. See, e.g., monoclonal and polyclonal antibodies. Typical large mol­ Jacques, J., et al., Enantiomers, Racemates and Resolutions ecule active agents are biological molecules, such as naturally (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., 20 occurring or artificially made proteins. Proteins that are par­ Tetrahedron 33:2725 (1977); Elie!, E. L., Stereochemistry of ticularly useful in this invention include proteins that stimu­ Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. late the survival and/or proliferation ofhematopoietic precur­ H., Tables ofResolving Agents and Optical Resolutions p. 268 sor cells and immunologically active poietic cells in vitro or (E. L. Elie!, Ed., Univ. of Notre Dame Press, Notre Dame, in vivo. Others stimulate the division and differentiation of Ind., 1972). 25 committed erythroid progenitors in cells in vitro or in vivo. As used herein and unless otherwise indicated, the term Particular proteins include, but are not limited to: interleu­ "stereomerically pure" means a composition that comprises kins, such as IL-2 (including recombinant IL-II ("rIL2") and one stereoisomer of a compound and is substantially free of canarypox TL-2), IL-10, IL-12, and IL-18; interferons, such other stereoisomers of that compound. For example, a stereo­ as interferon alfa-2a, interferon alfa-2b, interferon alfa-nl, merically pure composition of a compound having one chiral 30 interferon alfa-n3, interferon beta-I a, and interferon center will be substantially free of the opposite enantiomer of gamma-I b; GM-CF and GM-CSF; and EPO. the compound. A stereomerically pure composition of a com­ Particular proteins that can be used in the methods and pound having two chiral centers will be substantially free of compositions of the invention include, but are not limited to: other diastereomers of the compound. A typical stereomeri­ filgrastim, which is sold in the United States under the trade cally pure compound comprises greater than about 80% by 35 name Neupogen® (Amgen, Thousand Oaks, Calif.); sargra­ weight of one stereoisomer of the compound and less than mostim, which is sold in the United States under the trade about 20% by weight of other stereoisomers of the com­ name Leukine® (Immunex, Seattle, Wash.); and recombinant pound, more preferably greater than about 90% by weight of EPO, which is sold in the United States under the trade name one stereoisomer of the compound and less than about 10% Epogen® (Amgen, Thousand Oaks, Calif.). by weight of the other stereoisomers of the compound, even 40 Recombinant and mutated forms of GM-CSF can be pre­ more preferably greater than about 95% by weight of one pared as described in U.S. Pat. Nos. 5,391,485; 5,393,870; stereoisomer of the compound and less than about 5% by and 5,229,496; all of which are incorporated herein by refer­ weight of the other stereoisomers of the compound, and most ence. Recombinant and mutated forms of G-CSF can be preferably greater than about 97% by weight of one stereoi­ prepared as described in U.S. Pat. Nos. 4,810,643; 4,999,291; somer of the compound and less than about 3% by weight of 45 5,528,823; and 5,580,755; all of which are incorporated the other stereoisomers of the compound. As used herein and herein by reference. unless otherwise indicated, the term "stereomerically This invention encompasses the use of native, naturally enriched" means a composition that comprises greater than occurring, and recombinant proteins. The invention further about 60% by weight of one stereoisomer of a compound, encompasses mutants and derivatives (e.g., modified forms) preferably greater than about 70% by weight, more preferably 50 of naturally occurring proteins that exhibit, in vivo, at least greater than about 80% by weight of one stereoisomer of a some of the pharmacological activity of the proteins upon compound. As used herein and unless otherwise indicated, which they are based. Examples of mutants include, but are the term "enantiomerically pure" means a stereomerically not limited to, proteins that have one or more amino acid pure composition of a compound having one chiral center. residues that differ from the corresponding residues in the Similarly, the term "stereomerically enriched" means a ste- 55 naturally occurring forms of the proteins. Also encompassed reomerically enriched composition of a compound having by the term "mutants" are proteins that lack carbohydrate one chiral center. moieties normally present in their naturally occurring forms It should be noted that if there is a discrepancy between a (e.g., nonglycosylated forms). Examples of derivatives depicted structure and a name given that structure, the include, but are not limited to, pegylated derivatives and depicted structure is to be accorded more weight. In addition, 60 fusion proteins, such as proteins formed by fusing IgG 1 or if the stereochemistry of a structure or a portion of a structure IgG3 to the protein or active portion of the protein of interest. is not indicated with, for example, bold or dashed lines, the See, e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. structure or portion of the structure is to be interpreted as Methods 248:91-101 (2001). encompassing all stereoisomers of it. Antibodies that can be used in combination with com- 5.2 Second Active Agents 65 pounds of the invention include monoclonal and polyclonal Immunomodulatory compounds can be combined with antibodies. Examples of antibodies include, but are not lim­ other pharmacologically active compounds ("second active ited to, trastuzumab (Herceptin®), rituximab (Rituxan®), Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 95 of 148 PageID: 95

US 8,735,428 B2 13 14 bevacizumab (Avastin™), pertuzumab (Omnitarg™), tositu­ cin; pentamustine; peplomycin sulfate; perfosfamide; pipo­ momab (Bcxxar®), edrecolomab (Panorex®), and G250. broman; piposulfan; piroxantrone hydrochloride; Compounds of the invention can also be combined with, or plicamycin; plomestane; porfimer sodium; porfiromycin; used in combination with, anti-TNF-a antibodies. prednimustine; procarbazine hydrochloride; puromycin; Large molecule active agents may be administered in the 5 puromycin hydrochloride; pyrazofurin; riboprine; safingol; form of anti-cancer vaccines. For example, vaccines that safingol hydrochloride; semustine; simtrazene; sparfosate secrete, or cause the secretion of, cytokines such as IL-2, sodium; sparsomycin; spirogermaniumhydrochloride; spiro­ G-CSF, and GM-CSF can be used in the methods, pharma­ mustine; spiroplatin; streptonigrin; streptozocin; sulofenur; ceutical compositions, and kits of the invention. See, e.g., talisomycin; tecogalan sodium; taxotere; tegafur; telox- Emens, L.A., et al., Curr. Opinion Mal. Ther. 3(1):77-84 10 antrone hydrochloride; temoporfin; teniposide; teroxirone; (2001). testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; In one embodiment of the invention, the large molecule tirapazamine; toremifene citrate; trestolone acetate; tricirib­ active agent reduces, eliminates, or prevents an adverse effect ine phosphate; trimetrexate; trimetrexate glucuronate; trip­ associated with the administration of an immunomodulatory torelin; tubulozole hydrochloride; uracil mustard; uredepa; compound. Depending on the particular immunomodulatory 15 vapreotide; verteporfin; vinblastine sulfate; vincristine sul­ compound and the disease or disorder begin treated, adverse fate; vindesine; vindesine sulfate; vinepidine sulfate; vingly­ effects can include, but are not limited to, drowsiness and cinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vin­ somnolence, dizziness and orthostatic hypotension, neutro­ rosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; penia, infections that result from neutropenia, increased HIV­ zinostatin; and zorubicin hydrochloride. viral load, bradycardia, Stevens-Johnson Syndrome and toxic 20 Other anti-cancer drugs include, but are not limited to: epidermal necrolysis, and seizures (e.g., grand ma! convul­ 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater­ sions). A specific adverse effect is neutropenia. one; aclarubicin; acylfulvene; adecypenol; adozelesin; Second active agents that are small molecules can also be aldesleukin; ALL-TK antagonists; altretamine; ambamus­ used to alleviate adverse effects associated with the adminis­ tine; amidox; amifostine; aminolevulinic acid; amrubicin; tration of an immunomodulatory compound. However, like 25 amsacrine; anagrelide; anastrozole; andrographolide; angio­ some large molecules, many are believed to be capable of genesis inhibitors; antagonist D; antagonist G; antarelix; anti­ providing a synergistic effect when administered with ( e.g., dorsalizing morphogenetic protein-I; antiandrogen, prostatic before, after or simultaneously) an immunomodulatory com­ carcinoma; antiestrogen; antineoplaston; antisense oligo­ pound. Examples of small molecule second active agents nucleotides; aphidicolin glycinate; apoptosis gene modula- include, but are not limited to, anti-cancer agents, antibiotics, 30 tors; apoptosis regulators; apurinic acid; ara-CDP-DL­ immunosuppressive agents, and steroids. PTBA; argmme deaminase; asulacrine; atamestane; Examples of anti-cancer agents include, but are not limited atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azas­ to: acivicin; aclarubicin; acodazole hydrochloride; acronine; ctron; azatoxin; azatyrosine; baccatin ITT derivatives; bal­ adozelesin; aldesleukin; altretamine; ambomycin; amet­ anol; batimastat; BCR/ABL antagonists; benzochlorins; ben- antrone acetate; amsacrine; anastrozole; anthramycin; 35 zoylstaurosporine; beta lactam derivatives; beta-alethine; asparaginase; asperlin; azacitidine; azetepa; azotomycin; betaclamycin B; betulinic acid; bFGF inhibitor; bicaluta­ batimastat; benzodepa; bicalutamide; bisantrene hydrochlo­ mide; bisantrene; bisaziridinylspermine; bisnafide; bistratene ride; bisnafide dimesylate; bizelesin; bleomycin sulfate; bre­ A; bizelesin; breflate; bropirimine; budotitane; buthionine quinar sodium; bropirimine; busulfan; cactinomycin; calus­ sulfoximine; calcipotriol; calphostin C; camptothecin deriva- terone; caracemide; carbetimer; carboplatin; carmustine; 40 tives; capecitabine; carboxamide-amino-triazole; carboxya­ carubicin hydrochloride; carzelesin; cedefingol; celecoxib midotriazole; CaRest M3; CARN 700; cartilage derived (COX-2 inhibitor); chlorambucil; cirolemycin; cisplatin; inhibitor; carzelesin; casein kinase inhibitors (ICOS); cladribine; crisnatol mesylate; cyclophosphamide; cytara­ castanospermine; cecropinB; cetrorelix; chlorins; chloroqui­ bine; dacarbazine; dactinomycin; daunorubicin hydrochlo­ noxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; ride; decitabine; dexormaplatin; dezaguanine; dezaguanine 45 clomifene analogues; clotrimazole; collismycinA; collismy­ mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin cin B; combretastatin A4; combretastatin analogue; conage­ hydrochloride; droloxifene; droloxifene citrate; dromo­ nin; crambescidin 816; crisnatol; cryptophycin 8; cryptophy­ stanolone propionate; duazomycin; edatrexate; eflomithine cin A derivatives; curacin A; cyclopentanthraquinones; hydrochloride; elsamitrucin; enloplatin; enpromate; epipro­ cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic fac- pidine; epirubicin hydrochloride; erbulozole; esorubicin 50 tor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; hydrochloride; estramustine; estramustine phosphate deslorelin; dexamethasone; dexifosfamide; dexrazoxane; sodium; etanidazole; etoposide; etoposide phosphate; eto­ dexverapamil; diaziquone; didemnin B; didox; diethylnor­ prine; fadrozole hydrochloride; fazarabine; fenretinide; spermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamy­ floxuridine; fludarabine phosphate; fluorouracil; fluorocitab­ cin; diphenyl spiromustine; docetaxel; docosanol; dolas- ine; fosquidone; fostriecin sodium; gemcitabine; gemcitab­ 55 etron; doxifluridine; doxorubicin; droloxifene; dronabinol; ine hydrochloride; hydroxyurea; idarubicin hydrochloride; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolo­ ifosfamide; ilmofosine; iproplatin; irinotecan; irinotecan mab; eflornithine; elemene; emitefur; epirubicin; epristeride; hydrochloride; lanreotide acetate; letrozole; leuprolide estramustine analogue; estrogen agonists; estrogen antago­ acetate; liarozole hydrochloride; lometrexol sodium; lomus­ nists; etanidazole; etoposide phosphate; exemestane; fadro- tine; losoxantrone hydrochloride; masoprocol; maytansine; 60 zole; fazarabine; fenretinide; filgrastim; finasteride; fla­ mechlorethamine hydrochloride; megestrol acetate; vopiridol; flezelastine; fluasterone; fludarabine; melengestrol acetate; melphalan; menogaril; mercaptopu­ fluorodaunorunicin hydrochloride; forfenimex; formestane; rine; methotrexate; methotrexate sodium; metoprine; meture­ fostriecin; fotemustine; gadolinium texaphyrin; gallium depa; mitindomide; mitocarcin; mitocromin; mitogillin; nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit- mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone 65 abine; glutathione inhibitors; hepsulfam; heregulin; hexam­ hydrochloride; mycophenolic acid; nocodazole; nogalamy­ ethylene bisacetamide; hypericin; ibandronic acid; idarubi­ cin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomy- cin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 96 of 148 PageID: 96

US 8,735,428 B2 15 16 (e.g., Gleevec®), imiquimod; immunostimulant peptides; translation inhibitors; tretinoin; triacetyluridine; triciribine; insulin-like growth factor-I receptor inhibitor; interferon trimetrexate; triptorelin; tropisetron; turosteride; tyrosine agonists; interferons; interleukins; iobenguane; iododoxoru­ kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; bicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; iso­ urogenital sinus-derived growth inhibitory factor; urokinase homohalicondrin B; itasetron; jasplakinolide; kahalalide F; 5 receptor antagonists; vapreotide; variolin B; velaresol; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; veramine; verdins; verteporfin; vinorelbine; vinxaltine; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and factor; leukocyte alpha interferon; leuprolide+estrogen+ zinostatin stimalamer. progesterone; leuprorelin; levamisole; liarozole; linear Specific second active agents include, but are not limited polyamine analogue; lipophilic disaccharide peptide; lipo­ 10 to, oblimersen (Genasense®), remicade, docetaxel, cele­ philic platinum compounds; lissoclinamide 7; lobaplatin; coxib, melphalan, dexamethasone (Decadron®), steroids, lombricine; lometrexol; lonidamine; losoxantrone; loxorib­ gemcitabine, cisplatinum, temozolomide, etoposide, cyclo­ ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep­ phosphamide, temodar, carboplatin, procarbazine, gliadel, tides; maitansine; mannostatin A; marimastat; masoprocol; tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere, maspin; matrilysin inhibitors; matrix metalloproteinase 15 fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, inter­ inhibitors; menogaril; merbarone; meterelin; methioninase; feron alpha, pegylated interferon alpha (e.g., PEG INTRON­ metoclopramide; MIF inhibitor; mifepristone; miltefosine; A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, mirimostim; mitoguazone; mitolactol; mitomycin analogues; liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel, mitonafide; mitotoxin fibroblast growth factor-saporin; vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, mitoxantrone; mofarotene; molgramostim; Erbitux, human 20 zoledronic acid, palmitronate, biaxin, busulphan, prednisone, chorionic gonadotrophin; monophosphoryl lipidA+myobac­ bisphosphonate, arsenic trioxide, vincristine, doxorubicin terium cell wall sk; mopidamol; mustard anticancer agent; (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustine mycaperoxide B; mycobacterial cell wall extract; myriapor­ sodium phosphate (Emcyt®), sulindac, and etoposide. one; N-acetyldinaline; N-substituted benzamides; nafarelin; 5.3 Methods of Treatments and Prevention nagrestip; naloxone+pentazocine; napavin; naphterpin; nar- 25 Methods of this invention encompass methods of treating, tograstim; nedaplatin; nemorubicin; neridronic acid; niluta­ preventing and/or managing various types of cancer and dis­ mide; nisamycin; nitric oxide modulators; nitroxide antioxi­ eases and disorders associated with, or characterized by, dant; nitrullyn; oblimersen (Genasense®); undesired angiogenesis. As used herein, unless otherwise 0 6 -benzylguanine; octreotide; okicenone; oligonucleotides; specified, the term "treating" refers to the administration of a onapristone; ondansetron; ondansetron; oracin; oral cytokine 30 compound of the invention or other additional active agent inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; after the onset of symptoms of the particular disease or dis- paclitaxel; paclitaxel analogues; paclitaxel derivatives; order. As used herein, unless otherwise specified, the term palauamine; palmitoylrhizoxin; pamidronic acid; panax­ "preventing" refers to the administration prior to the onset of ytriol; panomifene; parabactin; pazelliptine; pegaspargase; symptoms, particularly to patients at risk of cancer, and other peldesine; pentosan polysulfate sodium; pentostatin; pentro- 35 diseases and disorders associated with, or characterized by, zole; perflubron; perfosfamide; perillyl alcohol; phenazino­ undesired angiogenesis. The term "prevention" includes the mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo­ inhibition of a symptom of the particular disease or disorder. carpine hydrochloride; pirarubicin; piritrexim; placetin A; Patients with familial history of cancer and diseases and placetin B; plasminogen activator inhibitor; platinum com­ disorders associated with, or characterized by, undesired plex; platinum compounds; platinum-triamine complex; por- 40 angiogenesis are preferred candidates for preventive regi­ fimer sodium; porfiromycin; prednisone; propyl bis-acri­ mens. As used herein and unless otherwise indicated, the term done; prostaglandin 12; proteasome inhibitors; protein "managing" encompasses preventing the recurrence of the A-based immune modulator; protein kinase C inhibitor; pro­ particular disease or disorder in a patient who had suffered tein kinase C inhibitors, microalgal; protein tyrosine phos­ from it, and/or lengthening the time a patient who had suf­ phatase inhibitors; purine nucleoside phosphorylase inhibi- 45 fered from the disease or disorder remains in remission. tors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin As used herein, the term "cancer" includes, but is not polyoxyethylene conjugate; raf antagonists; raltitrexed; limited to, solid tumors and blood born tumors. The term ramosetron; ras farnesyl protein transferase inhibitors; ras "cancer" refers to disease of skin tissues, organs, blood, and inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe­ vessels, including, but not limited to, cancers of the bladder, nium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; 50 bone or blood, brain, breast, cervix, chest, colon, rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; endrometrium, esophagus, eye, head, kidney, liver, lymph safingol; saintopin; SarCNU; sarcophytol A; sargramostim; nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, Sdi 1 mimetics; semustine; senescence derived inhibitor 1; stomach, testis, throat, and uterus. Specific cancers include, sense oligonucleotides; signal transduction inhibitors; sizofi­ but are not limited to, advanced malignancy, amyloidosis, ran; sobuzoxane; sodium borocaptate; sodium phenylacetate; 55 neuroblastoma, meningioma, hemangiopericytoma, multiple solverol; somatomedin binding protein; sonermin; sparfosic brain metastase, glioblastoma multiforms, glioblastoma, acid; spicamycin D; spiromustine; splenopentin; spongistatin brain stem glioma, poor prognosis malignant brain tumor, 1; squalamine; stipiamide; stromelysin inhibitors; sulfi­ malignant glioma, recurrent malignant glioma, anaplastic nosine; superactive vasoactive intestinal peptide antagonist; astrocytoma, anaplastic oligodendroglioma, neuroendocrine suradista; suramin; swainsonine; tallimustine; tamoxifen 60 tumor, rectal adenocarcinoma, Dukes C & D colorectal can­ methiodide; tauromustine; tazarotene; tecogalan sodium; cer, unresectable colorectal carcinoma, metastatic hepatocel- tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; lular carcinoma, Kaposi's sarcoma, karotype acute myelo­ teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; blastic leukemia, Hodgkin's lymphoma, non-Hodgkin's thiocoraline; thrombopoietin; thrombopoietin mimetic; thy­ lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell malfasin; thymopoietin receptor agonist; thymotrinan; thy- 65 lymphoma, diffuse large B-Cell lymphoma, low grade folli­ raid stimulating hormone; tin ethyl etiopurpurin; tira­ cular lymphoma, malignant melanoma, malignant mesothe- pazaminc; titanocene bichloride; topsentin; toremifene; lioma, malignant pleural effusion mesothelioma syndrome, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 97 of 148 PageID: 97

US 8,735,428 B2 17 18 peritoneal carcinoma, papillary serous carcinoma, gyneco­ This invention encompasses methods of treating patients logic sarcoma, soft tissue sarcoma, scleroderma, cutaneous who have been previously treated for cancer or diseases or vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, disorders associated with, or characterized by, undesired fibrodysplasia ossificans progressive, hormone refractory angiogenesis, but are non-responsive to standard therapies, as prostate cancer, resected high-risk soft tissue sarcoma, unre- 5 well as those who have not previously been treated. The spectable hepatocellular carcinoma, Waldenstrom's macro­ invention also encompasses methods of treating patients globulinemia, smoldering myeloma, indolent myeloma, fal­ regardless of patient's age, although some diseases or disor­ lopian tube cancer, androgen independent prostate cancer, ders are more common in certain age groups. The invention androgen dependent stage IV non-metastatic prostate cancer, further encompasses methods of treating patients who have hormone-insensitive prostate cancer, chemotherapy-insensi- 10 undergone surgery in an attempt to treat the disease or con­ tive prostate cancer, papillary thyroid carcinoma, follicular dition at issue, as well as those who have not. Because patients thyroid carcinoma, medullary thyroid carcinoma, and lei­ with cancer and diseases and disorders characterized by omyoma. In a specific embodiment, the cancer is metastatic. undesired angiogenesis have heterogenous clinical manifes­ In another embodiment, the cancer is refractory or resistance tations and varying clinical outcomes, the treatment given to to chemotherapy or radiation; in particular, refractory to tha- 15 a patient may vary, depending on his/her prognosis. The lidomide. skilled clinician will be able to readily determine without As used herein to refer to diseases and conditions other undue experimentation specific secondary agents, types of than cancer, the terms "diseases or disorders associated with, surgery, and types of non-drug based standard therapy that or characterized by, undesired angiogenesis," "diseases or can be effectively used to treat an individual patient with disorders associated with undesired angiogenesis," and "dis­ 20 cancer and other diseases or disorders. eases or disorders characterized by undesired angiogenesis" Methods encompassed by this invention comprise admin­ refer to diseases, disorders and conditions that are caused, istering one or more immunomodulatory compound of the mediated or attended by undesired, unwanted or uncontrolled invention, or a pharmaceutically acceptable salt, solvate, angiogenesis, including, but not limited to, inflanmiatory dis­ hydrate, stereoisomer, clathrate, or prodrug thereof, to a eases, autoimmune diseases, genetic diseases, allergic dis­ 25 patient (e.g., a human) suffering, or likely to suffer, from eases, bacterial diseases, ocular neovascular diseases, chor­ cancer or a disease or disorder mediated by undesired angio- oidal neovascular diseases, and retina neovascular diseases. genesis. Examples of such diseases or disorders associated with In one embodiment of the invention, an immunomodula­ undesired angiogenesis include, but are not limited to, dia­ tory compound of the invention can be administered orally betic retinopathy, retinopathy of prematurity, corneal graft 30 and in single or divided daily doses in an amount of from rejection, neovascular glaucoma, retrolental fibroplasia, pro­ about 0.10 to about 150 mg/day. In a particular embodiment, liferative vitreoretinopathy, trachoma, myopia, optic pits, 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione epidemic keratoconjunctivitis, atopic keratitis, superior lim­ (Actimid™) may be administered in an amount of from about bic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea, 0.1 to about 1 mg per day, or alternatively from about 0.1 to phylectenulosis, syphilis, lipid degeneration, bacterial ulcer, 35 about 5 mg every other day. In a preferred embodiment, fungal ulcer, Herpes simplex infection, Herpes zoster infec­ 3-(4-amino- l-oxo-l ,3-dihydro-isoindol-2-yl-piperidine-2,6- tion, protozoan infection, Kaposi sarcoma, Mooren ulcer, dione (Revimid™) may be administered in an amount of from Terrien's marginal degeneration, mariginal keratolysis, rheu­ about 5 to 25 mg per day, or alternatively from about 10 to matoid arthritis, systemic lupus, polyarteritis, trauma, Wege­ about 50 mg every other day. ners sarcoidosis, Scleritis, Steven's Johnson disease, periph- 40 In a specific embodiment, 4-(amino)-2-(2,6-dioxo(3-pip­ igoid radial keratotomy, sickle cell anemia, sarcoid, eridyl))-isoindoline-l,3-dione (Actimid™) may be adminis­ pseudoxanthoma elasticum, Pagets disease, vein occlusion, tered in an amount of about 1, 2, or 5 mg per day to patients artery occlusion, carotid obstructive disease, chronic uveitis, with relapsed multiple myeloma. In a particular embodiment, chronic vitritis, Lyme's disease, Eales disease, Behcet's dis­ 3-(4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2, ease, retinitis, choroiditis, presumed ocular histoplasmosis, 45 6-dione (Revimid™) may be administered initially in an Bests disease, Stargarts disease, pars planitis, chronic retinal amount of 5 mg/day and the dose can be escalated every week detachment, hyperviscosity syndromes, toxoplasmosis, to 10, 20, 25, 30 and 50 mg/day. In a specific embodiment, rubeosis, sarcodisis, sclerosis, soriatis, psoriasis, primary Revimid™ can be administered in an amount ofup to about sclerosing cholangitis, proctitis, primary biliary srosis, idio­ 30 mg/day to patients with solid tumor. In a particular pathic pulmonary fibrosis, and alcoholic hepatitis. 50 embodiment, Revimid™ can be administered in an amount of In specific embodiments of the invention, diseases or dis­ up to about 40 mg/day to patients with glioma. orders associated with undesired angiogenesis do not include 5 .3 .1 Combination Therapy with a Second Active Agent congestive heart failure, cardiomyopathy, pulmonary edema, Specific methods of the invention comprise administering endotoxin-mediated septic shock, acute viral myocarditis, an immunomodulatory compound of the invention, or a phar­ cardiac allograft rejection, myocardial infarction, HIV, hepa- 55 maceutically acceptable salt, solvate, hydrate, stereoisomer, titis, adult respiratory distress syndrome, bone-resorption clathrate, or prodrug thereof, in combination with one or disease, chronic obstructive pulmonary diseases, chronic pul­ more second active agents, and/ or in combination with radia­ monary inflanmiatory disease, dermatitis, cystic fibrosis, sep- tion therapy, blood transfusions, or surgery. Examples of tic shock, sepsis, endotoxic shock, hemodynamic shock, sep- immunomodulatory compounds of the invention are dis­ sis syndrome, post ischemic reperfusion injury, meningitis, 60 closed herein (see, e.g., section 5.1). Examples of second psoriasis, fibrotic disease, cachexia, graft rejection, rheuma­ active agents are also disclosed herein (see, e.g., section 5.2). toid spondylitis, osteoporosis, Crohn's disease, ulcerative Administration of the immunomodulatory compounds and colitis, inflammatory-bowel disease, multiple sclerosis, sys­ the second active agents to a patient can occur simultaneously temic lupus erythrematosus, erythema nodosum leprosum in or sequentially by the same or different routes of administra­ leprosy, radiation damage, asthma, hyperoxic alveolar injury, 65 tion. The suitability of a particular route of administration malaria, mycobacterial infection, and opportunistic infec­ employed for a particular active agent will depend on the tions resulting from HIV. active agent itself (e.g., whether it can be administered orally Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 98 of 148 PageID: 98

US 8,735,428 B2 19 20 without decomposing prior to entering the blood stream) and recurrent or progressive meningioma, malignant menin­ the disease being treated. A preferred route of administration gioma, hemangiopericytoma, multiple brain metastases, for an immunomodulatory compound of the invention is relapsed brain tumors, or newly diagnosed glioblastoma mul- orally. Preferred routes of administration for the second active tiforms; irinotecan to patients with recurrent glioblastoma; agents or ingredients of the invention are known to those of 5 carboplatin to pediatric patients with brain stem glioma; pro­ ordinary skill in the art. See, e.g., Physicians' Desk Refer­ carbazine to pediatric patients with progressive malignant ence, 1755-1760 (56'h ed., 2002). gliomas; cyclophosphamide to patients with poor prognosis In one embodiment of the invention, the second active malignant brain tumors, newly diagnosed or recurrent glio- agent is administered intravenously or subcutaneously and blastoma multiforms; Gliadel® for high grade recurrent once or twice daily in an amount of from about 1 to about 10 malignant gliomas; temozolomide and tamoxifen for ana­ 1000 mg, from about 5 to about 500 mg, from about 10 to plastic astrocytoma; or topotecan for gliomas, glioblastoma, about 350 mg, or from about 50 to about 200 mg. The specific anaplastic astrocytoma or anaplastic oligodendroglioma. amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the In another embodiment, an immunomodulatory compound is administered with methotrexate and cyclophosphamide to severity and stage of disease, and the amount(s) of immuno- 15 modulatory compounds of the invention and any optional patients with metastatic breast cancer. additional active agents concurrently administered to the In another embodiment, an immunomodulatory compound patient. In a particular embodiment, the second active agent is is administered with temozolomide to patients with neuroen­ oblimersen (Genasense®), GM-CSF, G-CSF, EPO, taxotere, docrine tumors. irinotecan, dacarbazine, transretinoic acid, topotecan, pen- 20 In another embodiment, an immunomodulatory compound toxifylline, ciprofloxacin, dexamethasone, vincristine, doxo­ is administered with gemcitabine to patients with recurrent or rubicin, COX-2 inhibitor, IL2, ILS, IL18, IFN, Ara-C, metastatic head or neck cancer. In another embodiment, an vinorelbine, or a combination thereof. immunomodulatory compound is administered with gemcit­ In a particular embodiment, GM-CSF, G-CSF or EPO is abine to patients with pancreatic cancer. administered subcutaneously during about five days in a four 25 In another embodiment, an immunomodulatory compound or six week cycle in an amount of from about 1 to about 750 is administered to patients with colon cancer in combination mg/m2 /day, preferably in an amount of from about 25 to about with Arisa®, taxol and/or taxotere. 500 mg/m2/day, more preferably in an amount of from about In another embodiment, an immunomodulatory compound 50 to about 250 mg/m2 /day, and most preferably in an amount is administered with capecitabine to patients with refractory 2 of from about 50 to about 200 mg/m /day. In a certain 30 colorectal cancer or patients who fail first line therapy or have embodiment, GM-CSF may be administered in an amount of poor performance in colon or rectal adenocarcinoma. from about 60 to about 500 mcg/m2 intravenously over 2 In another embodiment, an immunomodulatory compound hours, or from about 5 to about 12 mcg/m2/day subcutane­ is administered in combination with fluorouracil, leucovorin, ously. In a specific embodiment, G-CSF may be administered and irinotecan to patients with Dukes C & D colorectal cancer subcutaneously in an amount of about 1 mcg/kg/day initially 35 or to patients who have been previously treated for metastatic and can be adjusted depending on rise of total granulocyte colorectal cancer. counts. The maintenance dose ofG-CSF may be administered In another embodiment, an immunomodulatory compound in an amount of about 300 (in smaller patients) or 480 mcg is administered to patients with refractory colorectal cancer in subcutaneously. In a certain embodiment, EPO may be combination with capecitabine, xeloda, and/or CPT-11. administered subcutaneously in an amount of 10,000 Unit 3 40 In another embodiment, an immunomodulatory compound times per week. of the invention is administered with capecitabine and irino­ In another embodiment, Revimid™ in an amount of about tecan to patients with refractory colorectal cancer or to 25 mg/d and dacarbazine in an amount of about from 200 to patients with unresectable or metastatic colorectal carci­ 1,000 mg/m2 /d are administered to patients with metastatic noma. malignant melanoma. In a specific embodiment, Revimid™ 45 In another embodiment, an immunomodulatory compound is administered in an amount of from about 5 to about 25 mg/d is administered alone or in combination with interferon alpha to patients with metastatic malignant melanoma whose dis­ or capecitabine to patients with unresectable or metastatic ease has progressed on treatment with dacarbazine, IL-2 or hepatocellular carcinoma; or with cisplatin and thiotepa to IFN. In a specific embodiment, Revimid™ is administered to patients with primary or metastatic liver cancer. patients with relapsed or refractory multiple myeloma in an 50 In another embodiment, an immunomodulatory compound amount of about 15 mg/d twice a day or about 30 mg/d four is administered in combination with pegylated interferon times a day in a combination with dexamethasone. alpha to patients with Kaposi's sarcoma. In another embodiment, an immunomodulatory compound In another embodiment, an immunomodulatory compound is administered with melphalan and dexamethasone to is administered in combination with fludarabine, carboplatin, patients with amyloidosis. In a specific embodiment, an 55 and/or topotecan to patients with refractory or relapsed or immunomodulatory compound of the invention and steroids high-risk acuted myelogenous leukemia. can be administered to patients with amyloidosis. In another embodiment, an immunomodulatory compound In another embodiment, an immunomodulatory compound is administered in combination with liposomal daunorubicin, is administered with gemcitabine and cisplatinum to patients topotecan and/or cytarabine to patients with unfavorable with locally advanced or metastatic transitional cell bladder 60 karotype acute myeloblastic leukemia. cancer. In another embodiment, an immunomodulatory compound In another embodiment, an immunomodulatory compound is administered in combination with gemcitabine and irino­ is administered in combination with a second active ingredi­ tecan to patients with non-small cell lung cancer. In one ent as follows: temozolomide to pediatric patients with embodiment, an immunomodulatory compound is adminis- relapsed or progressive brain tumors or recurrent neuroblas­ 65 tered in combination with carboplatin and irinotecan to toma; celecoxib, etoposide and cyclophosphamide for patients with non-small cell lung cancer. In one embodiment, relapsed or progressive CNS cancer; temodar to patients with an immunomodulatory compound is administered with dox- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 99 of 148 PageID: 99

US 8,735,428 B2 21 22 etaxol to patients with non-small cell lung cancer who have solid tumors in combination with celebrex, etoposide, cyclo­ been previously treated with carboNP 16 and radiotherapy. phosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, In another embodiment, an immunomodulatory compound GM-CSF, or a combination thereof. is administered in combination with carboplatin and/or taxo­ In another embodiment, an immunomodulatory compound tere, or in combination with carboplatin, pacilitaxel and/or 5 is administered to patients with scleroderma or cutaneous thoracic radiotherapy to patients with non-small cell lung vasculitis in combination with celebrex, etoposide, cyclo­ cancer. In a specific embodiment, an immunomodulatory phosphamide, docetaxel, apecitabine, IFN, tamoxifen, IL-2, compound is administered in combination with taxotere to GM-CSF, or a combination thereof. patients with stage IIIB or IV non-small cell lung cancer. This invention also encompasses a method of increasing In another embodiment, an immunomodulatory compound 1 o the dosage of an anti-cancer drug or agent that can be safely of the invention is administered in combination with and effectively administered to a patient, which comprises oblimersen (Genasense®) to patients with small cell lung administering to a patient (e.g., a human) an immunomodu­ cancer. In another embodiment, an immunomodulatory compound latory compound of the invention, or a pharmaceutically acceptable derivative, salt, solvate, clathrate, hydrate, or pro­ is administered alone or in combination with a second active 15 ingredient such as vinblastine or fludarabine to patients with drug thereof. Patients that can benefit by this method are those various types of lymphoma, including, but not limited to, likely to suffer from an adverse effect associated with anti­ Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous cancer drugs for treating a specific cancer of the skin, subcu­ T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large taneous tissue, lymph nodes, brain, lung, liver, bone, intes- B-Cell lymphoma or relapsed or refractory low grade folli­ 20 tine, colon, heart, pancreas, adrenal, kidney, prostate, breast, cular lymphoma. colorectal, or combinations thereof. The administration of an In another embodiment, an immunomodulatory compound immunomodulatory compound of the invention alleviates or is administered in combination with taxotere, IL-2, IFN, GM­ reduces adverse effects which are of such severity that it CSF, and/or dacarbazine to patients with various types or would otherwise limit the amount of anti-cancer drug. stages of melanoma. 25 In one embodiment, an immunomodulatory compound of In another embodiment, an immunomodulatory compound the invention can be administered orally and daily in an is administered alone or in combination with vinorelbine to amount of from about 0.1 to about 150 mg, and preferably patients with malignant mesothelioma, or stage IIIB non­ from about 1 to about 50 mg, more preferably from about 2 to small cell lung cancer with pleural implants or malignant about 25 mg prior to, during, or after the occurrence of the pleural effusion mesothelioma syndrome. 30 adverse effect associated with the administration of an anti- In another embodiment, an immunomodulatory compound cancer drug to a patient. In a particular embodiment, an is administered to patients with various types or stages of immunomodulatory compound of the invention is adminis­ multiple myeloma in combination with dexamethasone, tered in combination with specific agents such as heparin, zoledronic acid, palmitronate, GM-CSF, biaxin, vinblastine, aspirin, coumadin, or G-CSF to avoid adverse effects that are melphalan, busulphan, cyclophosphamide, IFN, palmidr- 35 associated with anti-cancer drugs such as but not limited to onate, prednisone, bisphosphonate, celecoxib, arsenic triox­ neutropenia or thrombocytopenia. ide, PEG INTRON-A, vincristine, or a combination thereof. In one embodiment, an immunomodulatory compound of In another embodiment, an immunomodulatory compound the invention can be administered to patients with diseases is administered to patients with relapsed or refractory mul­ and disorders associated with, or characterized by, undesired tiple myeloma in combination with doxorubicin (Doxil®), 40 angiogenesis in combination with additional active ingredi­ vincristine and/or dexamethasone (Decadron®). ents including but not limited to anti-cancer drugs, anti-in- In another embodiment, an immunomodulatory compound flanimatories, antihistamines, antibiotics, and steroids. is administered to patients with various types or stages of In another embodiment, this invention encompasses a ovarian cancer such as peritoneal carcinoma, papillary serous method of treating, preventing and/or managing cancer, carcinoma, refractory ovarian cancer or recurrent ovarian 45 which comprises administering an immunomodulatory com­ cancer, in combination with taxol, carboplatin, doxorubicin, pound of the invention, or a pharmaceutically acceptable salt, gemcitabine, cisplatin, xeloda, paclitaxel, dexamethasone, or solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, a combination thereof. in conjunction with (e.g. before, during, or after) conven­ In another embodiment, an immunomodulatory compound tional therapy including, but not limited to, surgery, immu­ is administered to patients with various types or stages of 50 notherapy, biological therapy, radiation therapy, or other non­ prostate cancer, in combination with xeloda, 5 FU/LY, gem­ drug based therapy presently used to treat, prevent or manage citabine, irinotecan plus gemcitabine, cyclophosphamide, cancer. The combined use of the immunomodulatory com­ vincristine, dexamethasone, GM-CSF, celecoxib, taxotere, pounds of the invention and conventional therapy may pro­ ganciclovir, paclitaxel, adriamycin, docetaxel, estramustine, vide a unique treatment regimen that is unexpectedly effec- Emcyt, or a combination thereof. 55 tive in certain patients. Without being limited by theory, it is In another embodiment, an immunomodulatory compound believed that immunomodulatory compounds of the inven­ is administered to patients with various types or stages of tion may provide additive or synergistic effects when given renal cell cancer, in combination with capecitabine, IFN, concurrently with conventional therapy. tamoxifen, IL-2, GM-CSF, Celebrex®, or a combination As discussed elsewhere herein, the invention encompasses thereof. 60 a method of reducing, treating and/or preventing adverse or In another embodiment, an immunomodulatory compound undesired effects associated with conventional therapy is administered to patients with various types or stages of including, but not limited to, surgery, chemotherapy, radia­ gynecologic, uterus or soft tissue sarcoma cancer in combi­ tion therapy, hormonal therapy, biological therapy and immu­ nation with IFN, a COX-2 inhibitor such as Celebrex®, and/ notherapy. One or more immunomodulatory compounds of or sulindac. 65 the invention and other active ingredient can be administered In another embodiment, an immunomodulatory compound to a patient prior to, during, or after the occurrence of the is administered to patients with various types or stages of adverse effect associated with conventional therapy. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 100 of 148 PageID: 100

US 8,735,428 B2 23 24 In one embodiment, an immunomodulatory compound of In another embodiment, an immunomodulatory compound the invention can be administered in an amount of from about is administered following the administration of high dose of 0.1 to about 150 mg, and preferably from about 1 to about 25 melphalan and the transplantation of autologous stem cell to mg, more preferably from about 2 to about 10 mg orally and patients with chemotherapy responsive multiple myeloma. daily alone, or in combination with a second active agent 5 In another embodiment, an immunomodulatory compound disclosed herein (see, e.g., section 5.2), prior to, during, or and PEG INTRO-A are administered as maintenance therapy after the use of conventional therapy. to patients with multiple myeloma following the transplanta­ In a specific embodiment ofthis method, an immunomodu­ tion of autologous CD34-selected peripheral stem cell. latory compound of the invention and doxetaxol are admin­ In another embodiment, an immunomodulatory compound istered to patients with non-small cell lung cancer who were 10 is administered with post transplant consolidation chemo­ previously treated with carboNP 16 and radiotherapy. therapy to patients with newly diagnosed multiple myeloma 5.3.2 Use with Transplantation Therapy to evaluate anti-angiogenesis. Compounds of the invention can be used to reduce the risk In another embodiment, an immunomodulatory compound of Graft Versus Host Disease (GVHD). Therefore, the inven­ and dexamethasone are administered as maintenance therapy tion encompasses a method of treating, preventing and/or 15 after DCEP consolidation, following the treatment with high managing cancer, which comprises administering the immu­ dose of melphalan and the transplantation of peripheral blood nomodulatory compound of the invention, or a pharmaceuti­ stem cell to 65 years of age or older patients with multiple cally acceptable salt, solvate, hydrate, stereoisomer, clath­ myeloma. rate, or prodrug thereof, in conjunction with transplantation 5 .3 .3 Cycling Therapy therapy. 20 In certain embodiments, the prophylactic or therapeutic As those of ordinary skill in the art are aware, the treatment agents of the invention are cyclically administered to a of cancer is often based on the stages and mechanism of the patient. Cycling therapy involves the administration of an disease. For example, as inevitable leukemic transformation active agent for a period of time, followed by a rest for a develops in certain stages of cancer, transplantation ofperiph­ period of time, and repeating this sequential administration. eral blood stem cells, hematopoietic stem cell preparation or 25 Cycling therapy can reduce the development of resistance to bone marrow may be necessary. The combined use of the one or more of the therapies, avoid or reduce the side effects immunomodulatory compound of the invention and trans­ of one of the therapies, and/or improves the efficacy of the plantation therapy provides a unique and unexpected syner­ treatment. gism. In particular, an immunomodulatory compound of the Consequently, in one specific embodiment of the inven- invention exhibits immunomodulatory activity that may pro­ 30 tion, an immunomodulatory compound of the invention is vide additive or synergistic effects when given concurrently administered daily in a single or divided doses in a four to six with transplantation therapy in patients with cancer. week cycle with a rest period of about a week or two weeks. An immunomodulatory compound of the invention can The invention further allows the frequency, number, and work in combination with transplantation therapy reducing length of dosing cycles to be increased. Thus, another specific complications associated with the invasive procedure of 35 embodiment of the invention encompasses the administration transplantation and risk of GVHD. This invention encom­ of an immunomodulatory compound of the invention for passes a method of treating, preventing and/or managing more cycles than are typical when it is administered alone. In cancer which comprises administering to a patient (e.g., a yet another specific embodiment of the invention, an immu­ human) an immunomodulatory compound of the invention, nomodulatory compound of the invention is administered for or a pharmaceutically acceptable salt, solvate, hydrate, stere­ 40 a greater number of cycles that would typically cause dose­ oisomer, clathrate, or prodrug thereof, before, during, or after limiting toxicity in a patient to whom a second active ingre­ the transplantation of umbilical cord blood, placental blood, dient is not also being administered. peripheral blood stem cell, hematopoietic stem cell prepara­ In one embodiment, an immunomodulatory compound of tion or bone marrow. Examples of stem cells suitable for use the invention is administered daily and continuously for three in the methods of the invention are disclosed in U.S. provi­ 45 or four weeks at a dose of from about 0.1 to about 150 mg/d sional patent application No. 60/372,348, filed Apr. 12, 2002 followed by a break of one or two weeks. Actimid™ is pref­ by R. Hariri et al., the entirety of which is incorporated herein erably administered daily and continuously at an initial dose by reference. of0.1 to 5 mg/d with dose escalation (every week) by 1 to 10 In one embodiment of this method, an immunomodulatory mg/d to a maximum dose of 50 mg/d for as long as therapy is compound of the invention is administered to patients with 50 tolerated. In a particular embodiment, Revimid™ is admin­ multiple myeloma before, during, or after the transplantation istered in an amount of about 5, 10, or 25 mg/day, preferably of autologous peripheral blood progenitor cell. in an amount of about 10 mg/day for three to four weeks, In another embodiment, an immunomodulatory compound followed by one week or two weeks of rest in a four or six is administered to patients with relapsing multiple myeloma week cycle. after the stem cell transplantation. 55 In one embodiment of the invention, an immunomodula- In another embodiment, an immunomodulatory compound tory compound of the invention and a second active ingredi­ and prednisone are administered as maintenance therapy to ent are administered orally, with administration of an immu­ patients with multiple myeloma following the transplantation nomodulatory compound of the invention occurring 30 to 60 of autologous stem cell. minutes prior to a second active ingredient, during a cycle of In another embodiment, an immunomodulatory compound 60 four to six weeks. In another embodiment ofthe invention, the and dexamethasone are administered as salvage therapy for combination of an immunomodulatory compound of the low risk post transplantation to patients with multiple invention and a second active ingredient is administered by myeloma. intravenous infusion over about 90 minutes every cycle. In a In another embodiment, an immunomodulatory compound specific embodiment, one cycle comprises the administration and dexamethasone are administered as maintenance therapy 65 of from about 10 to about 25 mg/day ofRevimid™ and from to patients with multiple myeloma following the transplanta­ about 50 to about 200 mg/m2/day of a second active ingredi­ tion of autologous bone marrow. ent daily for three to four weeks and then one or two weeks of Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 101 of 148 PageID: 101

US 8,735,428 B2 25 26 rest. In another specific embodiment, each cycle comprises tablets may contain excipients not suited for use in parenteral the administration of from about 5 to about 10 mg/day of dosage forms. The suitability of a particular excipient may Actimid™ and from about 50 to about 200 mg/m2/day of a also depend on the specific active ingredients in the dosage second active ingredient for 3 to 4 weeks followed by one or form. For example, the decomposition of some active ingre- two weeks of rest. Typically, the number of cycles during 5 dients may be accelerated by some excipients such as lactose, which the combinatorial treatment is administered to a patient or when exposed to water. Active ingredients that comprise will be from about one to about 24 cycles, more typically from primary or secondary amines are particularly susceptible to about two to about 16 cycles, and even more typically from such accelerated decomposition. Consequently, this inven­ about four to about three cycles. tion encompasses pharmaceutical compositions and dosage 5.4 Pharmaceutical Compositions and Dosage Forms 10 forms that contain little, if any, lactose other mono- or di­ Pharmaceutical compositions can be used in the prepara­ saccharides. As used herein, the term "lactose-free" means tion of individual, single unit dosage forms. Pharmaceutical that the amount of lactose present, if any, is insufficient to compositions and dosage forms of the invention comprise an substantially increase the degradation rate of an active ingre­ immunomodulatory compound of the invention, or a pharma­ dient. ceutically acceptable salt, solvate, hydrate, stereoisomer, 15 Lactose-free compositions of the invention can comprise clathrate, or prodrug thereof. Pharmaceutical compositions excipients that are well known in the art and are listed, for and dosage forms of the invention can further comprise one or example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). more excipients. In general, lactose-free compositions comprise active ingre­ Pharmaceutical compositions and dosage forms of the dients, a binder/filler, and a lubricant in pharmaceutically invention can also comprise one or more additional active 20 compatible and pharmaceutically acceptable amounts. Pre­ ingredients. Consequently, pharmaceutical compositions and ferred lactose-free dosage forms comprise active ingredients, dosage forms of the invention comprise the active ingredients microcrystalline cellulose, pre-gelatinized starch, and mag­ disclosed herein (e.g., an immunomodulatory compound and nesium stearate. a second active agent). Examples of optional second, or addi­ This invention further encompasses anhydrous pharma­ tional, active ingredients are disclosed herein (see, e.g., sec- 25 ceutical compositions and dosage forms comprising active tion 5.2). ingredients, since water can facilitate the degradation of some Single unit dosage forms of the invention are suitable for compounds. For example, the addition of water (e.g., 5%) is oral, mucosa! ( e.g., nasal, sub lingual, vaginal, buccal, or rec­ widely accepted in the pharmaceutical arts as a means of tal), parenteral (e.g., subcutaneous, intravenous, bolus injec­ simulating long-term storage in order to determine character- tion, intramuscular, or intraarterial), topical (e.g., eye drops or 30 istics such as shelf-life or the stability of formulations over other ophthalmic preparations), transdermal or transcutane­ time. See, e.g., Jens T. Carstensen, Drug Stability: Principles ous administration to a patient. Examples of dosage forms & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. include, but are not limited to: tablets; caplets; capsules, such 379-80. In effect, water and heat accelerate the decomposi­ as soft elastic gelatin capsules; cachets; troches; lozenges; tion of some compounds. Thus, the effect of water on a dispersions; suppositories; powders; aerosols (e.g., nasal 35 formulation can be of great significance since moisture and/or sprays or inhalers); gels; liquid dosage forms suitable for oral humidity are commonly encountered during manufacture, or mucosa! administration to a patient, including suspensions handling, packaging, storage, shipment, and use of formula­ (e.g., aqueous or non-aqueous liquid suspensions, oil-in-wa- tions. ter emulsions, or a water-in-oil liquid emulsions), solutions, Anhydrous pharmaceutical compositions and dosage and elixirs; liquid dosage forms suitable for parenteral admin- 40 forms of the invention can be prepared using anhydrous or istration to a patient; eye drops or other ophthalmic prepara­ low moisture containing ingredients and low moisture or low tions suitable for topical administration; and sterile solids humidity conditions. Pharmaceutical compositions and dos­ (e.g., crystalline or amorphous solids) that can be reconsti­ age forms that comprise lactose and at least one active ingre­ tuted to provide liquid dosage forms suitable for parenteral dient that comprises a primary or secondary amine are pref- administration to a patient. 45 erably anhydrous if substantial contact with moisture and/or The composition, shape, and type of dosage forms of the humidity during manufacturing, packaging, and/or storage is invention will typically vary depending on their use. For expected. example, a dosage form used in the acute treatment of a An anhydrous pharmaceutical composition should be pre­ disease may contain larger amounts of one or more of the pared and stored such that its anhydrous nature is maintained. active ingredients it comprises than a dosage form used in the 50 Accordingly, anhydrous compositions are preferably pack­ chronic treatment of the same disease. Similarly, a parenteral aged using materials known to prevent exposure to water such dosage form may contain smaller amounts of one or more of that they can be included in suitable formulary kits. Examples the active ingredients it comprises than an oral dosage form of suitable packaging include, but are not limited to, hermeti­ used to treat the same disease. These and other ways in which cally sealed foils, plastics, unit dose containers (e.g., vials), specific dosage forms encompassed by this invention will 55 blister packs, and strip packs. vary from one another will be readily apparent to those skilled The invention further encompasses pharmaceutical com­ in the art. See, e.g., Remington's Pharmaceutical Sciences, positions and dosage forms that comprise one or more com­ 18th ed., Mack Publishing, Easton Pa. (1990). pounds that reduce the rate by which an active ingredient will Typical pharmaceutical compositions and dosage forms decompose. Such compounds, which are referred to herein as comprise one or more excipients. Suitable excipients are well 60 "stabilizers," include, but are not limited to, antioxidants such known to those skilled in the art of pharmacy, and non­ as ascorbic acid, pH buffers, or salt buffers. limiting examples of suitable excipients are provided herein. Like the amounts and types of excipients, the amounts and Whether a particular excipient is suitable for incorporation specific types of active ingredients in a dosage form may into a pharmaceutical composition or dosage form depends differ depending on factors such as, but not limited to, the on a variety of factors well known in the art including, but not 65 route by which it is to be administered to patients. However, limited to, the way in which the dosage form will be admin­ typical dosage forms of the invention comprise an immuno- istered to a patient. For example, oral dosage forms such as modulatory compound of the invention or a pharmaceutically Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 102 of 148 PageID: 102

US 8,735,428 B2 27 28 acceptable salt, solvate, hydrate, stereoisomer, clathrate, or starches, gelatin, natural and synthetic gums such as acacia, prodrug thereof in an amount of from about 0.10 to about 150 sodium alginate, alginic acid, other alginates, powdered mg. Typical dosage forms comprise an immunomodulatory tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl compound of the invention or a pharmaceutically acceptable cellulose, cellulose acetate, carboxymethyl cellulose cal- salt, solvate, hydrate, stereoisomer, clathrate, or prodrug 5 cium, sodium carboxymethyl cellulose), polyvinyl pyrroli­ thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, done, methyl cellulose, pre-gelatinized starch, hydroxypro­ 17.5, 20, 25, 50, 100, 150 or 200 mg. Ina particular embodi­ pyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910), ment, a preferred dosage form comprises 4-(amino )-2-(2,6- microcrystalline cellulose, and mixtures thereof. dioxo(3-piperidyl))-isoindoline-l,3-dione (Actimid™) in an Suitable forms of microcrystalline cellulose include, but amount of about 1, 2, 5, 10, 25 or 50 mg. In a specific 10 are not limited to, the materials sold as AVICEL-PH-101, embodiment, a preferred dosage form comprises 3-(4-amino­ AVICEL-PH-103AVICELRC-581,AVICEL-PH-105 (avail­ l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (Re­ able from FMC Corporation, American Viscose Division, vimid™) in an amount of about 5, 10, 25 or 50 mg. Typical Avicel Sales, Marcus Hook, PA), and mixtures thereof. An dosage forms comprise the second active ingredient in an specific binder is a mixture of microcrystalline cellulose and amount of 1 to about 1000 mg, from about 5 to about 500 mg, 15 sodium carboxymethyl cellulose sold as AVICEL RC-581. from about 10 to about 350 mg, or from about 50 to about 200 Suitable anhydrous or low moisture excipients or additives mg. Of course, the specific amount of the anti-cancer drug includeAVICEL-PH-103™ and Starch 1500 LM. will depend on the specific agent used, the type of cancer Examples of fillers suitable for use in the pharmaceutical being treated or managed, and the amount(s) of an immuno­ compositions and dosage forms disclosed herein include, but modulatory compound of the invention and any optional 20 are not limited to, talc, calcium carbonate (e.g., granules or additional active agents concurrently administered to the powder), microcrystalline cellulose, powdered cellulose, patient. dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre­ 5.4.1 Oral Dosage Forms gelatinized starch, and mixtures thereof. The binder or filler in Pharmaceutical compositions of the invention that are suit­ pharmaceutical compositions of the invention is typically able for oral administration can be presented as discrete dos- 25 present in from about 50 to about 99 weight percent of the age forms, such as, but are not limited to, tablets (e.g., chew­ pharmaceutical composition or dosage form. able tablets), caplets, capsules, and liquids (e.g., flavored Disintegrants are used in the compositions of the invention syrups). Such dosage forms contain predetermined amounts to provide tablets that disintegrate when exposed to an aque­ of active ingredients, and may be prepared by methods of ous environment. Tablets that contain too much disintegrant pharmacy well known to those skilled in the art. See gener- 30 may disintegrate in storage, while those that contain too little ally, Remington's Pharmaceutical Sciences, 18th ed., Mack may not disintegrate at a desired rate or under the desired Publishing, Easton Pa. (1990). conditions. Thus, a sufficient amount of disintegrant that is Typical oral dosage forms of the invention are prepared by neither too much nor too little to detrimentally alter the combining the active ingredients in an intimate admixture release of the active ingredients should be used to form solid with at least one excipient according to conventional pharma- 35 oral dosage forms of the invention. The amount of disinte­ ceutical compounding techniques. Excipients can take a wide grant used varies based upon the type of formulation, and is variety of forms depending on the form of preparation desired readily discernible to those of ordinary skill in the art. Typical for administration. For example, excipients suitable for use in pharmaceutical compositions comprise from about 0.5 to oral liquid or aerosol dosage forms include, but are not limited about 15 weight percent of disintegrant, preferably from to, water, glycols, oils, alcohols, flavoring agents, preserva- 40 about 1 to about 5 weight percent of disintegrant. tives, and coloring agents. Examples of excipients suitable for Disintegrants that can be used in pharmaceutical compo­ use in solid oral dosage forms (e.g., powders, tablets, cap­ sitions and dosage forms of the invention include, but are not sules, and caplets) include, but are not limited to, starches, limited to, agar-agar, alginic acid, calcium carbonate, micro­ sugars, micro-crystalline cellulose, diluents, granulating crystalline cellulose, croscarmellose sodium, crospovidone, agents, lubricants, binders, and disintegrating agents. 45 polacrilin potassium, sodium starch glycolate, potato or tapi­ Because of their ease of administration, tablets and cap­ oca starch, other starches, pre-gelatinized starch, other sules represent the most advantageous oral dosage unit forms, starches, clays, other al gins, other celluloses, gums, and mix­ in which case solid excipients are employed. If desired, tab­ tures thereof. lets can be coated by standard aqueous or nonaqueous tech­ Lubricants that can be used in pharmaceutical composi­ niques. Such dosage forms can be prepared by any of the 50 tions and dosage forms of the invention include, but are not methods of pharmacy. In general, pharmaceutical composi­ limited to, calcium stearate, magnesium stearate, mineral oil, tions and dosage forms are prepared by uniformly and inti­ light mineral oil, glycerin, sorbitol, mannitol, polyethylene mately admixing the active ingredients with liquid carriers, glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, finely divided solid carriers, or both, and then shaping the hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, product into the desired presentation if necessary. 55 sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), For example, a tablet can be prepared by compression or zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures molding. Compressed tablets can be prepared by compress­ thereof. Additional lubricants include, for example, a syloid ing in a suitable machine the active ingredients in a free­ silica gel (AEROSIL200, manufactured by W.R. Grace Co. of flowing form such as powder or granules, optionally mixed Baltimore, Md.), a coagulated aerosol of synthetic silica with an excipient. Molded tablets can be made by molding in 60 (marketed by Degussa Co. of Plano, Tex.), CAB-0-SIL (a a suitable machine a mixture of the powdered compound pyrogenic silicon dioxide product sold by Cabot Co. of Bos- moistened with an inert liquid diluent. ton, Mass.), and mixtures thereof. If used at all, lubricants are Examples of excipients that can be used in oral dosage typically used in an amount of less than about 1 weight forms of the invention include, but are not limited to, binders, percent of the pharmaceutical compositions or dosage forms fillers, disintegrants, and lubricants. Binders suitable for use 65 into which they are incorporated. in pharmaceutical compositions and dosage forms include, A preferred solid oral dosage form of the invention com­ but are not limited to, corn starch, potato starch, or other prises an immunomodulatory compound of the invention, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 103 of 148 PageID: 103

US 8,735,428 B2 29 30 anhydrous lactose, microcrystalline cellulose, polyvinylpyr­ Injection, Dextrose and Sodium Chloride Injection, and Lac­ rolidone, stearic acid, colloidal anhydrous silica, and gelatin. tated Ringer's Injection; water-miscible vehicles such as, but 5.4.2 Delayed Release Dosage Forms not limited to, ethyl alcohol, polyethylene glycol, and Active ingredients of the invention can be administered by polypropylene glycol; and non-aqueous vehicles such as, but controlled release means or by delivery devices that are well 5 not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, known to those of ordinary skill in the art. Examples include, ethyl oleate, isopropyl myristate, and benzyl benzoate. but are not limited to, those described in U.S. Pat. Nos. 3,845, Compounds that increase the solubility of one or more of 770; 3,916,899; 3,536,809; 3,598,123; and4,008,719, 5,674, the active ingredients disclosed herein can also be incorpo­ 533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, rated into the parenteral dosage forms of the invention. For 5,354,556, and 5,733,566, each of which is incorporated 10 example, cyclodextrin and its derivatives can be used to herein by reference. Such dosage forms can be used to pro­ increase the solubility of an immunomodulatory compound vide slow or controlled-release of one or more active ingre­ of the invention and its derivatives. See, e.g., U.S. Pat. No. dients using, for example, hydropropylmethyl cellulose, 5,134,127, which is incorporated herein by reference. otherpolymermatrices, gels, permeable membranes, osmotic 5.4.4 Topical and Mucosa! Dosage Forms systems, multilayer coatings, microparticles, liposomes, 15 Topical and mucosa! dosage forms of the invention microspheres, or a combination thereof to provide the desired include, but are not limited to, sprays, aerosols, solutions, release profile in varying proportions. Suitable controlled­ emulsions, suspensions, eye drops or other ophthalmic prepa­ release formulations known to those of ordinary skill in the rations, or other forms known to one of skill in the art. See, art, including those described herein, can be readily selected e.g., Remington's Pharmaceutical Sciences, 16th and 18th for use with the active ingredients ofthe invention. The inven­ 20 eds., Mack Publishing, Easton Pa. (1980 & 1990); and Intro­ tion thus encompasses single unit dosage forms suitable for duction to Pharmaceutical Dosage Forms, 4th ed., Lea & oral administration such as, but not limited to, tablets, cap­ Febiger, Philadelphia (1985). Dosage forms suitable for treat­ sules, gelcaps, and caplets that are adapted for controlled­ ing mucosa! tissues within the oral cavity can be formulated release. as mouthwashes or as oral gels. All controlled-release pharmaceutical products have a 25 Suitable excipients (e.g., carriers and diluents) and other common goal of improving drug therapy over that achieved materials that can be used to provide topical and mucosa! by their non-controlled counterparts. Ideally, the use of an dosage forms encompassed by this invention are well known optimally designed controlled-release preparation in medical to those skilled in the pharmaceutical arts, and depend on the treatment is characterized by a minimum of drug substance particular tissue to which a given pharmaceutical composi- being employed to cure or control the condition in a minimum 30 tion or dosage form will be applied. With that fact in mind, amount of time. Advantages of controlled-release formula­ typical excipients include, but are not limited to, water, tions include extended activity of the drug, reduced dosage acetone, ethanol, ethylene glycol, propylene glycol, butane- frequency, and increased patient compliance. In addition, 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral controlled-release formulations can be used to affect the time oil, and mixtures thereof to form solutions, emulsions or gels, of onset of action or other characteristics, such as blood levels 35 which are non-toxic and pharmaceutically acceptable. Mois­ of the drug, and can thus affect the occurrence of side ( e.g., turizers or humectants can also be added to pharmaceutical adverse) effects. compositions and dosage forms if desired. Examples of such Most controlled-release formulations are designed to ini­ additional ingredients are well known in the art. See, e.g., tially release an amount of drug (active ingredient) that Remington's Pharmaceutical Sciences, 16th and 18th eds., promptly produces the desired therapeutic effect, and gradu­ 40 Mack Publishing, Easton Pa. (1980 & 1990). ally and continually release of other amounts of drug to main­ The pH of a pharmaceutical composition or dosage form tain this level of therapeutic or prophylactic effect over an may also be adjusted to improve delivery of one or more extended period of time. In order to maintain this constant active ingredients. Similarly, the polarity of a solvent carrier, level of drug in the body, the drug must be released from the its ionic strength, or tonicity can be adjusted to improve dosage form at a rate that will replace the amount of drug 45 delivery. Compounds such as stearates can also be added to being metabolized and excreted from the body. Controlled­ pharmaceutical compositions or dosage forms to advanta­ release of an active ingredient can be stimulated by various geously alter the hydrophilicity or lipophilicity of one or conditions including, but not limited to, pH, temperature, more active ingredients so as to improve delivery. In this enzymes, water, or other physiological conditions or com­ regard, stearates can serve as a lipid vehicle for the formula- pounds. 50 tion, as an emulsifying agent or surfactant, and as a delivery­ 5.4.3 Parenteral Dosage Forms enhancing or penetration-enhancing agent. Different salts, Parenteral dosage forms can be administered to patients by hydrates or solvates of the active ingredients can be used to various routes including, but not limited to, subcutaneous, further adjust the properties of the resulting composition. intravenous (including bolus injection), intramuscular, and 5.4.5 Kits intraarterial. Because their administration typically bypasses 55 Typically, active ingredients of the invention are preferably patients' natural defenses against contaminants, parenteral not administered to a patient at the same time or by the same dosage forms are preferably sterile or capable of being ster­ route of administration. This invention therefore encom­ ilized prior to administration to a patient. Examples of passes kits which, when used by the medical practitioner, can parenteral dosage forms include, but are not limited to, solu­ simplify the administration of appropriate amounts of active tions ready for injection, dry products ready to be dissolved or 60 ingredients to a patient. suspended in a pharmaceutically acceptable vehicle for injec­ A typical kit ofthe invention comprises a dosage form of an tion, suspensions ready for injection, and emulsions. immunomodulatory compound of the invention, or a pharma­ Suitable vehicles that can be used to provide parenteral ceutically acceptable salt, solvate, hydrate, stereoisomer, pro­ dosage forms of the invention are well known to those skilled drug, or clathrate thereof. Kits encompassed by this invention in the art. Examples include, but are not limited to: Water for 65 can further comprise additional active ingredients such as Injection USP; aqueous vehicles such as, but not limited to, oblimersen (Genasense®), melphalan, G-CSF, GM-CSF, Sodium Chloride Injection, Ringer's Injection, Dextrose EPO, topotecan, dacarbazine, irinotecan, taxotere, IFN, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 104 of 148 PageID: 104

US 8,735,428 B2 31 32 COX-2 inhibitor, pentoxifylline, ciprofloxacin, dexametha­ dihydro-isoindol-2-yl)-piperidine-2,6-dione that is similar sone, IL2, IL8, IL 18, Ara-C, vinorelbine, isotretinoin, 13 to, but 50 to 2000 times more potent than, thalidomide. It has cis-retinoic acid, or a pharmacologically active mutant or been shown that the compound is approximately 50-100 derivative thereof, or a combination thereof. Examples of the times more potent than thalidomide in stimulating the prolif­ additional active ingredients include, but are not limited to, 5 eration of T-cells following primary induction by T-cell those disclosed herein (see, e.g., section 5.2). receptor (TCR) activation. 3-(4-amino-l-oxo-l ,3-dihydro- Kits of the invention can further comprise devices that are isoindol-2-yl)-piperidine-2,6-dione is also approximately 50 used to administer the active ingredients. Examples of such to 100 times more potent than thalidomide in augmenting the devices include, but are not limited to, syringes, drip bags, production of IL-2 and IFN-y following TCR activation of patches, and inhalers. 10 PBMC (IL-2) or T-cells (IFN-y). In addition, 3-(4-amino-l­ Kits of the invention can further comprise cells or blood for oxo-l,3-dihydro-isoindol-2-yl )-piperidine-2,6-dione exhib­ transplantation as well as pharmaceutically acceptable ited dose-dependent inhibition ofLPS-stimulated production vehicles that can be used to administer one or more active of the pro-inflarmnatory cytokines TNF-a, IL-1 ~' and IL-6 ingredients. For example, if an active ingredient is provided in by PBMC while it increased production of the anti-inflam­ a solid form that must be reconstituted for parenteral admin­ 15 istration, the kit can comprise a sealed container of a suitable matory cytokine IL-10. vehicle in which the active ingredient can be dissolved to 6.2 Inhibition of MM Cell Proliferation form a particulate-free sterile solution that is suitable for The ability of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2- parenteral administration. Examples of pharmaceutically yl)-piperidine-2,6-dione (Revimid™) and thalidomide for acceptable vehicles include, but are not limited to: Water for 20 comparison to effect the proliferation of MM cell lines has Injection USP; aqueous vehicles such as, but not limited to, been investigated in an in vitro study. Uptake [3 H]-thymidine Sodium Chloride Injection, Ringer's Injection, Dextrose by different MM cell lines (MM.IS, Hs Sultan, U266 and Injection, Dextrose and Sodium Chloride Injection, and Lac­ RPMI-8226) was measured as an indicator of cell prolifera­ tated Ringer's Injection; water-miscible vehicles such as, but tion. Cells were incubated in the presence of compounds for 3 not limited to, ethyl alcohol, polyethylene glycol, and 25 48 hours; [ H]-thymidine was included for the last 8 hours of polypropylene glycol; and non-aqueous vehicles such as, but the incubation period. Addition of 3-(4-amino-l-oxo-l ,3-di- not limited to, com oil, cottonseed oil, peanut oil, sesame oil, hydro-isoindol-2-yl)-piperidine-2,6-dione to MM.IS and Hs ethyl oleate, isopropyl myristate, and benzyl benzoate. Sultan cells resulted in 50% inhibition of cell proliferation at concentrations of0.4 µm and 1 µm, respectively. In contrast, 6. EXAMPLES 30 addition of thalidomide at concentrations up to 100 µm resulted in only 15% and 20% inhibition of cell proliferation Certain embodiments of the invention are illustrated by the in MM.IS and Hs Sultan cells, respectively. These data are following non-limiting examples. sUlllillarized in FIG. 1. 6.1 Modulation of Cytokine Production 6.3 Toxicology Studies A series of non-clinical pharmacology and toxicology 35 The effects of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2- studies have been performed to support the clinical evaluation yl)-piperidine-2,6-dione (Revimid™) on cardiovascular and of an immunomodulatory compound of the invention in respiratory function are investigated in anesthetized dogs. human subjects. These studies were performed in accordance Two groups ofBeagle dogs (2/sex/group) are used. One group with internationally recognized guidelines for study design receives three doses of vehicle only and the other receives and in compliance with the requirements of Good Laboratory 40 three ascending doses of 3-(4-amino-l-oxo-l ,3-dihydro­ Practice (GLP), unless otherwise noted. isoindol-2-yl)-piperidine-2,6-dione (2, 10, and 20 mg/kg). In Inhibition of TNF-a production following LPS-stimula­ all cases, doses of3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2- tion of human PBMC and human whole blood by 4-( amino)- yl)-piperidine-2,6-dione or vehicle are successively adminis­ 2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione (Ac­ tered via infusion through the jugular vein separated by inter- timid™), 3-(4-amino- l-oxo-l ,3-dihydro-isoindol-2-yl)­ 45 vals of at least 30 minutes. piperidine-2,6-dione and thalidomide (Revimid™) was The cardiovascular and respiratory changes induced by investigated in vitro (Muller et al., Bioorg. Med. Chem. Lett. 3-( 4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,

9:1625-1630, 1999). The IC50's of 4-(amino)-2-(2,6-dioxo 6-dione are minimal at all doses when compared to the (3-piperidyl))-isoindoline-1,3-dione for inhibiting produc­ vehicle control group. The only statistically significant dif­ tion of TNF-a following LPS-stimulation of PBMC and 50 ference between the vehicle and treatment groups is a small human whole blood were-24 nM (6.55 ng/mL) and-25 nM increase in arterial blood pressure (from 94 mmHg to 101 (6.83 ng/mL), respectively. In vitro studies suggest a pharma­ mmHg) following administration of the low dose of 3-(4- cological activity profile for 3-( 4-amino-l-oxo-l ,3-dihydro­ amino-l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-di­ isoindol-2-yl)-piperidine-2,6-dione that is similar to, but at one. This effect lasts approximately 15 minutes and is not least 200 times more potent than, thalidomide. In vitro studies 55 seen at higher doses. Deviations in femoral blood flow, res­ have also demonstrated that concentrations of 4-(amino)-2- piratory parameters, and Qtc interval are common to both the (2,6-dioxo(3-piperidyl))-isoindoline-l,3-dione of 2.73 to control and treated groups and are not considered treatment­ 27.3 ng/mL (0.01 to 0.1 µM) achieved 50% inhibition of the related. proliferation of MM.IS and Hs Sultan cells. 6.4 Cycling Therapy in Patients

The IC50's of 3-(4-amino-l-oxo-l,3-dihydro-isoindol-2- 60 In a specific embodiment, an immunomodulatory com­ yl)-piperidine-2,6-dione for inhibiting production of TNF-a pound of the invention are cyclically administered to patients following LPS-stimulation of PBMC and human whole blood with cancer. Cycling therapy involves the administration of a were -100 nM (25.9 ng/mL) and -480 nM (103.6 ng/mL), first agent for a period of time, followed by a rest for a period respectively. Thalidomide, in contrast, had an IC50 of -194 of time and repeating this sequential administration. Cycling µM ( 50.2 µg/mL) for inhibiting production ofTNF-a follow- 65 therapy can reduce the development of resistance to one or ing LPS-stimulation of PBMC. In vitro studies suggest a more of the therapies, avoid or reduce the side effects of one pharmacological activity profile for 3-(4-amino-l-oxo-1,3- ofthe therapies, and/or improves the efficacy ofthe treatment. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 105 of 148 PageID: 105

US 8,735,428 B2 33 34 In a specific embodiment, prophylactic or therapeutic additional patients are enrolled at that dose. If none of the agents are administered in a cycle of about 4 to 6 weeks, about three additional patients experience DLT, escalation to the once or twice every day. One cycle can comprise the admin­ next dose level occurs; dose escalations continue in a similar istration of a therapeutic on prophylactic agent for three to fashion until the MTD is established or the maximum daily dose (10 mg/day) is attained. However, if one of the three four weeks and at least a week or two weeks of rest. The 5 additional patients enrolled experiences DLT, the MTD has number of cycles administered is from about one to about 24 been reached. If two or more of the three additional patients cycles, more typically from about two to about 16 cycles, and enrolled experience DLT, the MTD is judged to have been more typically from about four to about eight cycles. exceeded and three additional patients are enrolled at the For example, ina cycle of four weeks, on day 1, the admin­ preceding dose level to confirm the MTD. Once the MTD has 10 istration of 25 mg/d of 3-(4-amino-l-oxo-l ,3-dihydro-isoin­ been identified, four additional patients are enrolled at that dol-2-yl)-piperidine-2,6-dione is started. On day 22, the dose level so that a total of 10 patients is treated at the MTD. administration of the compound is stopped for a week of rest. Blood sampling for analysis of pharmacokinetic param­ On day 29, the administration of25 mg/d 3-(4-amino-l-oxo- eters is performed on Days 1 and 28 according to the follow- 1,3-dihydro-isoindol-2-yl)-piperidin-2,6-dione is begun. 15 ing sampling schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 6.5 Clinical Studies in Patients 3, 4, 6, 8, 10, 12, 18, and 24 hours post-dose. An additional 6.5.1 Treatment of Relapsed Multiple Myeloma blood sample is collected at each weekly visit for the deter­ 4-(amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1,3-di­ mination of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindo­ one (Actimid™) was administered to patients with relapsed/ line-l,3-dione levels. Total urine collections are also made refractory multiple myeloma. The study was conducted in with urine pooled according to the following time intervals 20 compliance with Good Clinical Practices. Patients were at post-dose: 0 to 4, 4 to 8, 8 to 12, and 12 to 24 hours. Safety least 18 years old, had been diagnosed with multiple assessments are made by monitoring adverse events, vital myeloma (with paraprotein in serum and/or urine), and were signs, ECGs, clinical laboratory evaluations (blood chemis­ considered refractory to treatment after at least two cycles of try, hematology, lymphocyte phenotyping, and urinalysis), treatment, or have relapsed after two cycles of treatment. and physical examination at specific times during the study. Patients who have progressive disease, according to the 25 Results of interim pharmacokinetic analyses obtained fol­ Southwest Oncology Group (SWOG) criteria, on their prior lowing single- and multiple-dose administration of regimen are considered treatment refractory. Relapse follow­ 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione ing remission is defined as >25% increase in M component to multiple myeloma patients are presented below in Tables 1 from baseline levels; reappearance of the M paraprotein that and 2. These data show that 4-(amino)-2-(2,6-dioxo(3-pip­ 30 had previously disappeared; or a definite increase in the size eridyl))-isoindoline-l,3-dione was steadily absorbed at all and number oflytic bone lesions recognized on radiographs. dose levels in relapsed multiple myeloma patients. Maximum Patients may have had prior therapy with thalidomide, pro­ plasma concentrations occurred at a median T max of between vided they were able to tolerate the treatment. A Zubrod 2.5 and 2.8 hours post-dose at Day 1 and between 3 and 4 performance status ofO to 2 is required for all patients. hours post-dose at Week 4. At all doses, plasma concentra­ 35 4-(amino )-2-(2,6-dioxo(3-piperidyl) )-isoindoline-1,3-di­ tions declined in a monophasic manner after reaching Cmax· one is administered to patients at doses of!, 2, 5, or lOmg/day The start of the elimination phase occurred between 3 and 10 for up to four weeks; at each dose level, three patients are hours post-dose at Day 1 and Week 4, respectively. initially enrolled. Dosing occurs at approximately the same These data also showed that after 4 weeks of dosing, time each morning; all doses are administered in the fasted 4-( amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l ,3-dione 40 state (no eating for at least two hours prior to dosing and two accumulated to a small extent (mean accumulation ratios hours after dosing). 4-(amino)-2-(2,6-dioxo(3-piperidyl))­ -1.02 to 1.52 and-0.94 to 1.62 forCmax andAUCco-,;), respec­ isoindoline-l,3-dione doses are administered in an ascending tively). There was almost a dose proportional increase in fashion such that patients in the first cohort receive the lowest AUCco-,;) and Cmax values with increasing dose. A five-fold dose of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoindoline-l, higher dose of 4-(amino )-2-(2,6-dioxo(3-piperidyl))-isoin­ 45 3-dione (1 mg/day) and escalation to the next higher dose doline-l,3-dione produced a 3.2- and 2.2-fold increase in level occurs only following the establishment of safety and Cmax at Day 1 and Week 4, respectively. Similarly, a 5-fold tolerability at the current dose. If one out of three patients at increase in dose resulted in a 3.6- and 2.3-fold increase in any dose level experience dose limiting toxicity (DLT), three AUCco-,;), at Day 1 and Week 4, respectively. TABLE 1

Pharmacokinetic parameters of Actimid TM in relapsed multiple myeloma patients

1mg 2mg 5mg

Parameter (N- 6) (N-2) (N-3)

Day 1

cmax ng/mL 15.03 (4.04) 24.4* (12.1) 48.56 (14.03)

\max h 3.3 (2.6) 2.7* (0.3) 2.3 (0.3) AUC(O-oo) ng·h/mL 152.90 (36.62) 279.18 (51.10) 593.10 (335.23) AUC(O-x) 134.21 (27.14) 249.57 (29.26) 520.94 (267.32) ! 1/2 h 7.3 (3.4) 6.3 (1.4) 6.5 (2.2) CL/F mL/min 114.75 (29.20) 121.43 (22.22) 182.31 (117.06) Vz/f L 69.55 (44.97) 65.31 (2.80) 87.24 (22.61)

t = 24 hours NIA= not available Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 106 of 148 PageID: 106

US 8,735,428 B2 35 36 TABLE2

Pharmacokinetic parameters of Actimid TM following multiple oral doses (1, 2, and 5 mg/day) in relapsed multiple myeloma patients

1mg 2mg 5mg Parameter (N-5) (N-2) (N-3)

Week4 cm= nglmL 23.20 (7.48) 30.05* (15.64) 58.07 (38.08) tm= h 3.6 (1.5) 2.8* (0.3) 5.0 (2.6) AUC(O-oo) ng·hlmL NIA NIA NIA AUC(O-c) 239.31 (122.59) 269.36 (186.34) 597.24 (354.23) 1 t /2 h 6.2* (0.6) 7.7 (2.8) 7.8 (4.0) CL/F mL/min 87.85 (48.48) 162.68 (112.54) 207.50 (175.41) Vzlf L 41.35* (8.84) 95.04 (35.39) 103.95 (27.25)

-r = 24hours NIA= not available *N = 3 patients

6.5.2 Treatment of Relapsed Multiple Myeloma Preliminary pharmacokinetic analyses based on these two 20 Two Phase 1 clinical studies of3-(4-amino-l-oxo-l,3-di­ studies indicated that AUC and Cmax values increase propor­ hydro-isoindol-2-y l)-piperidine-2,6-dione (Revimid™) have tionally with dose following single and multiple doses in been conducted to identify the maximum tolerated dose multiple myeloma patients (as was seen in healthy volun­ (MTD) in patients with refractory or relapsed multiple teers). Further, there was no evidence of accumulation with myeloma. These studies have also characterized the safety 25 multiple dosing as single dose AUCco-=) was comparable to profile of 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)-pip­ multiple doseAUC0 _.,, following the same dose of3-(4-amino­ eridine-2,6-dione when ascending doses of 3-( 4-amino-l­ l-oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione. oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione were Similar to healthy volunteer studies, double peaks were given orally for up to 4 weeks. Patients started 3-(4-amino­ observed. Exposure inmultiplemyeloma patients appeared to l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione treat­ 30 be slightly higher based on Cmax andAUC values as compared ment at 5 mg/day with subsequent escalation to 10, 25, and 50 to healthy male volunteers while clearance in multiple mg/day. Patients were enrolled for 28 days at their assigned myeloma patients was lower than it was in healthy volunteers, dose, with the option of extended treatment for those who did consistent with their poorer renal function (both as a conse­ not exhibit disease progression or experience dose limiting quence of their age and their disease). Finally, 3-( 4-amino-1- toxicity (DLT). Patients were evaluated for adverse events at 35 oxo- l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione half­ each visit and the severity of these events was graded accord­ live in patients was shorter than in healthy volunteers (mean 8 hours, ranging up to 17 hours). ing to the National Cancer Institute (NCI) Common Toxicity In this study, the first cohort of3 patients was treated for 28 Criteria. Patients were discontinued if they experienced DLT days at 5 mg/day without any dose limiting toxicity (DLT). (Grade 3 or greater non-hematological, or Grade 4 hemato­ 40 The second cohort of 3 patients subsequently commenced logical toxicity). therapy at 10 mg/day. Patients in the second 10 mg/day of In this study, 27 patients were enrolled. All patients had 3-( 4-amino-l-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2, relapsed multiple myeloma and 18 (72%) were refractory to 6-dione cohort tolerated treatment well. salvage therapy. Among these patients, 15 had undergone 6.5.3 Treatment of Solid Tumors prior autologous stem cell transplantation and 16 patients had 45 Study with 3-(4-amino-l-oxo-l ,3-dihydro-isoindol-2-yl)- received prior thalidomide treatment. The median number of piperidine-2,6-dione (Revimid™) was conducted in patients prior regimens was 3 (range 2 to 6). with varying types of solid tumors, including malignant mela­ Blood and urine samples were collected for analysis of noma (13), carcinoma of the pancreas (2), carcinoid-un­ pharmacokinetic parameters on Days 1 and 28. Blood known primary (1 ), renal carcinoma (1 ), breast carcinoma (1) samples were collected according to the following sampling 50 and NSCLC (2). Patients received 5 mg/day 3-( 4-amino-l­ schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, oxo-l,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione for 12, 18, and 24 hours post-dose. In addition, a blood sample seven days and are subsequently escalated every seven days to was collected at each weekly clinic visit for 3-(4-amino-l­ 10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks oxo-l,3-dihydro-isoindol-2-y l)-piperidine-2,6-dione deter­ of treatment. Patients who, experienced clinical benefit were mination. Total urine was collected and pooled according to 55 permitted to continue on treatment as Named Patients. the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12, The study initially enrolled 20 patients and was subse­ and 12 to 24 hours. Response to treatment was assessed by quently amended to enroll 16 additional patients (adrenal M-protein quantification (by immunoelectrophoresis) from carcinoma, NSCLC, malignant mesothelioma, breast cancer, serum and a 24-hour urine collection, with creatinine clear­ malignant melanoma (8), renal cell cancer (4)) at a higher ance and 24-hour protein calculations undertaken at screen­ 60 dose. The 16 additional patients were given weekly escalating ing, baseline, Weeks 2 and 4, and monthly thereafter (or upon doses of25 mg/day, 50 mg/day, 75 mg/day, lOOmg/day, 125 early termination). Bone marrow aspirations and/or tissue mg/day, and 150 mg/day over a 6-week period with continu­ biopsy are also performed at Months 3, 6 and 12 ifa patient's ing treatment for an additional six weeks. paraprotein serum concentration or 24-hour urine protein The study of Phase 1 study was designed to determine a excretion declined to the next lower level, based on best 65 maximum tolerated dose (MTD) of 3-(4-amino-l-oxo-l,3- response criteria. Preliminary results for the 28-day treatment dihydro-isoindol-2-yl)-piperidine-2,6-dione in patients with period are summarized below. refractory solid tumors and/or lymphoma, as well as to char- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 107 of 148 PageID: 107

US 8,735,428 B2 37 38 acterize the pharmacokinetic and side effect profiles of 3-(4- Three patients are enrolled in each cohort. If at least one amino-l-oxo-l ,3-dihydro-isoindol-2-yl)-piperidine-2,6-di­ DLT occurs, three additional patients are added to the cohort one in this patient population. The study design dictates that at that particular dose level. If two DLTs occur, the MTD, at least 3 patients must be enrolled at a dose level and have defined as the dose at which fewer than one-third of patients completed 28 days oftreatment prior to enrollment ofpatients 5 at each dose level experiences DLT has been exceeded and at the next higher dose level. Patients in the first cohort began four more patients are treated at the previous dose. dosing at 5 mg/day of3-(4-amino-l-oxo-l,3-dihydro-isoin­ Patients who experience DLT during the first 4-week cycle dol-2-yl)-piperidine-2,6-dione. Patients will be escalated to are removed from the study, except if they have a response to 10, 20, 25, and 30 mg/day provided there is no toxicity. therapy. For patients who have completed their first 4-week In this study, the MTD is defined as the highest dose level 10 cycle of without DLT, but who subsequently experience in which fewer than two of six patients treated did not expe­ Grade 3 or 4 hematological and/or nonhematological toxicity, rience Grade 3 or greater non-hematological toxicity or treatment is suspended for a minimum of a week. If the Grade 4 or greater hematological toxicity. If, at any given dose level in either study, one out of three patients experi­ toxicity resolves to

US 8,735,428 B2 39 40 What is claimed is: 15. The method of claim 1, wherein the compound is 1. A method of treating multiple myeloma, which com­ administered orally in a capsule of 1 mg, 2 mg, 3 mg, or 4 mg. prises administering to a patient having multiple myeloma, 16. The method of claim 1, wherein the compound is orally and which patient has received previous therapy for multiple administered 4 mg per day on days 1 through 21 of repeated 28-day cycles until disease progression. myeloma, from about 1 mg to about 5 mg per day of a 5 compound having the formula: 17. The method of claim 1, which further comprises admin­ istering a therapeutically effective amount of an additional active agent. 18. The method of claim 17, wherein the additional active 10 agent is dexamethasone. 19. The method of claim 18, wherein 40 mg dexametha­ sone is administered. 20. The method of claim 18, wherein the dexamethasone is orally administered once daily on days 1, 8, 15 and 22 of each 15 28 day cycle. 21. The method of claim 18, wherein the dexamethasone is orally administered once a week of each 28 day cycle. or a pharmaceutically acceptable salt, solvate or stereoisomer 22. A method of treating multiple myeloma, which com­ thereof for 21 consecutive days followed by seven consecu­ prises administering to a patient having multiple myeloma, tive days of rest in a 28 day cycle, wherein the multiple 20 and which patient has received previous therapy for multiple myeloma is relapsed, refractory, or relapsed and refractory myeloma and has demonstrated disease progression on the multiple myeloma. previous therapy, from about 1 mg to about 5 mg per day of a 2. The method of claim 1, wherein the patient has demon­ compound having the formula: strated disease progression on the previous therapy. 3. The method of claim 1, wherein the previous therapy is treatment with thalidomide, a proteasome inhibitor, or a com- 25 bination thereof. 4. The method of claim 1, wherein the previous therapy is treatment with stem cell transplantation. 5. The method of claim 2, wherein the previous therapy is treatment with a proteasome inhibitor. 30 6. The method of claim 1, wherein the patient is 65 years or younger. 7. The method of claim 1, wherein the patient is older than 65 years. or a solvate thereof, for 21 consecutive days followed by 35 seven consecutive days of rest in a 28 day cycle. 8. The method of claim 1, wherein the compound is admin- istered in an amount of about 4 mg per day. 23. The method of claim 22, wherein the previous therapy 9. The method of claim 1, wherein the compound is admin­ is treatment with a proteasome inhibitor. istered in an amount of about 3 mg per day. 24. The method of claim 22, wherein the compound is 10. The method of claim 1, wherein the compound is administered in an amount of about 4 mg, 3 mg, 2 mg or 1 mg administered in an amount of about 2 mg per day. 40 per day. 11. The method of claim 1, wherein the compound is 25. The method of claim 22, wherein the compound is administered in an amount of about 1 mg per day. administered orally. 12. The method of claim 1, wherein the compound is 26. The method of claim 22, wherein the compound is administered orally. administered in a capsule. 45 27. The method of claim 22, which further comprises 13. The method of claim 1, wherein the compound is administered in a capsule. administering a therapeutically effective amount of dexam­ ethasone. 14. The method of claim 13, wherein the capsule comprises the compound, mannitol and pre-gelatinized starch. * * * * * Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 109 of 148 PageID: 109

EXHIBIT D Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 110 of 148 PageID: 110 111111 1111111111111111111111111111111111111111111111111111111111111 US008828427B2 c12) United States Patent (10) Patent No.: US 8,828,427 B2 Tutino et al. (45) Date of Patent: Sep.9,2014

(54) FORMULATIONS OF 4-AMIN0-2-(2,6- USPC ...... 424/452; 514/323 DIOXOPIPERIDINE-3-YL)ISOINDOLINE-1,3- See application file for complete search history. DIONE (56) References Cited (75) Inventors: Anthony Tutino, New Providence, NJ (US); Michael T. Kelly, Lake U.S. PATENT DOCUMENTS Hopatcong, OH (US) 5,593,696 A * 111997 McNally eta!...... 424/472 2007/0155791 Al * 7/2007 Zeldis eta!...... 514/323 (73) Assignee: Celgene Corporation, Sunnnit, NJ (US) FOREIGN PATENT DOCUMENTS ( *) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 wo WO 2006/058008 Al 6/2006 U.S.C. 154(b) by 398 days. OTHER PUBLICATIONS

(21) Appl. No.: 12/783,390 Remington's Pharmaceutical Sciences 17th Edition, Published 1985, pp. 1613-1615 and 1625-1626.* (22) Filed: May 19,2010 Crane and List, "Immunomodulatory Drugs," Cancer Investigation 23(7): 625-634 (2005). (65) Prior Publication Data * cited by examiner US 2011/0045064 AI Feb. 24, 2011 Primary Examiner- Richard Schnizer Related U.S. Application Data Assistant Examiner- Alma Pi pic (60) Provisional application No. 61/179,678, filed on May (74) Attorney, Agent, or Firm- Jones Day 19, 2009. (57) ABSTRACT (51) Int. Cl. Pharmaceutical compositions and single unit dosage forms of A61K 311454 (2006.01) 4-amino-2-(2, 6-dioxopiperidine-3-yl )isoindoline-1 ,3 -diane, A61K9/48 (2006.01) or a pharmaceutically acceptable stereoisomer, prodrug, salt, (52) U.S. Cl. solvate, hydrate, or clathrate, are provided herein. Also pro­ USPC ...... 424/452; 514/323 vided are methods of treating, managing, or preventing vari­ (58) Field of Classification Search ous disorders, such as cancer or an inflannnatory disease. CPC ..... A61K 31/454; A61K 47/26; A61K 47/36; A61K 9/4858; A61K 9/4866 12 Claims, No Drawings Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 111 of 148 PageID: 111

US 8,828,427 B2 1 2 FORMULATIONS OF 4-AMIN0-2-(2,6- prodrug, salt, solvate, hydrate, or clathrate thereof, in the DIOXOPIPERIDINE-3-YL)ISOINDOLINE-1,3- dosage forms described herein. DIONE 3 .1. Definitions This application claims priority to U.S. Provisional Appli­ cation No. 61/179,678, filed May 19, 2009, the entirety of As used herein and unless otherwise indicated, a compo­ which is incorporated herein by reference. sition that is "substantially free" of a compound means that the composition contains less than about 20 percent by 1. FIELD weight, more preferably less than about 10 percent by weight, 10 even more preferably less than about 5 percent by weight, and Provided herein are formulations and dosage forms of most preferably less than about 3 percent by weight of the pomalidomide, i.e., 4-amino-2-(2,6-dioxopiperidine-3-yl) compound. isoindoline-1 ,3-dione or CC-404 7. Methods of using the for­ As used herein and unless otherwise indicated, the term mulations and dosage forms are also provided herein. "stereomerically pure" means a composition that comprises 15 one stereoisomer of a compound and is substantially free of 2. BACKGROUND other stereoisomers of that compound. For example, a stereo­ merically pure composition of a compound having one chiral Drug substances are usually administered as part of a for­ center will be substantially free of the opposite enantiomer of mulation in combination with one or more other agents that 20 the compound. A stereomerically pure composition of a com­ serve varied and specialized pharmaceutical functions. Dos­ pound having two chiral centers will be substantially free of age forms ofvarious types may be made through selective use other diastereomers of the compound. A typical stereomeri­ of pharmaceutical excipients. As pharmaceutical excipients cally pure compound comprises greater than about 80 percent have various functions and contribute to the pharmaceutical by weight of one stereoisomer of the compound and less than formulations in many different ways, e.g., solubilization, 25 about 20 percent by weight of other stereoisomers of the dilution, thickening, stabilization, preservation, coloring, fla­ compound, more preferably greater than about 90 percent by voring, etc. The properties that are commonly considered weight of one stereoisomer of the compound and less than when formulating an active drug substance include bioavail­ about 10 percent by weight of the other stereoisomers of the ability, ease of manufacture, ease of administration, and sta­ compound, even more preferably greater than about 95 per- bility of the dosage form. Due to the varying properties of the 30 cent by weight of one stereoisomer of the compound and less active drug substance to be formulated, dosage forms typi­ than about 5 percent by weight of the other stereoisomers of cally require pharmaceutical excipients that are uniquely tai­ the compound, and most preferably greater than about 97 lored to the active drug substance in order to achieve advan­ percent by weight of one stereoisomer of the compound and tageous physical and pharmaceutical properties. less than about 3 percent by weight of the other stereoisomers Pomalidomide, which is also known as CC-404 7, is chemi­ 35 of the compound. cally named 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindo­ As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure com­ line-1,3-dione. Pomalidomide is an immunomodulatory position of a compound having one chiral center. compound that inhibits, for example, LPS induced monocyte As used herein, unless otherwise specified, the term "phar- TNFa, IL-l~, IL-12, IL-6, MIP-1, MCP-1, GM-CSF, G-CSF, 40 maceutically acceptable salt( s)," as used herein includes, but and COX-2 production. The compound is also known to is not limited to, salts of acidic or basic moieties of thalido­ co-stimulate the activation of T-cells. Pomalidomide and mide. Basic moieties are capable of forming a wide variety of method of synthesizing the compound are described, e.g., in salts with various inorganic and organic acids. The acids that U.S. Pat. No. 5,635,517, the entirety of which is incorporated can be used to prepare pharmaceutically acceptable acid addi- herein by reference. 45 tion salts of such basic compounds are those that form non­ Due to its diversified pharmacological properties, pomali­ toxic acid addition salts, i.e., salts containing pharmacologi­ domide is useful in treating, preventing, and/or managing cally acceptable anions. Suitable organic acids include, but various diseases or disorders. Thus, a need exists as to dosage are not limited to, maleic, fumaric, benzoic, ascorbic, suc­ forms of pomalidomide having advantageous physical and cinic, acetic, formic, oxalic, propionic, tartaric, salicylic, cit- pharmaceutical properties. 50 ric, gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspar­ tic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, 3.SUMMARY saccharic, isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic (i.e., Provided herein are pharmaceutical dosage forms of poma­ 1,1 '-methylene-bis-(2-hydroxy-3-naphthoate) acids. Suit- lidomide, or a pharmaceutically acceptable stereoisomer, 55 able inorganic acids include, but are not limited to, hydro­ prodrug, salt, solvate, hydrate, or clathrate thereof. Also pro­ chloric, hydrobromic, hydroiodic, sulfuric, phosphoric, or vided herein are methods oftreating, managing, or preventing nitric acids. Compounds that include an amine moiety can diseases and conditions such as, but not limited to, cancer, form pharmaceutically acceptable salts with various amino pain, Macular Degeneration, a skin disease, a pulmonary acids, in addition to the acids mentioned above. Chemical disorder, an asbestos-related disorder, a parasitic disease, an 60 moieties that are acidic in nature are capable of forming base immunodeficiency disorder, a CNS disorder, CNS injury, salts with various pharmacologically acceptable cations. atherosclerosis, a sleep disorder, hemoglobinopathy, anemia, Examples of such salts are alkali metal or alkaline earth metal an inflammatory disease, an autoimmune disease, a viral dis­ salts and, particularly, calcium, magnesium, sodium, lithium, ease, a genetic disease, an allergic disease, a bacterial disease, zinc, potassium, or iron salts. an ocular neovascular disease, a choroidal neovascular dis- 65 As used herein, and unless otherwise specified, the term ease, a retina neovascular disease, and rubeosis, using poma­ "solvate" means a compound provided herein or a salt lidomide, or a pharmaceutically acceptable stereoisomer, thereof, that further includes a stoichiometric or non-sto- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 112 of 148 PageID: 112

US 8,828,427 B2 3 4 ichiometric amount of solvent bound by non-covalent inter­ terms encompass modulating the threshold, development molecular forces. Where the solvent is water, the solvate is a and/or duration of the disease or disorder, or changing the hydrate. way that a patient responds to the disease or disorder. As used herein and unless otherwise indicated, the teen As used herein, and unless otherwise specified, the term "prodrug" means a derivative of a compound that can hydro­ "about," when used in connection with doses, amounts, or lyze, oxidize, or otherwise react under biological conditions weight percent of ingredients of a composition or a dosage (in vitro or in vivo) to provide the compound. Examples of form, means dose, amount, or weight percent that is recog­ prodrugs include, but are not limited to, derivatives of thali­ nized by those of ordinary skill in the art to provide a phar­ domide that include biohydrolyzable moieties such as biohy­ macological effect equivalent to that obtained from the speci­ drolyzable amides, biohydrolyzable esters, biohydrolyzable 10 fied dose, amount, or weight percent is encompassed. carbamates, biohydrolyzable carbonates, biohydrolyzable Specifically, the term "about" contemplates a dose, amount, ureides, and biohydrolyzable phosphate analogues. Other or weight percent within 30%, 25%, 20%, 15%, 10%, or 5% examples of prodrugs include derivatives of thalidomide that of the specified dose, amount, or weight percent is encom­ include -NO, -N02 , -ONO, or -ON02 moieties. passed. As used herein and unless otherwise indicated, the terms 15 As used herein, and unless otherwise specified, the term "biohydrolyzable carbamate," "biohydrolyzable carbonate," "stable," when used in connection with a formulation or a "biohydrolyzable ureide," "biohydrolyzable phosphate" dosage form, means that the active ingredient of the formu­ mean a carbamate, carbonate, ureide, or phosphate, respec­ lation or dosage form remains solubilized for a specified tively, of a compound that either: 1) does not interfere with the amount of time and does not significantly degrade or aggre­ biological activity of the compound but can confer upon that 20 gate or become otherwise modified (e.g., as determined, for compound advantageous properties in vivo, such as uptake, example, by HPLC). In some embodiments, about 70 percent duration of action, or onset of action; or 2) is biologically or greater, about 80 percent or greater or about 90 percent or inactive but is converted in vivo to the biologically active greater of the compound remains solubilized after the speci­ compound. Examples of biohydrolyzable carbamates fied period. include, but are not limited to, lower alkylamines, substituted 25 ethylenediamines, aminoacids, hydroxyalkylamines, hetero­ 4. DETAILED DESCRIPTION cyclic and heteroaromatic amines, and poly ether amines. As used herein and unless otherwise indicated, the term Provided herein are pharmaceutical dosage forms of poma­ "biohydrolyzable ester" means an ester of a compound that lidomide, or a pharmaceutically acceptable stereoisomer, either: 1) does not interfere with the biological activity of the 30 prodrug, salt, solvate, hydrate, or clathrate thereof. In some compound but can confer upon that compound advantageous embodiments, the dosage forms are suitable for oral admin- properties in vivo, such as uptake, duration of action, or onset istration to a patient. In other embodiments, the dosage forms of action; or 2) is biologically inactive but is converted in vivo provided herein exhibit advantageous physical and/or phar­ to the biologically active compound. Examples ofbiohydro­ macological properties. Such properties include, but are not lyzable esters include, but are not limited to, lower alkyl 35 limited to, ease of assay, content uniformity, flow properties esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, for manufacture, dissolution and bioavailability, and stability. and choline esters. In certain embodiments, the dosage forms provided herein As used herein and unless otherwise indicated, the term have a shelflife of at least about 12 months, at least about 24 "biohydrolyzable amide" means an amide of a compound that months, or at least about 36 months without refrigeration. either: 1) does not interfere with the biological activity of the 40 Also provided herein are kits comprising pharmaceutical compound but can confer upon that compound advantageous compositions and dosage forms provided herein. Also pro­ properties in vivo, such as uptake, duration of action, or onset vided herein are methods of treating, managing, and/or pre­ of action; or 2) is biologically inactive but is converted in vivo venting a disease or condition, which comprises administer­ to the biologically active compound. Examples ofbiohydro­ ing to a patient in need thereof a pharmaceutical composition lyzable amides include, but are not limited to, lower alkyl 45 or a dosage form provided herein. amides, a-amino acid amides, alkoxyacyl amides, and alky­ laminoalkylcarbonyl amides. 4.1 Compositions and Dosage Forms As used herein, and unless otherwise specified, the terms "treat," "treating" and "treatment" contemplate an action that In one embodiment, provided herein is a single unit dosage occurs while a patient is suffering from the specified disease 50 form suitable for oral administration to a human comprising: or disorder, which reduces the severity of the disease or dis­ an amount equal to or greater than about 1, 5, 10, 15, 20, 25, order, or retards or slows the progression of the disease or 30, 50, 75, 100, 150, or 200 mg of an active ingredient; and a disorder. pharmaceutically acceptable excipient; wherein the active As used herein, and unless otherwise specified, the terms ingredient is pomalidomide, or a pharmaceutically accept- "prevent," "preventing" and "prevention" refer to the preven­ 55 able stereoisomer, prodrug, salt, solvate, or clathrate thereof. tion of the onset, recurrence or spread of a disease or disorder, In some embodiments, the amount of active ingredient is from or of one or more symptoms thereof. The terms "prevent," about 0.1 to about 100 mg, from about 0.5 to about 50 mg, "preventing" and "prevention" contemplate an action that from, about 0.5 to about 25 mg, from about 1 mg to about 10 occurs before a patient begins to suffer from the specified mg, from about 0.5 to about 5 mg, or from about 1 mg to about disease or disorder, which inhibits or reduces the severity of 60 5 mg. In one embodiment, the amount of the active ingredient the disease or disorder. is about 0.5 mg. In another embodiment, the amount of the As used herein, and unless otherwise indicated, the terms active ingredient is about 1 mg. In another embodiment, the "manage," "managing" and "management" encompass pre­ amount of the active ingredient is about 2 mg. In another venting the recurrence of the specified disease or disorder in embodiment, the amount of the active ingredient is about 5 a patient who has already suffered from the disease or disor­ 65 mg. der, and/or lengthening the time that a patient who has suf­ Pharmaceutical compositions and formulations provided fered from the disease or disorder remains in remission. The herein can be presented as discrete dosage forms, such as Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 113 of 148 PageID: 113

US 8,828,427 B2 5 6 capsules (e.g., gelcaps ), caplets, tablets, troches, lozenges, from about 0.1 to about 5 weight percent of total weight ofthe dispersions, and suppositories each containing a predeter­ composition. In another embodiment, pomalidomide, or a mined amount of an active ingredient as a powder or in pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ granules, a solution, or a suspension in an aqueous or non­ vate, or clathrate thereof, comprises from about 0.1 to about 3 aqueous liquid, an oil-in-water emulsion, or a water-in-oil weight percent of total weight of the composition. In another liquid emulsion. Because of their ease of administration, tab­ embodiment, pomalidomide, or a pharmaceutically accept­ lets, caplets, and capsules represent a preferred oral dosage able stereoisomer, prodrug, salt, solvate, or clathrate thereof, unit forms. comprises from about 0.5 to about 3 weight percent of total Tablets, caplets, and capsules typically contain from about weight of the composition. In another embodiment, pomali- 50 mg to about 500 mg of the pharmaceutical composition 10 domide, or a pharmaceutically acceptable stereoisomer, pro­ (i.e., active ingredient and excipient(s)). Capsules can be of drug, salt, solvate, or clathrate thereof, comprises from about any size. Examples of standard sizes include #000, #00, #0, 0.5 to about 2 weight percent of total weight of the composi­ #1, #2, #3, #4, and #5. See, e.g., Remington's Pharmaceutical Sciences, page 1658-1659 (Alfonso Gennaro ed., Mack Pub­ tion. In another embodiment, pomalidomide, or a pharmaceu- lishing Company, Easton Pa., 18th ed., 1990), which is incor­ 15 tically acceptable stereoisomer, prodrug, salt, solvate, or porated by reference. In some embodiments, capsules pro­ clathrate thereof, comprises about 1 weight percent of total vided herein are of size #1 or larger, #2 or larger, or #4 or weight of the composition. In another embodiment, pomali­ larger. domide, or a pharmaceutically acceptable stereoisomer, pro­ Also provided herein are anhydrous pharmaceutical com­ drug, salt, solvate, or clathrate thereof, comprises about 0.8 positions and dosage forms including an active ingredient, 20 weight percent of total weight of the composition. In another since water can facilitate the degradation of some com­ embodiment, pomalidomide, or a pharmaceutically accept­ pounds. For example, the addition of water (e.g., 5 percent) is able stereoisomer, prodrug, salt, solvate, or clathrate thereof, widely accepted in the pharmaceutical arts as a means of comprises about 2 weight percent of total weight of the com­ simulating shelf-life, i.e., long-term storage in order to deter­ position. In another embodiment, pomalidomide, or a phar- mine characteristics such as shelf-life or the stability of for­ 25 maceutically acceptable stereoisomer, prodrug, salt, solvate, mulations over time. See, e.g., Jens T. Carstensen, Drug Sta­ or clathrate thereof, comprises about 1.7 weight percent of bility: Principles & Practice, 2d. Ed., Marcel Dekker, NY, total weight of the composition. N.Y., 1995, pp. 379-80. In effect, water and heat accelerate In one embodiment, the active ingredient and carrier, dilu­ decomposition. Thus, the effect of water on a formulation can ent, binder, or filler are directly blended as described herein be of great significance since moisture and/or humidity are 30 elsewhere. In another embodiment, the carrier, diluent, commonly encountered during manufacture, handling, pack­ binder, or filler comprises mannitol and/or starch. In one aging, storage, shipment, and use of formulations. embodiment, the mannitol is spray dried mannitol. In another An anhydrous pharmaceutical compositions should be pre­ embodiment, the starch is pregelatinized starch. pared and stored such that the anhydrous nature is main­ In one embodiment, the carrier, diluent, binder, or filler tained. Accordingly, in some embodiments, anhydrous com­ 35 comprises from about 70 to about 99 weight percent of total positions are packaged using materials known to prevent weight of the composition. In another embodiment, the car­ exposure to water such that they can be included in suitable rier, diluent, binder, or filler comprises from about 80 to about formulary kits. Examples of suitable packaging include, but 99 weight percent of total weight of the composition. In are not limited to, hermetically sealed foils, plastic or the like, another embodiment, the carrier, diluent, binder, or filler unit dose containers, blister packs, and strip packs. 40 comprises from about 85 to about 99 weight percent of total In this regard, also provided herein is a method ofpreparing weight of the composition. In another embodiment, the car­ a solid pharmaceutical formulation including an active ingre­ rier, diluent, binder, or filler comprises from about 90 to about dient through admixing the active ingredient and an excipient 99 weight percent of total weight of the composition. In under anhydrous or low moisture/humidity conditions, another embodiment, the carrier, diluent, binder, or filler wherein the ingredients are substantially free of water. The 45 comprises from about 95 to about 99 weight percent of total method can further include packaging the anhydrous or non­ weight of the composition. In another embodiment, the car­ hygroscopic solid formulation under low moisture condi­ rier, diluent, binder, or filler comprises about 98 weight per­ tions. By using such conditions, the risk of contact with water cent of total weight of the composition. In another embodi­ is reduced and the degradation of the active ingredient can be ment, the carrier, diluent, binder, or filler comprises about 99 prevented or substantially reduced. 50 weight percent of total weight of the composition. Also provided herein are lactose-free pharmaceutical com­ In one embodiment, the dosage forms provided herein positions and dosage forms. Compositions and dosage forms comprise both mannitol and starch. In one embodiment, man­ that comprise an active ingredient that is a primary or second­ nitol and starch comprise from about 70 to about 99 weight ary amine are preferably lactose-free. As used herein, the term percent of total weight of the composition. In another "lactose-free" means that the amount of lactose present, if 55 embodiment, mannitol and starch comprise from about 80 to any, is insufficient to substantially increase the degradation about 99 weight percent oftotal weight of the composition. In rate of an active ingredient that is a primary or secondary another embodiment, mannitol and starch comprise from amine. Lactose-free compositions provided herein can com­ about 85 to about 99 weight percent of total weight of the prise excipients which are well known in the art and are listed composition. In another embodiment, mannitol and starch in the USP (XXI)/NF (XVI), which is incorporated herein by 60 comprise from about 90 to about 99 weight percent of total reference. weight of the composition. In another embodiment, mannitol In one embodiment, pomalidomide, or a pharmaceutically and starch comprise from about 95 to about 99 weight percent acceptable stereoisomer, prodrug, salt, solvate, or clathrate of total weight of the composition. In another embodiment, thereof, comprises from about 0.1 to about 10 weight percent mannitol and starch comprise about 98 weight percent of total of total weight of the composition. In another embodiment, 65 weight of the composition. In another embodiment, mannitol pomalidomide, or a pharmaceutically acceptable stereoiso­ and starch comprise about 99 weight percent of total weight mer, prodrug, salt, solvate, or clathrate thereof, comprises of the composition. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 114 of 148 PageID: 114

US 8,828,427 B2 7 8 In one embodiment, the ratio of mannitol:starch in the mg. In one embodiment, the sodium stearyl fumarate is dosage form is from about 1: 1 to about 1:1.5. In one embodi­ present at an amount of about 0.16 mg. ment, the ratio of mannitol: starch in the dosage form is about In one embodiment, provided herein is a dosage form com­ 1: 1.3. prising: 1) pomalidomide, or a pharmaceutically acceptable In another embodiment, the dosage form comprises a lubri­ stereoisomer, prodrug, salt, solvate, or clathrate thereof, cant. In one embodiment, the dosage form comprises about present at an amount that provides about 0.5 mg potency of 0.2, 0.3, 0.5, 0.6, or 0.8 mg oflubricant. In another embodi­ pomalidomide; 2) about 35 mg of pregelatinized starch; 3) ment, the dosage form comprises about 0.16, 0.32, 0.64, or about 0.16 mg of sodium stearyl fumarate; and 4) spray dried 0.75 mg of lubricant. In one embodiment, the lubricant is mannitol at an amonnt that brings the total weight of the sodium stearyl fumarate (PRUV). 10 dosage form to 62.5 mg. In one embodiment, the dosage form In one embodiment, the lubricant, e.g., PRUV, comprises is suitable for administration in a size 4 or larger capsule. from about 0.01 to about 5 weight percent of total weight of In one embodiment, provided herein is a dosage form com­ the composition. In another embodiment, the lubricant, e.g., prising: 1) pomalidomide, or a pharmaceutically acceptable

PRUV, comprises from about 0.01 to about 1 weight percent 15 stereoisomer, prodrug, salt, solvate, or clathrate thereof, of total weight of the composition. In another embodiment, present at an amount that provides about 1 mg potency of the lubricant, e.g., PRUV, comprises from about 0.1 to about pomalidomide; and 2) a pharmaceutically acceptable excipi­ 1 weight percent of total weight of the composition. In ent. In one embodiment, the total weight of the dosage form is another embodiment, the lubricant, e.g., PRUV, comprises about 125 mg. In one embodiment, the dosage form is suitable from about 0.1 to about 0.5 weight percent of total weight of 20 for administration in a size 4 or larger capsule. In one embodi­ the composition. In another embodiment, the lubricant, e.g., ment, the excipient comprises a carrier, diluent, binder, or PRUV, comprises from about 0.2 to about 0.3 weight percent filler. In one embodiment, the excipients comprise a carrier, of total weight of the composition. In another embodiment, diluent, binder, or filler and a lubricant. the lubricant, e.g., PRUV, comprises about 0.25 weight per­ In one embodiment where the total weight of the dosage cent of total weight of the composition. 25 form is about 125 mg, the carrier, diluent, binder, or filler In some embodiments, because it is typical to obtain poma­ comprises mannitol and/or starch. In one embodiment, the lidomide, or a pharmaceutically acceptable stereoisomer, excipient comprises both mannitol and starch. In one embodi­ prodrug, salt, solvate, or clathrate thereof, at a purity of less ment, where both mannitol and starch are present in the than 100%, the formulations and dosage forms provided dosage form, the dosage form comprises about 70 mg of herein may be defined as compositions, formulations, or dos­ 30 starch, and the remaining weight is filled by starch. In one age forms that comprise pomalidomide, or a pharmaceuti­ embodiment, the mannitol is spray dried mannitol. In another cally acceptable stereoisomer, prodrug, salt, solvate, or clath­ embodiment, the starch is pregelatinized starch. rate thereof, at an amount that provides the potency of a In one embodiment where the total weight of the dosage specified amount of 100% pure pomalidomide. form is about 125 mg and where a lubricant is present, the For example, in one embodiment, provided herein is a 35 lubricant is sodium stearyl fumarate. In one embodiment, the single unit dosage form comprising: 1) pomalidomide, or a sodium stearyl fumarate is present at an amount of about 0.3 pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ mg. In one embodiment, the sodium stearyl fumarate is vate, or clathrate thereof, present at an amount that provides present at an amount of about 0.32 mg. about 0.5, 1, 2, 3, 4, or 5 mg potency of pomalidomide; and 2) In one embodiment, provided herein is a dosage form com- about 60, 120, 250, 180, 240, or 300 mg of a carrier, diluent, 40 prising: 1) pomalidomide, or a pharmaceutically acceptable binder, or filler, respectively. In one embodiment, the amount stereoisomer, prodrug, salt, solvate, or clathrate thereof, of a carrier, diluent, binder, or filler is about 62, 124, 248, 177, present at an amount that provides about 1 mg potency of 236, or 295 mg, respectively. pomalidomide; 2) about 70 mg of pregelatinized starch; 3) In one embodiment, provided herein is a dosage form com­ about 0.32 mg of sodium stearyl fumarate; and 4) spray dried prising: 1) pomalidomide, or a pharmaceutically acceptable 45 mannitol at an amonnt that brings the total weight of the stereoisomer, prodrug, salt, solvate, or clathrate thereof dosage form to 125 mg. In one embodiment, the dosage form present at an amount that provides about 0.5 mg potency of is suitable for administration in a size 4 or larger capsule. pomalidomide; and 2) a pharmaceutically acceptable excipi­ In one embodiment, provided herein is a dosage form com­ ent. In one embodiment, the total weight of the dosage form is prising: 1) pomalidomide, or a pharmaceutically acceptable about 62.5 mg. In one embodiment, the dosage form is suit­ 50 stereoisomer, prodrug, salt, solvate, or clathrate thereof, able for administration in a size 4 or larger capsule. In one present at an amount that provides about 2 mg potency of embodiment, the excipient comprises a carrier, diluent, pomalidomide; and 2) a pharmaceutically acceptable excipi­ binder, or filler. In one embodiment, the excipients comprise ent. In one embodiment, the total weight of the dosage form is a carrier, diluent, binder, or filler and a lubricant. about 250 mg. In one embodiment, the dosage form is suitable In one embodiment where the total weight of the dosage 55 for administration in a size 2 or larger capsule. In one embodi­ form is about 62.5 mg, the carrier, diluent, binder, or filler ment, the excipient comprises a carrier, diluent, binder, or comprises mannitol and/or starch. In one embodiment, the filler. In one embodiment, the excipients comprise a carrier, excipient comprises both mannitol and starch. In one embodi­ diluent, binder, or filler and a lubricant. ment, where both mannitol and starch are present in the In one embodiment where the total weight of the dosage dosage form, the dosage form comprises about 35 mg of 60 form is about 250 mg, the carrier, diluent, binder, or filler starch, and the remaining weight is filled by starch. In one comprises mannitol and/or starch. In one embodiment, the embodiment, the mannitol is spray dried mannitol. In another excipient comprises both mannitol and starch. In one embodi­ embodiment, the starch is pregelatinized starch. ment, where both mannitol and starch are present in the In one embodiment where the total weight of the dosage dosage form, the dosage form comprises about 140 mg of form is about 62.5 mg and where a lubricant is present, the 65 starch, and the remaining weight is filled by starch. In one lubricant is sodium stearyl fumarate. In one embodiment, the embodiment, the mannitol is spray dried mannitol. In another sodium stearyl fumarate is present at an amount of about 0.2 embodiment, the starch is pregelatinized starch. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 115 of 148 PageID: 115

US 8,828,427 B2 9 10 In one embodiment where the total weight of the dosage starch, and the remaining weight is filled by starch. In one form is about 250 mg and where a lubricant is present, the embodiment, the mannitol is spray dried mannitol. In another lubricant is sodium stearyl fumarate. In one embodiment, the embodiment, the starch is pregelatinized starch. sodium stearyl fumarate is present at an amount of about 0.6 In one embodiment where the total weight of the dosage mg. In one embodiment, the sodium stearyl fumarate is form is about 240 mg and where a lubricant is present, the present at an amount of about 0.64 mg. lubricant is sodium stearyl fumarate. In one embodiment, the In one embodiment, provided herein is a dosage form com­ sodium stearyl fumarate is present at an amount of about 0.6 prising: 1) pomalidomide, or a pharmaceutically acceptable mg. stereoisomer, prodrug, salt, solvate, or clathrate thereof, In one embodiment, provided herein is a dosage form com- present at an amount that provides about 2 mg potency of 10 prising: 1) pomalidomide, or a pharmaceutically acceptable pomalidomide; 2) about 140 mg of pregelatinized starch; 3) stereoisomer, prodrug, salt, solvate, or clathrate thereof, about 0.64 mg of sodium stearyl fumarate; and4) spray dried present at an amount that provides about 4 mg potency of mannitol at an amount that brings the total weight of the pomalidomide; 2) about 134.4 mg of pregelatinized starch; 3) dosage form to 250 mg. In one embodiment, the dosage form about 0.6 mg of sodium stearyl fumarate; and 4) spray dried is suitable for administration in a size 2 or larger capsule. 15 mannitol at an amount that brings the total weight of the In one embodiment, provided herein is a dosage form com­ dosage form to 240 mg. In one embodiment, the dosage form prising: 1) pomalidomide, or a pharmaceutically acceptable is suitable for administration in a size 2 or larger capsule. stereoisomer, prodrug, salt, solvate, or clathrate thereof, In one embodiment, provided herein is a dosage form com­ present at an amount that provides about 3 mg potency of prising: 1) pomalidomide, or a pharmaceutically acceptable pomalidomide; and 2) a pharmaceutically acceptable excipi­ 20 stereoisomer, prodrug, salt, solvate, or clathrate thereof, ent. In one embodiment, the total weight of the dosage form is present at an amount that provides about 5 mg potency of about 180 mg. In one embodiment, the dosage form is suitable pomalidomide; and 2) a pharmaceutically acceptable excipi­ for administration in a size 2 or larger capsule. In one embodi­ ent. In one embodiment, the total weight of the dosage form is ment, the excipient comprises a carrier, diluent, binder, or about 300 mg. In one embodiment, the dosage form is suitable filler. In one embodiment, the excipients comprise a carrier, 25 for administration in a size 1 or larger capsule. In one embodi­ diluent, binder, or filler and a lubricant. ment, the excipient comprises a carrier, diluent, binder, or In one embodiment where the total weight of the dosage filler. In one embodiment, the excipients comprise a carrier, form is about 180 mg, the carrier, diluent, binder, or filler diluent, binder, or filler and a lubricant. comprises mannitol and/or starch. In one embodiment, the In one embodiment where the total weight of the dosage excipient comprises both mannitol and starch. In one embodi­ 30 form is about 300 mg, the carrier, diluent, binder, or filler ment, where both mannitol and starch are present in the comprises mannitol and/or starch. In one embodiment, the dosage form, the dosage form comprises about 100 mg of excipient comprises both mannitol and starch. In one embodi­ starch, and the remaining weight is filled by starch. In one ment, where both mannitol and starch are present in the embodiment, the mannitol is spray dried mannitol. In another dosage form, the dosage form comprises about 168 mg of embodiment, the starch is pregelatinized starch. 35 starch, and the remaining weight is filled by starch. In one In one embodiment where the total weight of the dosage embodiment, the mannitol is spray dried mannitol. In another form is about 180 mg and where a lubricant is present, the embodiment, the starch is pregelatinized starch. lubricant is sodium stearyl fumarate. In one embodiment, the In one embodiment where the total weight of the dosage sodium stearyl fumarate is present at an amount of about 0.5 form is about 300 mg and where a lubricant is present, the mg. In one embodiment, the sodium stearyl fumarate is 40 lubricant is sodium stearyl fumarate. In one embodiment, the present at an amount of about 0.45 mg. sodium stearyl fumarate is present at an amount of about 0.8 In one embodiment, provided herein is a dosage form com­ mg. In one embodiment, the sodium stearyl fumarate is prising: 1) pomalidomide, or a pharmaceutically acceptable present at an amount of about 0.75 mg. stereoisomer, prodrug, salt, solvate, or clathrate thereof, In one embodiment, provided herein is a dosage form com- present at an amount that provides about 3 mg potency of 45 prising: 1) pomalidomide, or a pharmaceutically acceptable pomalidomide; 2) about 100.8 mg of pregelatinized starch; 3) stereoisomer, prodrug, salt, solvate, or clathrate thereof, about 0.45 mg of sodium stearyl fumarate; and 4) spray dried present at an amount that provides about 5 mg potency of mannitol at an amount that brings the total weight of the pomalidomide; 2) about 168 mg of pregelatinized starch; 3) dosage form to 180 mg. In one embodiment, the dosage form about 0.75 mg of sodium stearyl fumarate; and 4) spray dried is suitable for administration in a size 2 or larger capsule. 50 mannitol at an amount that brings the total weight of the In one embodiment, provided herein is a dosage form com­ dosage form to 300 mg. In one embodiment, the dosage form prising: 1) pomalidomide, or a pharmaceutically acceptable is suitable for administration in a size 1 or larger capsule. stereoisomer, prodrug, salt, solvate, or clathrate thereof, In another embodiment, provided herein is a dosage form present at an amount that provides about 4 mg potency of comprising pomalidomide, or a pharmaceutically acceptable pomalidomide; and 2) a pharmaceutically acceptable excipi­ 55 stereoisomer, prodrug, salt, solvate, or clathrate thereof, ent. In one embodiment, the total weight of the dosage form is present at an amount that provides about 0.5 mg potency of about 240 mg. In one embodiment, the dosage form is suitable pomalidomide, which is stable for a period of at least about for administration in a size 2 or larger capsule. In one embodi­ 12, about 24, or about 36 months without refrigeration. In ment, the excipient comprises a carrier, diluent, binder, or some embodiments, the dosage form comprises mannitol filler. In one embodiment, the excipients comprise a carrier, 60 and/or starch. In one embodiment where both starch and diluent, binder, or filler and a lubricant. mannitol are present in the dosage form, starch is present at an In one embodiment where the total weight of the dosage amount of about 35 mg, and mannitol is present at an amount form is about 240 mg, the carrier, diluent, binder, or filler that brings the total weight of composition to about 62.5 mg. comprises mannitol and/or starch. In one embodiment, the In some embodiments, the dosage form further comprises excipient comprises both mannitol and starch. In one embodi- 65 sodium stearyl fumarate at an amount of about 0.2 mg or ment, where both mannitol and starch are present in the about 0.16 mg. In some embodiments, provided herein is a dosage form, the dosage form comprises about 135 mg of dosage form comprising: 1) pomalidomide, or a pharmaceu- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 116 of 148 PageID: 116

US 8,828,427 B2 11 12 tically acceptable stereoisomer, prodrug, salt, solvate, or that brings the total weight of composition to about 300 mg. clathrate thereof, present at an amount that provides about 0.5 In some embodiments, the dosage form further comprises mg potency of pomalidomide; about 35 mg pregelatinized sodium stearyl fumarate at an amount of about 0.8 mg or starch; about 0.16 mg sodium stearyl fumarate; and spray about 0.75 mg. In some embodiments, provided herein is a dried mannitol at an amount that brings the total weight of the dosage form comprising: 1) pomalidomide, or a pharmaceu­ dosage form to 62.5 mg; wherein the dosage form is stable for tically acceptable stereoisomer, prodrug, salt, solvate, or a period of at least about 12, about 24, or about 36 months clathrate thereof, present at an amount that provides about 5 without refrigeration. In one embodiment, the dosage form is mg potency of pomalidomide; about 168 mg pregelatinized suitable for administration in a size 4 or larger capsule. starch; about 0.75 mg sodium stearyl fumarate; and spray In another embodiment, provided herein is a dosage form 10 dried mannitol at an amount that brings the total weight of the comprising pomalidomide, or a pharmaceutically acceptable dosage form to 300 mg; wherein the dosage form is stable for stereoisomer, prodrug, salt, solvate, or clathrate thereof, a period of at least 12, about 24, or about 36 months without present at an amount that provides about 1 mg potency of refrigeration. In one embodiment, the dosage form is suitable pomalidomide, which is stable for a period of at least about for administration in a size 1 or larger capsule. 12, about 24, or about 36 months without refrigeration. In 15 4 .1.1 Second Active Agents some embodiments, the dosage form comprises mannitol In certain embodiments, provided herein are compositions and/or starch. In one embodiment where both starch and and dosage form of pomalidomide, or a pharmaceutically mannitol are present in the dosage form, starch is present at an acceptable stereoisomer, prodrug, salt, solvate, or clathrate amount of about 70 mg, and mannitol is present at an amount thereof, which may further comprise one or more secondary that brings the total weight of composition to about 125 mg. 20 active ingredients. Certain combinations may work synergis­ In some embodiments, the dosage farm further comprises tically in the treatment of particular types diseases or disor­ sodium stearyl fumarate at an amount of about 0.3 mg or ders, and conditions and symptoms associated with such dis­ about 0.32 mg. In some embodiments, provided herein is a eases or disorders. Pomalidomide, or a pharmaceutically dosage form comprising: 1) pomalidomide, or a pharmaceu­ acceptable stereoisomer, prodrug, salt, solvate, or clathrate tically acceptable stereoisomer, prodrug, salt, solvate, or 25 thereof, can also work to alleviate adverse effects associated clathrate thereof, present at an amount that provides about 1 with certain second active agents, and vice versa. mg potency of pomalidomide; about 70 mg pregelatinized Specific second active compounds that can be contained in starch; about 0.32 mg sodium stearyl fumarate; and spray the formulations and dosage forms provided herein vary dried mannitol at an amount that brings the total weight of the depending on the specific indication to be treated, prevented dosage form to 125 mg; wherein the dosage form is stable for 30 or managed. a period of at least about 12, about 24, or about 36 months For instance, for the treatment, prevention or management without refrigeration. In one embodiment, the dosage form is of cancer, second active agents include, but are not limited to: suitable for administration in a size 4 or larger capsule. semaxanib; cyclosporin; etanercept; doxycycline; bort­ In another embodiment, provided herein is a dosage form ezomib; acivicin; aclarubicin; acodazole hydrochloride; comprising pomalidomide, or a pharmaceutically acceptable 35 acronine; adozelesin; aldesleukin; altretamine; ambomycin; stereoisomer, prodrug, salt, solvate, or clathrate thereof, ametantrone acetate; amsacrine; anastrozole; anthramycin; present at an amount that provides about 2 mg potency of asparaginase; asperlin; azacitidine; azetepa; azotomycin; pomalidomide, which is stable for a period of at least about batimastat; benzodepa; bicalutamide; bisantrene hydrochlo­ 12, about 24, or about 36 months without refrigeration. In ride; bisnafide dimesylate; bizelesin; bleomycin sulfate; bre- some embodiments, the dosage form comprises mannitol 40 quinar sodium; bropirimine; busulfan; cactinomycin; calus­ and/or starch. In one embodiment where both starch and terone; caracemide; carbetimer; carboplatin; carmustine; mannitol are present in the dosage form, starch is present at an carubicin hydrochloride; carzelesin; cedefingol; celecoxib; amount of about 140 mg, and mannitol is present at an amount chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol that brings the total weight of composition to about 250 mg. mesylate; cyclophosphamide; cytarabine; dacarbazine; dac- In some embodiments, the dosage form further comprises 45 tinomycin; daunorubicin hydrochloride; decitabine; dexor­ sodium stearyl fumarate at an amount of about 0.6 mg or maplatin; dezaguanine; dezaguanine mesylate; diaziquone; about 0.64 mg. In some embodiments, provided herein is a docetaxel; doxorubicin; doxorubicin hydrochloride; drolox­ dosage form comprising: 1) pomalidomide, or a pharmaceu­ ifene; droloxifene citrate; dromostanolone propionate; dua­ tically acceptable stereoisomer, prodrug, salt, solvate, or zomycin; edatrexate; eflornithine hydrochloride; elsamitru- clathrate thereof, present at an amount that provides about 2 50 cin; enloplatin; enpromate; epipropidine; epirubicin mg potency ofpomalidomide; about 140 mg pregelatinized hydrochloride; erbulozole; esorubicin hydrochloride; estra­ starch; about 0.64 mg sodium stearyl fumarate; and spray mustine; estramustine phosphate sodium; etanidazole; etopo­ dried mannitol at an amount that brings the total weight of the side; etoposide phosphate; etoprine; fadrozole hydrochlo­ dosage form to 250 mg; wherein the dosage form is stable for ride; fazarabine; fenretinide; floxuridine; fludarabine a period of at least about 12, about 24, or about 36 months 55 phosphate; fluorouracil; fluorocitabine; fosquidone; fostrie­ without refrigeration. In one embodiment, the dosage form is cin sodium; gemcitabine; gemcitabine hydrochloride; suitable for administration in a size 2 or larger capsule. hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofos­ In another embodiment, provided herein is a dosage form ine; iproplatin; irinotecan; irinotecan hydrochloride; lan­ comprising pomalidomide, or a pharmaceutically acceptable reotide acetate; letrozole; leuprolide acetate; liarozole hydro- stereoisomer, prodrug, salt, solvate, or clathrate thereof, 60 chloride; lometrexol sodium; lomustine; losoxantrone present at an amount that provides about 5 mg potency of hydrochloride; masoprocol; maytansine; mechlorethamine pomalidomide, which is stable for a period of at least about hydrochloride; megestrol acetate; melengestrol acetate; mel­ 12, about 24, or about 36 months without refrigeration. In phalan; menogaril; mercaptopurine; methotrexate; methotr­ some embodiments, the dosage form comprises mannitol exate sodium; metoprine; meturedepa; mitindomide; mito- and/or starch. In one embodiment where both starch and 65 carcin; mitocromin; mitogillin; mitomalcin; mitomycin; mannitol are present in the dosage form, starch is present at an mitosper; mitotane; mitoxantrone hydrochloride; mycophe­ amount of about 168 mg, and mannitol is present at an amount nolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 117 of 148 PageID: 117

US 8,828,427 B2 13 14 paclitaxel; pegaspargase; peliomycin; pentamustine; peplo­ (Gleevec®), imiquimod; immunostimulantpeptides; insulin­ mycin sulfate; perfosfamide; pipobroman; piposulfan; pirox­ like growth factor-! receptor inhibitor; interferon agonists; antrone hydrochloride; plicamycin; plomestane; porfimer interferons; interleukins; iobenguane; iododoxorubicin; sodium; porfiromycin; prednimustine; procarbazine hydro­ ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomo­ chloride; puromycin; puromycin hydrochloride; pyrazofurin; halicondrin B; itasetron; jasplakinolide; kahalalide F; lamel­ riboprine; safingol; safingol hydrochloride; semustine; larin-N triacetate; lanreotide; leinamycin; lenograstim; len­ simtrazene; sparfosate sodium; sparsomycin; spirogerma­ tinan sulfate; leptolstatin; letrozole; leukemia inhibiting niumhydrochloride; spiromustine; spiroplatin; streptonigrin; factor; leukocyte alpha interferon; leuprolide+estrogen+ streptozocin; sulofenur; talisomycin; tecogalan sodium; progesterone; leuprorelin; levamisole; liarozole; linear taxotere; tegafur; teloxantrone hydrochloride; temoporfin; 10 polyamine analogue; lipophilic disaccharide peptide; lipo­ teniposide; teroxirone; testolactone; thiamiprine; thiogua­ philic platinum compounds; lissoclinamide 7; lobaplatin; nine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; lombricine; lometrexol; lonidamine; losoxantrone; loxorib­ trestolone acetate; triciribine phosphate; trimetrexate; trime­ ine; lurtotecan; lutetium texaphyrin; lysofylline; lytic pep­ trexate glucuronate; triptorelin; tubulozole hydrochloride; tides; maitansine; manr10statin A; marimastat; masoprocol; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine 15 maspin; matrilysin inhibitors; matrix metalloproteinase sulfate; vincristine sulfate; vindesine; vindesine sulfate; vine­ inhibitors; menogaril; merbarone; meterelin; methioninase; pidine sulfate; vinglycinate sulfate; vinleurosine sulfate; metoclopramide; MIF inhibitor; mifepristone; miltefosine; vinorelbine tartrate; vinzolidine sulfate; vinzolidine sulfate; mirimostim; mitoguazone; mitolactol; mitomycin analogues; vorozole; zeniplatin; zinostatin; andzorubicinhydrochloride. mitonafide; mitotoxin fibroblast growth factor-saporin; Other second agents include, but are not limited to: 20-epi- 20 mitoxantrone; mofarotene; molgramostim; Erbitux, human 1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; chorionic gonadotrophin; monophosphoryllipidA+myobac­ aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleu­ terium cell wall sk; mopidamol; mustard anticancer agent; kin; ALL-TK antagonists; altretamine; ambamustine; ami­ mycaperoxide B; mycobacterial cell wall extract; myriapor­ dox; amifostine; aminolevulinic acid; arnrubicin; amsacrine; one; N-acetyldinaline; N-substituted benzamides; nafarelin; anagrelide; anastrozole; andrographolide; angiogenesis 25 nagrestip; naloxone+pentazocine; napavin; naphterpin; nar­ inhibitors; antagonist D; antagonist G; antarelix; anti-dorsal­ tograstim; nedaplatin; nemorubicin; neridronic acid; niluta­ izing morphogenetic protein-!; antiandrogen, prostatic car­ mide; nisamycin; nitric oxide modulators; nitroxide antioxi­ cinoma; antiestrogen; antineoplaston; antisense oligonucle­ dant; nitrullyn; oblimersen (Genasense®); otides; aphidicolin glycinate; apoptosis gene modulators; 06-benzylguanine; octreotide; okicenone; oligonucleotides; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; 30 onapristone; ondansetron; ondansetron; oracin; oral cytokine arginine deaminase; amsacrine; atamestane; atrimustine; axi­ inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; nastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; azatyrosine; baccatin III derivatives; balanol; batimastat; palauamine; palmitoylrhizoxin; pamidronic acid; panax­ BCR/ABL antagonists; benzochlorins; benzoylstaurospo­ ytriol; panomifene; parabactin; pazelliptine; pegaspargase; rine; beta lactam derivatives; beta-alethine; betaclamycin B; 35 peldesine; pentosan polysulfate sodium; pentostatin; pentro­ betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; zole; perflubron; perfosfamide; perillyl alcohol; phenazino­ bisaziridinylspermine; bisnafide; bistratene A; bizelesin; mycin; phenylacetate; phosphatase inhibitors; picibanil; pilo­ breflate; bropirimine; budotitane; buthionine sulfoximine; carpine hydrochloride; pirarubicin; piritrexim; placetin A; calcipotriol; calphostin C; camptothecin derivatives; capecit­ placetin B; plasminogen activator inhibitor; platinum com- abine; carboxamide-amino-triazole; carboxyamidotriazole; 40 plex; platinum compounds; platinum-triamine complex; par­ CaRest M3; CARN 700; cartilage derived inhibitor; carze­ timer sodium; porfiromycin; prednisone; propyl bis-acri­ lesin; casein kinase inhibitors (ICOS); castanospermine; done; prostaglandin J2; proteasome inhibitors; protein cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfona­ A-based immune modulator; protein kinase C inhibitor; pro­ mide; cicaprost; cis-porphyrin; cladribine; clomifene ana­ tein kinase C inhibitors, microalgal; protein tyrosine phos- logues; clotrimazole; collismycinA; collismycin B; combre­ 45 phatase inhibitors; purine nucleoside phosphorylase inhibi­ tastatin A4; combretastatin analogue; conagenin; tors; purpurins; pyrazoloacridine; pyridoxylatedhemoglobin crambescidin 816; crisnatol; cryptophycin 8; cryptophycinA polyoxyethylene conjugate; raf antagonists; raltitrexed; derivatives; curacin A; cyclopentanthraquinones; cyclo­ ramosetron; ras farnesyl protein transferase inhibitors; ras platam; cypemycin; cytarabine ocfosfate; cytolytic factor; inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhe- cytostatin; dacliximab; decitabine; dehydrodidenmin B; 50 nium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; dexverapamil; diaziquone; didenmin B; didox; diethylnor­ safingol; saintopin; SarCNU; sarcophytol A; sargramostim; spermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamy­ Sdi 1 mimetics; semustine; senescence derived inhibitor 1; cin; diphenyl spiromustine; docetaxel; docosanol; dolas­ sense oligonucleotides; signal transduction inhibitors; sizofi- etron; doxifluridine; doxorubicin; droloxifene; dronabinol; 55 ran; sobuzoxane; sodium borocaptate; sodium phenylacetate; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolo­ solverol; somatomedin binding protein; sonermin; sparfosic mab; eflomithine; elemene; emitefur; epirubicin; epristeride; acid; spicamycin D; spiromustine; splenopentin; spongistatin estramustine analogue; estrogen agonists; estrogen antago­ 1; squalamine; stipiamide; stromelysin inhibitors; sulfi­ nists; etanidazole; etoposide phosphate; exemestane; fadro­ nosine; superactive vasoactive intestinal peptide antagonist; zole; fazarabine; fenretinide; filgrastim; finasteride; fla­ 60 suradista; suramin; swainsonine; tallimustine; tamoxifen vopiridol; flezelastine; fluasterone; fludarabine; methiodide; tauromustine; tazarotene; tecogalan sodium; fluorodaunorunicin hydrochloride; forfenimex; formestane; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; fostriecin; fotemustine; gadolinium texaphyrin; gallium teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcit­ thiocoraline; thrombopoietin; thrombopoietin mimetic; thy- abine; glutathione inhibitors; hepsulfam; heregulin; hexam­ 65 malfasin; thymopoietin receptor agonist; thymotrinan; thy­ ethylene bisacetamide; hypericin; ibandronic acid; idarubi­ roid stimulating hormone; tin ethyl etiopurpurin; tira­ cin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib pazamine; titanocene bichloride; topsentin; toremifene; Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 118 of 148 PageID: 118

US 8,828,427 B2 15 16 translation inhibitors; tretinoin; triacetyluridine; triciribine; Examples of second active agents that may be used for the trimetrexate; triptorelin; tropisetron; turosteride; tyrosine treatment, prevention and/or management of macular degen­ kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; eration and related syndromes include, but are not limited to, urogenital sinus-derived growth inhibitory factor; urokinase a steroid, a light sensitizer, an integrin, an antioxidant, an receptor antagonists; vapreotide; variolin B; velaresol; interferon, a xanthine derivative, a growth hormone, a neu­ veramine; verdins; verteporfin; vinorelbine; vinxaltine; trotrophic factor, a regulator of neovascularization, an anti­ vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and VEGF antibody, a prostaglandin, an antibiotic, a phytoestro­ zinostatin stimalamer. gen, an anti-inflmatory compound or an antiangiogenesis Yet other second active agents include, but are not limited compound, or a combination thereof. Specific examples 10 include, but are not limited to, verteporfin, purlytin, an angio­ to, 2-methoxyestradiol, telomestatin, inducers of apoptosis in static steroid, rhuFab, interferon-2a, pentoxifylline, tin multiple myeloma cells (such as, for example, TRAIL), etiopurpurin, motexafin, lucentis, lutetium, 9-fluoro-11 ,21- statins, semaxanib, cyclosporin, etanercept, doxycycline, dihydroxy-16, 17 -1-methylethylidinebis(oxy)pregna-1 ,4-di­ bortezomib, oblimersen (Genasense®), remicade, docetaxel, ene-3,20-dione, latanoprost (see U.S. Pat. No. 6,225,348), celecoxib, melphalan, dexamethasone (Decadron®), ste- 15 tetracycline and its derivatives, rifamycin and its derivatives, raids, gemcitabine, cisplatinum, temozolomide, etoposide, macrolides, metronidazole (U.S. Pat. Nos. 6,218,369 and cyclophosphamide, temodar, carboplatin, procarbazine, glia­ 6,015,803), genistein, genistin, 6'-0-Mal genistin, 6'-0-Ac del, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxo­ genistin, daidzein, daidzin, 6'-0-Mal daidzin, daidzin, gly­ tere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, citein, glycitin, 6'-0-Mal glycitin, biochaninA, formononetin interferon alpha, pegylated interferon alpha (e.g., PEG 20 (U.S. Pat. No. 6,001,368), triamcinolone acetamide, dexam­ INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, ethasone (U.S. Pat. No. 5,770,589), thalidomide, glutathione carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, (U.S. Pat. No. 5,632,984), basic fibroblast growth factor pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorel­ (bFGF), transforming growth factor b (TGF -b), brain-derived bine, zoledronic acid, palmitronate, biaxin, busulphan, pred­ neurotrophic factor (BDNF), plasminogen activator factor nisone, bisphosphonate, arsenic trioxide, vincristine, doxo- 25 type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), rubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, LY333531 (Eli Lilly), Miravant, and RETISERT implant estramustine sodium phosphate (Emcyt® ), sulindac, and eto­ (Bausch & Lomb). All of the references cited herein are poside. incorporated in their entireties by reference. In another embodiment, examples of specific second Examples of second active agents that may be used for the agents according to the indications to be treated, prevented, or 30 treatment, prevention and/or management of skin diseases managed can be found in the following references, all of include, but are not limited to, keratolytics, retinoids, a-hy­ which are incorporated herein in their entireties: U.S. Pat. droxy acids, antibiotics, collagen, botulinum toxin, inter­ Nos. 6,281,230 and 5,635,517; U.S. publication nos. 2004/ feron, steroids, and immunomodulatory agents. Specific 0220144, 2004/0190609, 2004/0087546, 2005/0203142, examples include, but are not limited to, 5-fluorouracil, maso­ 2004/0091455, 2005/0100529, 2005/0214328, 2005/ 35 procol, trichloroacetic acid, salicylic acid, lactic acid, ammo­ 0239842,2006/0154880,2006/0122228, and 2005/0143344; nium lactate, urea, tretinoin, isotretinoin, antibiotics, col­ and U.S. provisional application No. 60/631,870. lagen, botulinum toxin, interferon, corticosteroid, Examples of second active agents that may be used for the transretinoic acid and collagens such as human placental treatment, prevention and/or management ofpain include, but collagen, animal placental collagen, Dermalogen, AlloDerm, are not limited to, conventional therapeutics used to treat or 40 Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast, prevent pain such as antidepressants, anticonvulsants, antihy­ and Isola gen. pertensives, anxiolytics, calcium channel blockers, muscle Examples of second active agents that may be used for the relaxants, non-narcotic analgesics, opioid analgesics, anti­ treatment, prevention and/or management of pulmonary hep­ inflammatories, cox-2 inhibitors, immunomodulatory agents, ertension and related disorders include, but are not limited to, alpha-adrenergic receptor agonists or antagonists, immuno- 45 anticoagulants, diuretics, cardiac glycosides, calcium chan­ suppressive agents, corticosteroids, hyperbaric oxygen, ket­ nel blockers, vasodilators, prostacyclin analogues, endothelin amine, other anesthetic agents, NMDA antagonists, and other antagonists, phosphodiesterase inhibitors (e.g., PDE V therapeutics found, for example, in the Physician's Desk inhibitors), endopeptidase inhibitors, lipid lowering agents, Reference 2003. Specific examples include, but are not lim­ thromboxane inhibitors, and other therapeutics known to ited to, salicylic acid acetate (Aspirin®), celecoxib (Cele- 50 reduce pulmonary artery pressure. Specific examples include, brex®), Enbrel®, ketamine, gabapentin (Neurontin®), phe­ but are not limited to, warfarin (Coumadin®), a diuretic, a nyloin (Dilantin®), carbamazepine (Tegretol®), cardiac glycoside, digoxin-oxygen, diltiazem, nifedipine, a oxcarbazepine (Trileptal®), valproic acid (Depakene®), vasodilator such as prostacyclin (e.g., prostaglandin I2 morphine sulfate, hydromorphone, prednisone, griseofulvin, (PGI2), epoprostenol (EPO, Floran®), treprostinil (Remodu­ penthonium, alendronate, dyphenhydramide, guanethidine, 55 lin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine, ketorolac (Acular®), thyrocalcitonin, dimethylsulfoxide epoprostenol (Floran®), treprostinil (Remodulin®), prosta­ (DMSO), clonidine (Catapress®), bretylium, ketanserin, cyclin, tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat reserpine, droperidol, atropine, phentolamine, bupivacaine, (Vanlev®), irbesartan (Avapro®), pravastatin (Pravachol®), lidocaine, acetaminophen, nortriptyline (Pamelor®), ami­ digoxin, L-arginine, iloprost, betaprost, and sildenafil (Via­ triptyline (Elavil®), imipramine (Tofranil®), doxepin (Sine- 60 gra®). quan®), clomipramine (Anafranil®), fluoxetine (Prozac®) Examples of second active agents that may be used for the sertraline (Zoloft®), naproxen, nefazodone (Serzone®), ven­ treatment, prevention and/or management of asbestos-related lafaxine (Effexor®), trazodone (Desyrel®), bupropion (Well­ disorders include, but are not limited to, anthracycline, plati­ butrin®), mexiletine, nifedipine, propranolol, tramadol, lam­ num, alkylating agent, oblimersen (Genasense®), cisplati­ otrigine, vioxx, ziconotide, ketamine, dextromethorphan, 65 num, cyclophosphamide, temodar, carboplatin, procarba­ benzodiazepines, baclofen, tizanidine and phenoxyben­ zine, gliadel, tamoxifen, topotecan, methotrexate, taxotere, zamme. irinotecan, capecitabine, cisplatin, thiotepa, fludarabine, car- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 119 of 148 PageID: 119

US 8,828,427 B2 17 18 boplatin, liposomal daunorubicin, cytarabine, doxetaxol, apazone, zileuton, aurothioglucose, gold sodium thiomalate, pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorel­ auranofin, methotrexate, colchicine, allopurinol, probenecid, bine, zoledronic acid, palmitronate, Biaxin, busulphan, pred­ sulfinpyrazone and benzbromarone or betamethasone and nisone, bisphosphonate, arsenic trioxide, vincristine, doxo­ other glucocorticoids; and an antiemetic agent, such as, but rubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, not limited to, metoclopromide, domperidone, prochlorpera­ bleomycin, hyaluronidase, mitomycin C, mepacrine, zine, promethazine, chlorpromazine, trimethobenzamide, thiotepa, tetracycline and gemcitabine. ondansetron, granisetron, hydroxyzine, acetylleucine mono­ Examples of second active agents that may be used for the ethanolamine, alizapride, azasetron, benzquinamide, biet­ treatment, prevention and/or management of parasitic dis­ anautine, bromopride, buclizine, clebopride, cyclizine, eases include, but are not limited to, chloroquine, quinine, 10 dimenhydrinate, diphenidol, dolasetron, meclizine, methal­ quinidine, pyrimethamine, sulfadiazine, doxycycline, clinda­ latal, metopimazine, nabilone, oxyperndyl, pipamazine, sco­ mycin, mefloquine, halofantrine, primaquine, hydroxychlo­ polamine, sulpiride, tetrahydrocannabinol, thiethylperazine, roquine, proguanil, atovaquone, azithromycin, suramin, pen­ thioproperazine, tropisetron, and a mixture thereof. tamidine, melarsoprol, nifurtimox, benznidazole, Examples of second active agents that may be used for the amphotericin B, pentavalent antimony compounds (e.g., 15 treatment, prevention and/or management of CNS injuries sodium stiboglucuronate ), interferon gamma, itraconazole, a and related syndromes include, but are not limited to, immu­ combination of dead promastigotes and BCG, leucovorin, nomodulatory agents, immunosuppressive agents, antihyper­ corticosteroids, sulfonamide, spiramycin, IgG (serology), tri­ tensives, anticonvulsants, fibrinolytic agents, antiplatelet methoprim, and sulfamethoxazole. agents, antipsychotics, antidepressants, benzodiazepines, Examples of second active agents that may be used for the 20 buspirone, amantadine, and other known or conventional treatment, prevention and/or management of immunodefi­ agents used in patients with CNS injury/damage and related ciency disorders include, but are not limited to: antibiotics syndromes. Specific examples include, but are not limited to: (therapeutic or prophylactic) such as, but not limited to, ampi­ steroids (e.g., glucocorticoids, such as, but not limited to, cillin, tetracycline, penicillin, cephalosporins, streptomycin, methylprednisolone, dexamethasone and betamethasone); an kanamycin, and erythromycin; antivirals such as, but not 25 anti-inflammatory agent, including, but not limited to, limited to, amantadine, rimantadine, acyclovir, and ribavirin; naproxen sodium, diclofenac sodium, diclofenac potassium, immunoglobulin; plasma; immunologic enhancing drugs celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxi­ such as, but not limited to, levami sole and isoprinosine; cam, ibuprofen, ketoprofen, nabumetone, refecoxib, methotr­ biologics such as, but not limited to, gamma globulin, transfer exate, leflunomide, sulfasalazine, gold salts, RHo-D Immune factor, interleukins, and interferons; hormones such as, but 30 Globulin, mycophenylate mofetil, cyclosporine, azathio­ not limited to, thymic; and other immunologic agents such as, prine, tacrolimus, basiliximab, daclizumab, salicylic acid, but not limited to, B cell stimulators (e.g., BAFF/BlyS), acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, cytokines (e.g., IL-2, IL-4, and IL-5), growth factors (e.g., olsalazine, sulfasalazine, acetaminophen, indomethacin, TGF-a), antibodies (e.g., anti-CD40 and IgM), oligonucle­ sulindac, mefenamic acid, meclofenamate sodium, tolmetin, otides containing unmethylated CpG motifs, and vaccines 35 ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam, (e.g., viral and tumor peptide vaccines). meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, Examples of second active agents that may be used for the phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, treatment, prevention and/or management of CNS disorders apazone, zileuton, aurothioglucose, gold sodium thiomalate, include, but are not limited to: opioids; a dopamine agonist or auranofin, methotrexate, colchicine, allopurinol, probenecid, antagonist, such as, but not limited to, Levodopa, L-DOPA, 40 sulfinpyrazone and benzbromarone; a cAMP analog includ­ cocaine, a-methyl-tyrosine, reserpine, tetrabenazine, ben­ ing, but not limited to, db-cAMP; an agent comprising a zotropine, pargyline, fenodolpam mesylate, cabergoline, methylphenidate drug, which comprises 1-threo-meth­ pramipexole dihydrochloride, ropinorole, amantadine hydro­ y lphenidate, d-threo-methylphenidate, dl-threo-meth­ chloride, selegiline hydrochloride, carbidopa, pergolide ylphenidate, 1-erythro-methylphenidate, d-erythro-meth­ mesylate, Sinemet CR, and Symmetrel; a MAO inhibitor, 45 ylphenidate, dl-erythro-methylphenidate, and a mixture such as, but not limited to, iproniazid, clorgyline, phenelzine thereof; and a diuretic agent such as, but not limited to, and isocarboxazid; a COMT inhibitor, such as, but not limited mannitol, furosemide, glycerol, and urea. to, tolcapone and entacapone; a cholinesterase inhibitor, such Examples of second active agent that may be used for the as, but not limited to, physostigmine saliclate, physostigmine treatment, prevention and/or management of dysfunctional sulfate, physostigmine bromide, meostigmine bromide, neo- 50 sleep and related syndromes include, but are not limited to, a stigmine methylsulfate, ambenonim chloride, edrophonium tricyclic antidepressant agent, a selective serotonin reuptake chloride, tacrine, pralidoxime chloride, obidoxime chloride, inhibitor, an antiepileptic agent (gabapentin, pregabalin, car­ trimedoxime bromide, diacetyl monoxim, endrophonium, bamazepine, oxcarbazepine, levitiracetam, topiramate), an pyridostigmine, and demecarium; an anti-inflmatory antiaryhthmic agent, a sodium channel blocking agent, a agent, such as, but not limited to, naproxen sodium, 55 selective inflammatory mediator inhibitor, an opioid agent, a diclofenac sodium, diclofenac potassium, celecoxib, sulin­ second immunomodulatory compound, a combination agent, dac, oxaprozin, diflunisal, etodolac, meloxicam, ibuprofen, and other known or conventional agents used in sleep therapy. ketoprofen, nabumetone, refecoxib, methotrexate, lefluno­ Specific examples include, but are not limited to, Neurontin, mide, sulfasalazine, gold salts, Rho-D Immune Globulin, oxycontin, morphine, topiramate, amitryptiline, nortryp­ mycophenylate mofetil, cyclosporine, azathioprine, tacroli- 60 tiline, carbamazepine, Levodopa, L-DOPA, cocaine, a-me­ mus, basiliximab, daclizumab, salicylic acid, acetylsalicylic thyl-tyrosine, reserpine, tetrabenazine, benzotropine, par­ acid, methyl salicylate, diflunisal, salsalate, olsalazine, sul­ gyline, fenodolpam mesylate, cabergoline, pramipexole fasalazine, acetaminophen, indomethacin, sulindac, mefe­ dihydrochloride, ropinorole, amantadine hydrochloride, sel­ namic acid, meclofenamate sodium, tolmetin, ketorolac, egiline hydrochloride, carbidopa, pergolide mesylate, dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxi- 65 Sinemet CR, Symmetrel, iproniazid, clorgyline, phenelzine, cam, ampiroxicam, droxicam, pivoxicam, tenoxicam, phe­ isocarboxazid, tolcapone, entacapone, physostigmine sali­ nylbutazone, oxyphenbutazone, antipyrine, aminopyrine, clate, physostigmine sulfate, physostigmine bromide, meo- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 120 of 148 PageID: 120

US 8,828,427 B2 19 20 stigmine bromide, neostigmine methylsulfate, ambenonim In some embodiments, the active ingredients and excipi­ chloride, edrophonium chloride, tacrine, pralidoxime chlo­ ents are directly blended and loaded into, for example, a ride, obidoxime chloride, trimedoxime bromide, diacetyl capsule, or compressed directly into tablets. A direct-blended monoxim, endrophonium, pyridostigmine, demecarium, dosage form may be more advantageous than a compacted naproxen sodium, diclofenac sodium, diclofenac potassium, (e.g., roller-compacted) dosage form in certain instances, celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxi­ since direct-blending can reduce or eliminate the harmful cam, ibuprofen, ketoprofen, nabumetone, refecoxib, methotr­ health effects that may be caused by airborne particles of exate, leflunomide, sulfasalazine, gold salts, RHo-D Immune ingredients during the manufacture using compaction pro­ Globulin, mycophenylate mofetil, cyclosporine, azathio­ cess. prine, tacrolimus, basiliximab, daclizumab, salicylic acid, 10 Direct blend formulations may be advantageous in certain acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, instances because they require only one blending step, that of olsalazine, sulfasalazine, acetaminophen, indomethacin, the active and excipients, before being processed into the final sulindac, mefenamic acid, meclofenamate sodium, tolmetin, dosage form, e.g., tablet or capsule. This can reduce the ketorolac, dichlofenac, flurbinprofen, oxaprozin, piroxicam, production of airborne particle or dust to a minimum, while meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, 15 roller-compaction processes may be prone to produce dust. In phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, roller-compaction process, the compacted material is often apazone, zileuton, aurothioglucose, gold sodium thiomalate, milled into smaller particles for further processing. The mill­ auranofin, methotrexate, colchicine, allopurinol, probenecid, ing operation can produce significant amounts of airborne sulfinpyrazone, benzbromarone, betamethasone and other particles, since the purpose for this step in manufacturing is to glucocorticoids, metoclopromide, domperidone, prochlor- 20 reduce the materials particle size. The milled material is then perazine, promethazine, chlorpromazine, trimetho benza­ blended with other ingredients prior to manufacturing the mide, ondansetron, granisetron, hydroxyzine, acetylleucine final dosage form. monoethanolamine, alizapride, azasetron, benzquinamide, For certain active ingredients, in particular for a compound bietanautine, bromopride, buclizine, clebopride, cyclizine, with a low solubility, the active ingredient's particle size is dimenhydrinate, diphenidol, dolasetron, meclizine, methal- 25 reduced to a fine powder in order to help increase the active lata!, metopimazine, nabilone, oxyperndyl, pipamazine, sco­ ingredient's rate of solubilization. The increase in the rate of polamine, sulpiride, tetrahydrocarmabinol, thiethylperazine, solubilization is often necessary for the active ingredient to be thioproperazine, tropisetron, and a mixture thereof. effectively absorbed in the gastrointestinal tract. However for Examples of second active agents that may be used for the fine powders to be directly-blended and loaded onto capsules, treatment, prevention and/or management of hemoglobin- 30 the excipients should preferably provide certain characteris­ apathy and related disorders include, but are not limited to: tics which render the ingredients suitable for the direct-blend interleukins, such as IL-2 (including recombinant IL-II process. Examples of such characteristics include, but are not ("riL2") and canarypox IL-2), IL-l 0, IL-12, and IL-18; inter­ limited to, acceptable flow characteristics. In one embodi­ ferons, such as interferon alfa-2a, interferon alfa-2b, inter­ ment, therefore, provided herein is the use of, and composi­ feronalfa-nl, interferonalfa-n3, interferon beta-I a, and inter- 35 tions comprising, excipients which may provide characteris­ feron gamma-! b; and G-CSF; hydroxyurea; butyrates or tics, which render the resulting mixture suitable for direct­ butyrate derivatives; nitrous oxide; hydroxy urea; blend process, e.g., good flow characteristics. HEMOXIN™ (NIPRISAWM; see U.S. Pat. No. 5,800,819); 4.2.1. Screening Gardos channel antagonists such as clotrimazole and triaryl The process for making the pharmaceutical compositions methane derivatives; Deferoxamine; protein C; and transfu- 40 of the invention preferably includes the screening of the sions of blood, or of a blood substitute such as Hemospan™ active ingredient and the excipient(s ). In one embodiment, the or Hemospan™ PS (Sangart). active ingredient is passed through a screen having openings of about 200 microns to about 750 microns. In another 4.2. Process for Making Dosage Forms embodiment, the active ingredient is passed through a screen 45 with openings of about 200 microns to about 400 microns. In Dosage forms provided herein can be prepared by any of one embodiment, the active ingredient is passed through a the methods of pharmacy, but all methods include the step of screen having openings of about 300 to about 400 microns. bringing the active ingredient into association with the excipi­ Depending on the excipient(s) used, the screen openings vary. ent, which constitutes one or more necessary ingredients. In For example, disintegrants and binders are passed through general, the compositions are prepared by uniformly admix­ 50 openings of about 430 microns to about 750 microns, from ing (e.g., direct blend) the active ingredient with liquid excipi­ about 600 microns to about 720 microns, or about 710 ents or finely divided solid excipients or both, and then, if microns. Lubricants are typically passed through smaller necessary, shaping the product into the desired presentation openings, e.g., about 150 microns to about 250 microns (e.g., compaction such as roller-compaction). If desired, tab­ screen. In one embodiment, the lubricant is passed through a lets can be coated by standard aqueous or non-aqueous tech­ 55 screen opening of about 210 microns. niques. 4.2.2. Pre-Blending A dosage form provided herein can be prepared by com­ After the ingredients are screened, the excipient and active pression or molding, optionally with one or more accessory ingredient are mixed in a diffusion mixer. In one embodiment, ingredients. Compressed tablets can be prepared by com­ the mixing time is from about 1 minute to about 50 minutes, pressing in a suitable machine the active ingredient in a free­ 60 from about 5 minutes to about 45 minutes, from about 10 flowing form such as powder or granules, optionally mixed minutes to about 40 minutes, or from about 10 minutes to with an excipient as above and/or a surface active or dispers­ about 25 minutes. In another embodiment, the mixing time is ing agent. Molded tablets can be made by molding in a suit­ about 15 minutes. able machine a mixture of the powdered compound moist­ When more than one excipients are used, the excipients ened with an inert liquid diluent. Encapsulation of the dosage 65 may be admixed in a tumble blender for about 1 minute to forms provided herein can be done using capsules of meth­ about 20 minutes, or for about 5 minutes to about 10 minutes, ylcellulose, calcium alginate, or gelatin. prior to mixing with the active ingredient. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 121 of 148 PageID: 121

US 8,828,427 B2 21 22 4.2.3. Roller Compaction Other cancers include, but are not limited to, advanced In one embodiment, the pre-blend may optionally be malignancy, amyloidosis, neuroblastoma, meningioma, passed through a roller compactor with a hammer mill hemangiopericytoma, multiple brain metastase, glioblastoma attached at the discharge of the compactor. multiforms, glioblastoma, brain stem glioma, poor prognosis 4.2.4. Final Blend malignant brain tumor, malignant glioma, recurrent malig­ When a lubricant, e.g., sodium stearyl fumarate, is used, nant glioma, anaplastic astrocytoma, anaplastic oligodendro­ the lubricant is mixed with the pre-blend at the end of the glioma, neuroendocrine tumor, rectal adenocarcinoma, process to complete the pharmaceutical composition. This Dukes C & D colorectal cancer, unresectable colorectal car- additional mixing is from about 1 minute to about 10 minutes, cinoma, metastatic hepatocellular carcinoma, Kaposi's sar­ or from about 3 minutes to about 5 minutes. 10 coma, karotype acute myeloblastic leukemia, chronic lym­ 4.2.5. Encapsulation phocytic leukemia (CLL), Hodgkin's lymphoma, non- The formulation mixture is then encapsulated into the Hodgkin's lymphoma, cutaneous T-Cell lymphoma, desired size capsule shell using, for example, a capsule filling cutaneous B-Cell lymphoma, diffuse large B-Cell lym- machine or a rotary tablet press. 15 phoma, low grade follicular lymphoma, metastatic melanoma (localized melanoma, including, but not limited to, ocular 4.3. Kits melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, pap­ Pharmaceutical packs or kits which comprise pharmaceu­ illary serous carcinoma, gynecologic sarcoma, soft tissue tical compositions or dosage forms provided herein are also 20 sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell provided. An example of a kit comprises notice in the form histiocytosis, leiomyosarcoma, fibrodysplasia ossificans pro­ prescribed by a governmental agency regulating the manu­ gressive, hormone refractory prostate cancer, resected high­ facture, use or sale of pharmaceuticals or biological products, risk soft tissue sarcoma, unrescectable hepatocellular carci­ which notice reflects approval by the agency of manufacture, noma, Waldenstrom's macroglobulinemia, smoldering use or sale for human administration. 25 myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV 4.4. Methods of Treatment, Prevention, and non-metastatic prostate cancer, hormone-insensitive prostate Management cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary Provided herein are methods oftreating, preventing, and/or 30 thyroid carcinoma, and leiomyoma. In a specific embodi­ managing certain diseases or disorders using the formula­ ment, the cancer is metastatic. In another embodiment, the tions, compositions, or dosage forms provided herein. cancer is refractory or resistance to chemotherapy or radia- Examples of diseases or disorders include, but are not tion. limited to, cancer, disorders associated with angiogenesis, In one embodiment, the diseases or disorders are various pain including, but not limited to, Complex Regional Pain 35 Syndrome ("CRPS"), Macular Degeneration ("MD") and forms of leukemias such as chronic lymphocytic leukemia, related syndromes, skin diseases, pulmonary disorders, chronic myelocytic leukemia, acute lymphoblastic leukemia, asbestos-related disorders, parasitic diseases, immunodefi­ acute myelogenous leukemia and acute myeloblastic leuke­ ciency disorders, CNS disorders, CNS injury, atherosclerosis mia, including leukemias that are relapsed, refractory or and related disorders, dysfunctional sleep and related disor- 40 resistant, as disclosed in U.S. publication no. 2006/0030594, ders, hemoglobinopathy and related disorders (e.g., anemia), published Feb. 9, 2006, which is incorporated in its entirety INFa related disorders, and other various diseases and disor­ by reference. ders. The term "leukemia" refers malignant neoplasms of the Examples of cancer and precancerous conditions include, blood-forming tissues. The leukemia includes, but is not lim- but are not limited to, those described in U.S. Pat. Nos. 6,281, 45 ited to, chronic lymphocytic leukemia, chronic myelocytic 230 and 5,635,517 to Muller et a!., in various U.S. patent leukemia, acute lymphoblastic leukemia, acute myelogenous publications to Zeldis, including publication nos. 2004/ leukemia and acute myeloblastic leukemia. The leukemia can 0220144A1, published Nov. 4, 2004 (Treatment ofMyelod­ be relapsed, refractory or resistant to conventional therapy. ysplastic Syndrome); 2004/0029832A1, published Feb. 12, The term "relapsed" refers to a situation where patients who 2004 (Treatment of Various Types of Cancer); and 2004/ 50 have had a remission of leukemia after therapy have a return 0087546, published May 6, 2004 (Treatment of Myeloprolif­ of leukemia cells in the marrow and a decrease in normal erative Diseases). Examples also include those described in blood cells. The term "refractory or resistant" refers to a WO 2004/103274, published Dec. 2, 2004. All of these ref­ circumstance where patients, even after intensive treatment, erences are incorporated herein in their entireties by refer­ have residual leukemia cells in their marrow. ence. 55 In another embodiment, the diseases or disorders are vari- Certain examples of cancer include, but are not limited to, ous types of lymphomas, including Non-Hodgkin's lym­ cancers of the skin, such as melanoma; lymph node; breast; phoma (NHL). The term "lymphoma" refers a heterogenous cervix; uterus; gastrointestinal tract; lung; ovary; prostate; group of neoplasms arising in the reticuloendothelial and colon; rectum; mouth; brain; head and neck; throat; testes; lymphatic systems. "NHL" refers to malignant monoclonal kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal 60 proliferation oflymphoid cells in sites of the immune system, passages; and AIDS-related cancers. The compounds are also including lymph nodes, bone marrow, spleen, liver and gas­ useful for treating cancers ofthe blood and bone marrow, such trointestinal tract. Examples of NHL include, but are not as multiple myeloma and acute and chronic leukemias, for limited to, mantle cell lymphoma (MCL), lymphocytic lym­ example, lymphoblastic, myelogenous, lymphocytic, and phoma of intermediate differentiation, intermediate lympho- myelocytic leukemias. The compounds provided herein can 65 cytic lymphoma (ILL), diffuse poorly differentiated lympho­ be used for treating, preventing or managing either primary or cytic lymphoma (PDL), centrocytic lymphoma, diffuse metastatic tumors. small-cleaved cell lymphoma (DSCCL), follicular lym- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 122 of 148 PageID: 122

US 8,828,427 B2 23 24 phoma, and any type of the mantle cell lymphomas that can be keratoses and related symptoms, skin diseases or disorders seen under the microscope (nodular, diffuse, blastic and characterized with overgrowths of the epidermis, acne, and mentle zone lymphoma). wrinkles. Examples of diseases and disorders associated with, or As used herein, the term "keratosis" refers to any lesion on characterized by, undesired angiogenesis include, but are not the epidermis marked by the presence of circumscribed over­ limited to, inflammatory diseases, autoimmune diseases, growths of the horny layer, including but not limited to actinic viral diseases, genetic diseases, allergic diseases, bacterial keratosis, seborrheic keratosis, keratoacanthoma, keratosis diseases, ocular neovascular diseases, choroidal neovascular follicularis (Darier disease), inverted follicular keratosis, pal- diseases, retina neovascular diseases, and rubeosis (neovas­ moplantar keratoderma (PPK, keratosis palmaris et planta­ cularization of the angle). Specific examples of the diseases 10 ris), keratosis pilaris, and stucco keratosis. The term "actinic and disorders associated with, or characterized by, undesired keratosis" also refers to senile keratosis, keratosis senilis, angiogenesis include, but are not limited to, arthritis, verruca senilis, plana senilis, solar keratosis, keratoderma or endometriosis. Crohn's disease, heart failure, advanced heart keratoma. The term "seborrheic keratosis" also refers to seb­ failure, renal impairment, endotoxemia, toxic shock syn­ orrheic wart, senile wart, or basal cell papilloma. Keratosis is drome, osteoarthritis, retrovirus replication, wasting, menin- 15 characterized by one or more of the following symptoms: gitis, silica-induced fibrosis, asbestos-induced fibrosis, vet­ rough appearing, scaly, erythematous papules, plaques, spi- erinary disorder, malignancy-associated hypercalcemia, cules or nodules on exposed surfaces (e.g., face, hands, ears, stroke, circulatory shock, periodontitis, gingivitis, macro­ neck, legs and thorax), excrescences of keratin referred to as cytic anemia, refractory anemia, and 5q-deletion syndrome. cutaneous horns, hyperkeratosis, telangiectasias, elastosis, Examples of pain include, but are not limited to those 20 pigmented lentigines, acanthosis, parakeratosis, dyskera­ described in U.S. patent publication no. 2005/0203142, pub­ toses, papillomatosis, hyperpigmentation of the basal cells, lished Sep. 15, 2005, which is incorporated herein by refer­ cellular atypia, mitotic figures, abnormal cell-cell adhesion, ence. Specific types of pain include, but are not limited to, dense inflammatory infiltrates and small prevalence of squa­ nociceptive pain, neuropathic pain, mixed pain ofnociceptive mous cell carcinomas. and neuropathic pain, visceral pain, migraine, headache and 25 Examples of skin diseases or disorders characterized with post-operative pain. overgrowths of the epidermis include, but are not limited to, Examples of nociceptive pain include, but are not limited any conditions, diseases or disorders marked by the presence to, pain associated with chemical or thermal burns, cuts of the of overgrowths of the epidermis, including but not limited to, skin, contusions of the skin, osteoarthritis, rheumatoid arthri­ infections associated with papilloma virus, arsenical kera- tis, tendonitis, and myofascial pain. 30 toses, sign of Leser-Tn§lat, warty dyskeratoma (WD), tricho­ Examples of neuropathic pain include, but are not limited stasis spinulosa (TS), erythrokeratodermia variabilis (EKV), to, CRPS type I, CRPS type II, reflex sympathetic dystrophy ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cuta­ (RSD), reflex neurovascular dystrophy, reflex dystrophy, neous melanoacanthoma, parakeratosis, psoriasis, squamous sympathetically maintained pain syndrome, causalgia, cell carcinoma, confluent and reticulated papillomatosis Sudeck atrophy of bone, algoneurodystrophy, shoulder hand 35 (CRP), acrochordons, cutaneous horn, cowden disease (mul­ syndrome, post-traumatic dystrophy, trigeminal neuralgia, tiple hamartoma syndrome), dermatosis papulosa nigra post herpetic neuralgia, cancer related pain, phantom limb (DPN), epidermal nevus syndrome (ENS), ichthyosis vul­ pain, fibromyalgia, chronic fatigue syndrome, spinal cord garis, molluscum contagiosum, prurigo nodularis, and acan­ injury pain, central post-stroke pain, radiculopathy, diabetic thosis nigricans (AN). neuropathy, post-stroke pain, luetic neuropathy, and other 40 Examples of pulmonary disorders include, but are not lim­ painful neuropathic conditions such as those induced by ited to, those described in U.S. publication no. 2005/ drugs such as vincristine and velcade. 0239842A1, published Oct. 27, 2005, which is incorporated As used herein, the terms "complex regional pain syn­ herein by reference. Specific examples include pulmonary drome," "CRPS" and "CRPS and related syndromes" mean a hypertension and related disorders. Examples of pulmonary chronic pain disorder characterized by one or more of the 45 hypertension and related disorders include, but are not limited following: pain, whether spontaneous or evoked, including to: primary pulmonary hypertension (PPH); secondary pul- allodynia (painful response to a stimulus that is not usually monary hypertension (SPH); familial PPH; sporadic PPH; painful) and hyperalgesia (exaggerated response to a stimulus precapillary pulmonary hypertension; pulmonary arterial that is usually only mildly painful); pain that is disproportion- hypertension (PAH); pulmonary artery hypertension; idio­ ate to the inciting event (e.g., years of severe pain after an 50 pathic pulmonary hypertension; thrombotic pulmonary arte­ ankle sprain); regional pain that is not limited to a single riopathy (TPA); plexogenic pulmonary arteriopathy; func- peripheral nerve distribution; and autonomic dysregulation tional classes I to IV pulmonary hypertension; and pulmonary (e.g., edema, alteration in blood flow and hyperhidrosis) asso­ hypertension associated with, related to, or secondary to, left ciated with trophic skin changes (hair and nail growth abnor­ ventricular dysfunction, mitral valvular disease, constrictive malities and cutaneous ulceration). 55 pericarditis, aortic stenosis, cardiomyopathy, mediastinal Examples of MD and related syndromes include, but are fibrosis, anomalous pulmonary venous drainage, pulmonary not limited to, those described in U.S. patent publication no. venoocclusive disease, collagen vascular disease, congenital 2004/0091455, published May 13, 2004, which is incorpo­ heart disease, HIV virus infection, drugs and toxins such as rated herein by reference. Specific examples include, but are fenfluramines, congenital heart disease, pulmonary venous not limited to, atrophic (dry) MD, exudative (wet) MD, age- 60 hypertension, chronic obstructive pulmonary disease, inter­ related maculopathy (ARM), choroidal neovascularisation stitial lung disease, sleep-disordered breathing, alveolar (CNVM), retinal pigment epithelium detachment (PED), and hypoventilation disorder, chronic exposure to high altitude, atrophy of retinal pigment epithelium (RPE). neonatal lung disease, alveolar-capillary dysplasia, sickle cell Examples of skin diseases include, but are not limited to, disease, other coagulation disorder, chronic thromboemboli, those described in U.S. publication no. 2005/0214328A1, 65 connective tissue disease, lupus including systemic and cuta­ published Sep. 29, 2005, which is incorporated herein by neous lupus, schistosomiasis, sarcoidosis or pulmonary cap- reference. Specific examples include, but are not limited to illary hemangiomatosis. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 123 of 148 PageID: 123

US 8,828,427 B2 25 26 Examples of asbestos-related disorders include, but not medullaris syndrome, cauda equina syndrome, neurogenic limited to, those described in U.S. publication no. 2005/ shock, spinal shock, altered level of consciousness, headache, 0100529, published May 12, 2005, which is incorporated nausea, emesis, memory loss, dizziness, diplopia, blurred herein by reference. Specific examples include, but are not vision, emotional lability, sleep disturbances, irritability, limited to, mesothelioma, asbestosis, malignant pleural effu­ inability to concentrate, nervousness, behavioral impairment, sion, benign exudative effusion, pleural plaques, pleural c~l­ cognitive deficit, and seizure. cification, diffuse pleural thickening, rounded atelectasis, Other disease or disorders include, but not limited to, viral, fibrotic masses, and lung cancer. genetic, allergic, and autoimmune diseases. Specific Examples of parasitic diseases include, but are not limited examples include, but not limited to, HIV, hepatitis, adult to, those described in U.S. publication no. 2006/0154880, 10 respiratory distress syndrome, bone resorption diseases, published Jul. 13, 2006, which is incorporated he.rein by chronic pulmonary inflammatory diseases, dermatitis, cystic reference. Parasitic diseases include diseases and d1sorders fibrosis, septic shock, sepsis, endotoxic shock, hemodynamic caused by human intracellular parasites such as, but not lim­ shock, sepsis syndrome, post ischemic reperfusion injury, ited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L. meningitis, psoriasis, fibrotic disease, cachexia, graft versus donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. 15 host disease, graft rejection, auto-immune disease, rheuma­ mexicana, L. braziliensis, T. Gondii, B. microti, B. divergens, toid spondylitis, Crohn's disease, ulcerative colitis, inflam­ B. coli, C. parvum, C. cayetanensis, E. histolytica, Z belli, S. matory-bowel disease, multiple sclerosis, systemic lupus mansonii, S. haematobium, Trypanosoma ssp., Toxoplasma erythrematosus, ENL in leprosy, radiation damage, cancer, ssp., and 0. volvulus. Other diseases and disorders caused by asthma, or hyperoxic alveolar injury. non-human intracellular parasites such as, but not limited to, 20 Examples of atherosclerosis and related conditions Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia include, but are not limited to, those disclosed in U.S. publi­ darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., cation no. 2002/0054899, published May 9, 2002, which is and Theileria ssp., are also encompassed. Specific examples incorporated herein by reference. Specific examples include, include, but are not limited to, malaria, babesiosis, trypano­ but are not limited to, all forms of conditions involving ath- somiasis, leishmaniasis, toxoplasmosis, meningoencephali­ 25 erosclerosis, including restenosis after vascular intervention tis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isospo­ such as angioplasty, stenting, atherectomy and grafting. All riasis, cyclosporiasis, microsporidiosis, ascar~as!s, forms of vascular intervention are contemplated herein, trichuriasis, ancylostomiasis, strongyloidiasis, toxocanas1s, including diseases of the cardiovascular and renal system, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, such as, but not limited to, renal angioplasty, percutaneous schistosomiasis, and dermatitis caused by animal schisto- 30 coronary intervention (PCI), percutaneous transluminal coro­ somes. nary angioplasty (PTCA), carotid percutaneous transluminal Examples of immunodeficiency disorders include, but are angioplasty (PTA), coronary by-pass grafting, angioplasty not limited to, those described in U.S. application Ser. No. with stent implantation, peripheral percutaneous translumi­ 11/289,723, filed Nov. 30, 2005. Specific examples include, nal intervention of the iliac, femoral or popliteal arteries, and but not limited to, adenosine deaminase deficiency, antibody 35 surgical intervention using impregnated artificial grafts. The deficiency with normal or elevated Igs, ataxia-tenlangiecta­ following chart provides a listing of the major systemic arter­ sia, bare lymphocyte syndrome, common variable immun?­ ies that may be in need of treatment, all of which are contem­ deficiency, Ig deficiency with hyper-IgM, Ig heavy cham plated herein: deletions, IgA deficiency, immunodeficiency with thymoma, reticular dysgenesis, Nezelof syndrome, selective IgG sub- 40 class deficiency, transient hypogammaglobulinemia of Artery Body Areas Supplied infancy, Wistcott-Aldrich syndrome, X-linked agamma­ globulinemia, X-linked severe combined immunodeficiency. Axillary Shoulder and axilla Examples of CNS disorders include, but are not limited to, Brachial Upper arm Brachiocephalic Head, neck, and ann those described in U.S. publication no. 2005/0143344, pub­ 45 Celiac Divides into left gastric, splenic, and hepatic arteries lished Jun. 30, 2005, which is incorporated herein by refer­ Common carotid Neck ence. Specific examples include, but are not limited to, Common iliac Divides into external and internal iliac arteries Coronary Heart include, but are not limited to, Amyotrophic Lateral Sclerosis, Deep femoral Thigh Alzheimer Disease, Parkinson Disease, Huntington's Dis­ Digital Fingers ease, Multiple Sclerosis other neuroimmunological disorders 50 Dorsalis pedis Foot such as Tourette Syndrome, delerium, or disturbances in con­ External carotid Neck and external head regions sciousness that occur over a short period of time, and amnes- External iliac Femoral artery Femoral Thigh tic disorder, or discreet memory impairments that occur in the Gastric Stomach absence of other central nervous system impairments. Hepatic Liver, gallbladder, pancreas, and duodenwn Examples of CNS injuries and related syndromes include, 55 Inferior mesenteric Descending colon, rectum, and pelvic wall but are not limited to, those described in U.S. publication no. Internal carotid Neck and internal head regions Internal iliac Rectum, urinary bladder, external genitalia, 2006/0122228, published Jun. 8, 2006, which is incorporated buttocks muscles, uterus and vagina herein by reference. Specific examples include, but are not Left gastric Esophagus and stomach limited to, CNS injury/damage and related syndromes, Middle sacral Sacrum Ovarian Ovaries 60 include, but are not limited to, primary brain injury, second­ Palmar arch Hand ary brain injury, traumatic brain injury, focal brain injury, Peroneal Calf diffuse axonal injury, head injury, concussion, post-concus­ Popliteal Knee sion syndrome, cerebral contusion and laceration, subdural Posterior tibial Calf hematoma, epidermal hematoma, post-traumatic epilepsy, Pulmonary Lungs Radial Forearm chronic vegetative state, complete SCI, incomplete SCI, acute 65 Renal Kidney SCI, subacute SCI, chronic SCI, central cord syndrome, Splenic Stomach, pancreas, and spleen Brown-Sequard syndrome, anterior cord syndrome, conus Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 124 of 148 PageID: 124

US 8,828,427 B2 27 28 -continued and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, con­ Artery Body Areas Supplied gestive heart failure, fibrotic disease, cachexia, graft rejec­

Subclavian Shoulder tion, oncogenic or cancerous conditions, asthma, autoim­ Superior mesenteric Pancreas, small intestine, ascending and transverse mune disease, radiation damages, and hyperoxic alveolar colon injury; viral infections, such as those caused by the herpes Testicular Testes Ulnar Forearm viruses; viral conjunctivitis; or atopic dermatitis. In other embodiments, the use of formulations, composi­ tions or dosage forms provided herein in various immuno- Examples of dysfunctional sleep and related syndromes 10 logical applications, in particular, as vaccine adjuvants, par­ include, but are not limited to, those disclosed in U.S. publi­ ticularly anticancer vaccine adjuvants, as disclosed in U.S. cationno. 2005/0222209A1, published Oct. 6, 2005, which is Publication No. 2007/0048327, published Mar. 1, 2007, incorporated herein by reference. Specific examples include, which is incorporated herein in its entirety by reference, is but are not limited to, snoring, sleep apnea, insonmia, narco­ 15 also encompassed. These embodiments also relate to the uses lepsy, restless leg syndrome, sleep terrors, sleep walking of the compositions, formulations, or dosage forms provided sleep eating, and dysfunctional sleep associated with chronic herein in combination with vaccines to treat or prevent cancer neurological or inflammatory conditions. Chronic neurologi- or infectious diseases, and other various uses such as reduc- cal or inflammatory conditions, include, but are not limited to, tion or desensitization of allergic reactions. Complex Regional Pain Syndrome, chronic low back pain, 20 musculoskeletal pain, arthritis, radiculopathy, pain associ­ 5. EXAMPLES ated with cancer, fibromyalgia, chronic fatigue syndrome, visceral pain, bladder pain, chronic pancreatitis, neuropathies Embodiments provided herein may be more fully under­ (diabetic, post-herpetic, traumatic or inflammatory), and neu­ stood by reference to the following examples. These rodegenerative disorders such as Parkinson's Disease, Alzhe- 25 examples are meant to be illustrative of pharmaceutical com­ imer's Disease, amyotrophic lateral sclerosis, multiple scle­ positions and dosage forms provided herein, but are not in any rosis, Huntington's Disease, bradykinesia; muscle rigidity; way limiting. parkinsonian tremor; parkinsonian gait; motion freezing; depression; defective long-term memory, Rubinstein-Taybi 5.1 Example 1 syndrome (RTS); dementia; postural instability; hypokinetic 30 disorders; synuclein disorders; multiple system atrophies; 0.5 mg Strength Pomalidomide Dosage Capsule striatonigral degeneration; olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron disease with parkinso­ Table 1 illustrates a batch formulation and single dosage nian features; Lewy body dementia; Tau pathology disorders; formulation for a 0.5 mg strength pomalidomide single dose progressive supranuclear palsy; corticobasal degeneration; 35 unit in a size #4 capsule. frontotemporal dementia; amyloid pathology disorders; mild cognitive impairment; Alzheimer disease with parkinsonism; TABLE 1 Wilson disease; Hallervorden-Spatz disease; Chediak-Ha­ gashi disease; SCA-3 spinocerebellar ataxia; X-linked dysto­ Formulation for 0.5 mg strength pomolidomide capsule nia parkinsonism; prion disease; hyperkinetic disorders; cho­ 40 Percent By Quantity rea; ballismus; dystonia tremors; Amyotrophic Lateral Material Weight (mg/capsule) Sclerosis (ALS); CNS trauma and myoclonus. Pomolidomide ~1% 0.5* Examples of hemoglobinopathy and related disorders Starch 1500 56% 35 include, but are not limited to, those described in U.S. publi­ Sodium Stearyl Fumarate (PRUV) -0.3% 0.16 cation no. 2005/0143420A1, published Jun. 30, 2005, which 45 Spray Dried Mannitol (Manno gem EZ) remainder remainder is incorporated herein by reference. Specific examples Total 100.0% 62.5 include, but are not limited to, hemoglobinopathy, sickle cell anemia, and any other disorders related to the differentiation *Denotes amount ofpomolidomide that corresponds to the amount that provides the potency of CD34+ cells. of0.5 mg ofpomolidomide. Examples of TNF a related disorders include, but are not 50 Pomalidomide was passed through a 35-mesh screen. limited to, those described in WO 98/03502 and WO Mannitol and starch were each separately passed through a 98/54170, both of which are incorporated herein in their 25-mesh screen. Pomalidomide was pre-blended with a por­ entireties by reference. Specific examples include, but are not tion ofmannitol and starch. The pre-blend was milled through limited to: endotoxemia or toxic shock syndrome; cachexia; a 0.039 inch screen. The remainder of the mannitol and starch adult respiratory distress syndrome; bone resorption diseases 55 was also milled through a 0.039 inch screen. The pre-blend such as arthritis; hypercalcemia; Graft versus Host Reaction; was blended with the reminder of mannitol and starch. To this cerebral malaria; inflammation; tumor growth; chronic pul­ blend, sodium fumarate, which was passed through a 60 mesh monary inflammatory diseases; reperfusion injury; myocar­ screen, was further blended. The final blend was encapsulated dial infarction; stroke; circulatory shock; rheumatoid arthri­ into a size #4 capsule. tis; Crohn' s disease; HIV infection and AIDS; other disorders 60 such as rheumatoid arthritis, rheumatoid spondylitis, osteoar­ 5.2 Example 2 thritis, psoriatic arthritis and other arthritic conditions, septic shock, septis, endotoxic shock, graft versus host disease, 1 mg Strength Pomalidomide Dosage Capsule wasting, Crohn's disease, ulcerative colitis, multiple sclero­ sis, systemic lupus erythromatosis, ENL in leprosy, HIV, 65 Table 2 illustrates a batch formulation and single dosage AIDS, and opportunistic infections in AIDS; disorders such formulation for a 1 mg strength pomalidomide single dose as septic shock, sepsis, endotoxic shock, hemodynamic shock unit in a size #4 capsule. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 125 of 148 PageID: 125

US 8,828,427 B2 29 30 TABLE2 TABLE4

Formulation for 1 mg strength pomolidomide capsule Formulation for 3 mg strength pomolidomide capsule

Percent By Quantity Percent By Quantity Material Weight (mg/ capsule) Material Weight (mg/capsule)

Pomolidomide ~1% 1* Pomolidomide -1.6% 3* Starch 1500 56% 70 Starch 1500 56% 100.8 Sodium Stearyl Fumarate (PRUV) -0.3% 0.32 Sodium Stearyl Fumarate (PRUV) -0.3% 0.45 Spray Dried Mannitol (Manno gem EZ) remainder remainder Spray Dried Mannitol (Manno gem EZ) remainder remainder 10 Total 100.0% 125 Total 100.0% 180

*Denotes amount ofpomolidomide that corresponds to the amount that provides the potency *Denotes amount ofpomolidomide that corresponds to the amount that provides the potency of 1 mg of pomolidomide. of 3 mg of pomolidomide.

Pomalidomide was passed through a 35-mesh screen. 15 Pomalidomide was passed through a 35-mesh screen. Mannitol and starch were each separately passed through a Mannitol and starch were each separately passed through a 25-mesh screen. Pomalidomide was pre-blended with a por­ 25-mesh screen. Pomalidomide was pre-blended with a por­ tion ofmannitol and starch. The pre-blend was milled through tion ofmannitol and starch. The pre-blend was milled through a 0.03 9 inch screen. The remainder of the mannitol and starch a 0.039 inch screen. The remainder of the mannitol and starch was also milled through a 0.039 inch screen. The pre-blend 20 was also milled through a 0.039 inch screen. The pre-blend was blended with the reminder of mannitol and starch. To this was blended with the reminder of mannitol and starch. To this blend, sodium fumarate, which was passed through a 60 mesh blend, sodium fumarate, which was passed through a 60 mesh screen, was further blended. The final blend was encapsulated screen, was further blended. The final blend was encapsulated into a size #4 capsule. into a size #2 capsule. 25 5.3 Example 3 5.5 Example 5

2 mg Strength Pomalidomide Dosage Capsule 4 mg Strength Pomalidomide Dosage Capsule 30 Table 3 illustrates a batch formulation and single dosage Table 5 illustrates a batch formulation and single dosage formulation for a 2 mg pomalidomide single dose unit in a formulation for a 0.5 mg strength pomalidomide single dose size #2 capsule. unit in a size #2 capsule.

TABLE3 35 TABLES

Formulation for 2 mg strength pomolidomide capsule Formulation for 4 mg strength pomolidomide capsule

Percent By Quantity Percent By Quantity Material Weight (mg/ capsule) Material Weight (mg/capsule) 40 Pomolidomide ~1% 2* Pomolidomide -1.6% 4* Starch 1500 56% 140 Starch 1500 56% 134.4 Sodium Stearyl Fumarate (PRUV) -0.3% 0.64 Sodium Stearyl Fumarate (PRUV) -0.3% 0.6 Spray Dried Mannitol (Manno gem EZ) remainder remainder Spray Dried Mannitol (Manno gem EZ) remainder remainder

Total 100.0% 250 45 Total 100.0% 240

*Denotes amount ofpomolidomide that corresponds to the amount that provides the potency *Denotes amount ofpomolidomide that corresponds to the amount that provides the potency of2 mg ofpomolidomide. of 4 mg of pomolidomide.

Pomalidomide was passed through a 35-mesh screen. Pomalidomide was passed through a 35-mesh screen. Mannitol and starch were each separately passed through a Mannitol and starch were each separately passed through a 50 25-mesh screen. Pomalidomide was pre-blended with a por­ 25-mesh screen. Pomalidomide was pre-blended with a por­ tion ofmannitol and starch. The pre-blend was milled through tion ofmannitol and starch. The pre-blend was milled through a 0.03 9 inch screen. The remainder of the mannitol and starch a 0.039 inch screen. The remainder of the mannitol and starch was also milled through a 0.039 inch screen. The pre-blend was also milled through a 0.039 inch screen. The pre-blend was blended with the reminder of mannitol and starch. To this was blended with the reminder of mannitol and starch. To this 55 blend, sodium fumarate, which was passed through a 60 mesh blend, sodium fumarate, which was passed through a 60 mesh screen, was further blended. The final blend was encapsulated screen, was further blended. The final blend was encapsulated into a size #2 capsule. into a size #2 capsule.

5.4 Example 4 60 5.6 Example 6

3 mg Strength Pomalidomide Dosage Capsule 5 mg Strength Pomalidomide Dosage Capsule

Table 4 illustrates a batch formulation and single dosage 65 Table 6 illustrates a batch formulation and single dosage formulation for a 0.5 mg strength pomalidomide single dose formulation for a 5 mg pomalidomide single dose unit in a unit in a size #2 capsule. size #1 capsule. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 126 of 148 PageID: 126

US 8,828,427 B2 31 32 TABLE4 What is claimed is: 1. An oral dosage form in the form of a capsule which Formulation for 5 mg strength pomolidomide capsule weighs 62.5 mg and comprises: 1) pomalidomide, or a phar­ Percent By Quantity maceutically acceptable salt or solvate thereof, at an amount Material Weight (mg/ capsule) that provides 0.5 mg of 100% pure pomalidomide; 2) prege­ latinized starch at an amount of 35 mg; 3) sodium stearyl Pomolidomide ~2% 5* fumarate at an amount of0.16 mg; and 4) spray dried man­ Starch 1500 56% 168 Sodium Stearyl Fumarate (PRUV) -0.3% 0.75 nitol at an amonnt that brings the total weight of the compo- Spray Dried Mannitol (Manno gem EZ) remainder remainder sition to 62.5 mg. 10 2. The dosage form of claim 1, which is to be administered Total 100.0% 300 in the form of a size 4 or larger capsule. *Denotes amount ofpomolidomide that corresponds to the amount that provides the potency 3. An oral dosage form in the form of a capsule which of 5 mg of pomolidomide. weighs 125 mg and comprises: 1) pomalidomide, or a phar­ Pomalidomide was passed through a 35-mesh screen. maceutically acceptable salt or solvate thereof, at an amount Mannitol and starch were each separately passed through a 15 that provides 1 mg of 100% pure pomalidomide; 2) pregela­ 25-mesh screen. Pomalidomide was pre-blended with a por­ tinized starch at an amonnt of 70 mg; 3) sodium stearyl tion ofmannitol and starch. The pre-blend was milled through fumarate at an amount of 0.32 mg; and 4) spray dried man­ a 0.03 9 inch screen. The remainder of the mannitol and starch nitol at an amonnt that brings the total weight of the compo- was also milled through a 0.039 inch screen. The pre-blend sition to 125 mg. was blended with the reminder of mannitol and starch. To this 20 4. The dosage form of claim 3, which is to be administered blend, sodium fumarate, which was passed through a 60 mesh in the form of a size 4 or larger capsule. screen, was further blended. The final blend was encapsulated 5. An oral dosage form in the form of a capsule which into a size #1 capsule. weighs 250 mg and comprises: 1) pomalidomide, or a phar­ maceutically acceptable salt or solvate thereof, at an amount 5.7 Example 7 25 that provides 2 mg of 100% pure pomalidomide; 2) pregela­ tinized starch at an amount of 140 mg; 3) sodium stearyl Stability ofF ormulation fumarate at an amount of 0.64 mg; and 4) spray dried man­ nitol at an amonnt that brings the total weight of the compo- Accelerated stability was assessed under 40° C./75% RH, sition to 250 mg. and levels of impurities over the time period of initial, 1 30 6. The dosage form of claim 5, which is to be administered month, 3 months, and 6 months were determined. Long term in the form of a size 2 or larger capsule. stability under 25° C./60% RH is also assessed during 0-24 7. An oral dosage form in the form of a capsule which months. For determination of the level of Impurities, an weighs 180 mg and comprises: 1) pomalidomide, or a phar­ HPLC gradient method was employed using the following maceutically acceptable salt or solvate thereof, at an amount conditions: 35 that provides 3 mg of 100% pure pomalidomide; 2) pregela­ tinized starch at an amount of 100.8 mg; 3) sodium stearyl fumarate at an amount of 0.45 mg; and 4) spray dried man­ Column: Zorbax SB-CN, 150 mm x 4.6 mm id, 5 f1II1 nitol at an amonnt that brings the total weight of the compo- particle size Temperature: Ambient sition to 180 mg. Mobile Phase: A: 10/90 methanol/0.1% trifluoroacetic acid 40 8. The dosage form of claim 7, which is to be administered B: 80/20 methanol/0.1% trifluoroacetic acid in the form of a size 2 or larger capsule. Gradient Profile: Time (min) %A % B 9. An oral dosage form in the form of a capsule which 0 90 10 weighs 240 mg and comprises: 1) pomalidomide, or a phar­ 90 10 50 20 80 maceutically acceptable salt or solvate thereof, at an amount 51 90 10 45 that provides 4 mg of 100% pure pomalidomide; 2) pregela­ 60 90 10 tinized starch at an amount of 134.4 mg; 3) sodium stearyl Flow Rate: l.OmL/min fumarate at an amount of0.6 mg; and 4) spray dried mannitol Injection Volume: 25 f!L Detection: UV, 240nm at an amount that brings the total weight of the composition to Run Time: 60 minutes. 240mg. 50 10. Thedosageformofclaim9, which is to be administered From the experiments, it was observed that the impurities in the form of a size 2 or larger capsule. in the formulation provided herein stayed negligent through­ 11. An oral dosage form in the form of a capsule which out the time period investigated. The performance character­ weighs 300 mg and comprises: 1) pomalidomide, or a phar­ istics of the dosage also maintained throughout the time maceutically acceptable salt or solvate thereof, at an amount 55 that provides 5 mg of 100% pure pomalidomide; 2) pregela­ period investigated. These results show that the formulations provided herein have adequate stability for clinical and other tinized starch at an amount of 168 mg; 3) sodium stearyl uses. fumarate at an amount of 0.75 mg; and 4) spray dried man­ While examples of certain particular embodiments are pro­ nitol at an amonnt that brings the total weight of the compo- vided herein, it will be apparent to those skilled in the art that sition to 300 mg. 60 various changes and modifications may be made. Such modi­ 12. The dosage form of claim 11, which is to be adminis­ fications are also intended to fall within the scope of the tered in the form of a size 1 or larger capsule. appended claims. * * * * * Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 127 of 148 PageID: 127

EXHIBIT E Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 128 of 148 PageID: 128 I 1111111111111111 11111 1111111111 11111 111111111111111 IIIII IIIIII IIII IIII IIII US009993467B2 c12) United States Patent (IO) Patent No.: US 9,993,467 B2 Tutino et al. (45) Date of Patent: *Jun. 12, 2018

(54) FORMULATIONS OF 4-AMINO-2-(2,6- 5,832,449 A 11/1998 Cunningham DIOXOPIPERIDINE-3-YL)ISOINDOLINE- 5,882,656 A 3/ 1999 Bechard et al. 1,3-DIONE 5,974,203 A 10/1999 Tadokoro et al. 6,045,501 A 4/2000 Elsayed et al. 6,055,507 A 4/2000 Cunningham (71) Applicant: CELGENE CORPORATION, 6,063,026 A 5/2000 Schauss et al. Summit, NJ (US) 6,131,090 A 10/2000 Basso et al. 6,202,923 Bl 3/2001 Boyer et al. (72) Inventors: Anthony J. Tutino, New Providence, 6,281,230 Bl 8/2001 Muller et al. 6,315,720 Bl 11/2001 Williams et al. NJ (US); Michael T. Kelly, Lake 6,316,471 Bl 11/2001 Muller et al. Hopatcong, NJ (US) 6,476,052 Bl 11/2002 Muller et al. 6,555,554 B2 4/2003 Muller et al. (73) Assignee: Celgene Corporation, Summit, NJ 6,561,976 B2 5/2003 Elsayed et al. (US) 6,561,977 B2 5/2003 Williams et al. 6,755,784 B2 6/2004 Williams et al. 6,878,733 Bl 4/2005 Shenoy et al. ( *) Notice: Subject to any disclaimer, the term ofthis 6,896,399 B2 5/2005 Nomura et al. patent is extended or adjusted under 35 6,908,432 B2 6/2005 Elsayed et al. U.S.C. 154(b) by O days. days. 7,119,106 B2 10/2006 Muller et al. 7,189,740 B2 3/2007 Zeldis This patent is subject to a terminal dis­ 7,393,862 B2 7/2008 Zeldis claimer. 7,465,800 B2 12/2008 Jaworsky et al. 7,855,217 B2 12/2010 Jaworski et al. (21) Appl. No.: 14/998,262 7,959,566 B2 6/2011 Williams et al. 7,968,569 B2 6/2011 Zeldis 8,158,653 B2 4/2012 Muller et al. (22) Filed: Dec. 23, 2015 8,188,118 B2 5/2012 Zeldis 8,198,262 B2 6/2012 Zeldis (65) Prior Publication Data 8,198,306 B2 6/2012 Zeldis 8,204,763 B2 6/2012 Elsayed et al. US 2016/0206607 Al Jul. 21, 2016 8,207,200 B2 6/2012 Zeldis 8,315,886 B2 11/2012 Williams et al. Related U.S. Application Data 8,530,498 Bl 9/2013 Zeldis 8,589,188 B2 11/2013 Elsayed et al. (63) Continuation of application No. 14/447,450, filed on 8,626,531 B2 1/2014 Williams et al. Jul. 30, 2014, now abandoned, which is a 8,648,095 B2 2/2014 Zeldis continuation of application No. 12/783,390, filed on 8,673,939 B2 3/2014 Zeldis 8,735,428 B2 5/2014 Zeldis May 19, 2010, now Pat. No. 8,828,427. 8,828,427 B2 * 9/2014 Tutino ...... A61K 9/4858 (60) Provisional application No. 61/179,678, filed on May 514/323 9,101,621 B2 8/2015 Zeldis 19, 2009. 9,101,622 B2 8/2015 Zeldis 2002/0054899 Al 5/2002 Zeldis et al. (51) Int. Cl. 2004/0087 546 Al 5/2004 Zeldis A61K 311454 (2006.01) 2007/0155791 Al 7/2007 Zeldis et al. A61K 9/48 (2006.01) A61K 47126 (2006.01) FOREIGN PATENT DOCUMENTS A61K 47136 (2006.01) CA 2712724 Al 8/2009 A61K 47110 (2017.01) WO WO 96/013790 5/1996 A61K 47114 (2017.01) (Continued) (52) U.S. Cl. CPC ...... A61K 311454 (2013.01); A61K 9/4858 OTHER PUBLICATIONS (2013.01); A61K 9/4866 (2013.01); A61K 47110 (2013.01); A61K 47114 (2013.01); A61K Crane and List, "Immunomodulatory Drugs," Cancer Investigation, 47126 (2013.01); A61K 47136 (2013.01) 23(7):625-634 (2005). ( 58) Field of Classification Search (Continued) CPC ...... A61K 31/454 See application file for complete search history. Primary Examiner - Alma Pipic (74) Attorney, Agent, or Firm - Jones Day (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Pharmaceutical compositions and single unit dosage forms 4,551,177 A ll/ 1985 Trubiano et al. of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-l ,3-di­ 5,385,901 A 1/1995 Kaplan et al. one, or a pharmaceutically acceptable stereoisomer, prod­ 5,593,696 A 1/1997 McNally et al. rug, salt, solvate, hydrate, or clathrate, are provided herein. 5,594,637 A 1/1997 Eisenberg et al. Also provided are methods of treating, managing, or pre­ 5,619,991 A 4/ 1997 Sloane venting various disorders, such as cancer or an inflammatory 5,635,517 A 6/ 1997 Muller et al. 5,712,291 A 1/1998 D'Amato disease. 5,731,325 A 3/1998 Andrulis, Jr. et al. 5,798,368 A 8/ 1998 Muller et al. 8 Claims, No Drawings Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 129 of 148 PageID: 129

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Ther., 6(3):292-297 (1965). Preliminary results," VIII the International Myeloma Workshop, Palumbo et al., "Low-dose thalidomide plus dexamethasone is an Banff, Alberta, Canada, May 4-8, 2001; Abstract #P230. effective salvage therapy for advanced myeloma," Haematologica Richardson et al., "Immunomodulatory drug CC-5013 overcomes 86:399-403 (2001). drug resistance and is well tolerated in patients with relapsed Pastuszak et al., "Use of the retinoid pregnancy prevention program multiple myeloma," Blood 100:3063-3067 (2002). in Canada: Patterns of contraception use in women treated with Robert et al., "Phase I and pharmacologic study of 7- and 21-day isotretinoin and etretinate," Reprod. Toxicol. 8:63-68 (1994). continuous etoposide infusion in patients with advanced cancer," Pestotnik et al., "Therapeutic antibiotic monitoring: Surveillance Cancer Chemother. Pharmacol. 38:459-465 (1996). using a computerized expert system," Am. J Med. 88:43-48 (1990). Samlowski et al., "Evaluation of gemcitabine in patients with Piper et al., "Anti-inflanunatory immunosuppressive thalidomide recurrent or metastatic squamous cell carcinoma of the head and analogs. Screening," Int. J Leprosy 49:511-512 (1981). neck: A southwest oncology group phase II study," Invest. New Powell et al., "Guideline for the clinical use and dispensing of Drugs 19:311-315 (2001). thalidomide," Postgrad. Med. J. 70:901-904 (1994). Sampaio et al., "Prolonged treatment with recombinant interferon Pro et al., "Phase II study of thalidomide in patients with recurrent Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL)," ganuna induces erythema nodosum leprosum in lepromatous lep­ Blood 98:246b (Abstract# 4712) (2001). rosy patients," J Exp. Med. 175:1729-1737 (1992). Querfeld et al., "Preliminary results of a phase II study of CC-5013 Sampaio et al., "Thalidomide selectively inhibits tumor necrosis (lenalidomide, revlimid®) in patients with cutaneous T-cell lym­ factor alpha production by stimulated human monocytes," J Exp. phoma," Blood 106:936a-937a (2005). Med. 173:699-703 (1991). Raje et al., "Thalidomide-a revival story," N Engl. J Med. Schey et al., "Phase I Study of an Immunomodulatory Thalidomide 341(21): 1606-1609 (1999). Analog, CC-4047, in Relapsed or Refractory Multiple Myeloma," J Rajkumar et al., "Lenalidomide plus high-dose dexamethasone Clin. Oneal. 22(16):3269-3276 (2004). versus lenalidomide plus low-dose dexamethasone as initial therapy Schey et al., "Pomalidomide therapy for myeloma," Expert Opin. for newly diagnosed multiple myeloma: an open-label randomised Invest. Drugs 20:691-700 (2011 ). controlled trial," Lancet 11:29-37 (2010). Schey et al., "A phase I study of an immunomodulatory thalidomide Rajkumar et al., "Phase III trial of lenalidomide plus highdose analogue (CC4047) in relapse/refractory multiple myeloma," Inter­ dexamethasone versus lenalidomide plus low-dose dexamethasone national Society for Experimental Hematology, Abstract #248, in newly diagnosed multiple myelorna (E4A03): A trial coordinated (2002). by the Eastern Cooperative Oncology Group," J Clin. Oneal. Schey, "Thalidomide in the management of multiple myeloma," 25: 18S (2007). Hematology 7:291-299 (2002). Rajkumar et al., "Thalidomide plus dexamethasone (Thal/Dex) and Schlossman et al., "Bone marrow transplatation in multiple thalidomide alone (Thal) as first line therapy for newly diagnosed myeloma," Curr. Opin. Oneal. 11:102-108 (1999). myeloma (MM)," Blood 96(Supp.):168a (2000). Seppa, "Thalidomide combats myeloma blood cancer," Science Rajkumar et al., "Combination therapy with lenalidomide plus News 156:326 (1999). dexamethasone (Rev/Dex) for newly diagnosed myeloma," Blood, Shinn et al., "Development of a computerized drug interaction 106(13):4050-4053 (2005). database (MEDICOM) for use in a patient specific environment," Rajkumar et al., "Thalidomide in the treatment of plasma cell Drug Inf J 17:205-210 (1983). malignancies," J Clin. Oneal. 19:3593-3595 (2001). Siegel et al., "Long-term safety and efficacy of pomalidomide Rajkumar, "Thalidomide in multiplem myelorna," Oncology 14: 11- (POM) with or without low-dose dexamethasone (LoDEX) in 16 (2000). relapsed and refractory multiple myeloma (RRMM) patients Ratain, "Pharmacology of Cancer Chemotherapy." In Cancer: Prin­ enrolled in the MM-002 phase II trial," J Clin. Oneal. 31, 2013 ciples & Practice of Oncology, pp. 335-459 (2001). (Abstract No. 8588). Reiman et al., "Meeting synopsis, VIII International Myelorna Singhal et al., "Antitumor activity of thalidomide in refractory Workshop, Banff Springs Hotel, Banff, Alberta, Canada, May 4-8, multiple myeloma," N Engl. J Med., 341(21):1565-1571 (1999). 2001," Eur. J Haematol. 67:199-202 (2001). Smith, R. et al., "Studies on the Relationship Between the Chemical Ribatti et al., "Angiogenesis spectrum in the stroma of B-cell Structure and Embryotoxic Activity of Thalidomide and Related non-Hodgkin's lymphomas. An immunohistochemical and Compounds," in A Symposium on Embryopathic Activity ofDrugs, ultrastructural study," Eur. J Haematol. 56:45-53 (1996). J. & A. Churchill Ltd., Session 6, pp. 194-209 (1965). Richardson et al., "A randomized phase 2 study of lenalidomide Sorbera et al., "CC-5013. Treatment of multiple myeloma. Treat­ therapy for patients with relapsed or relapsed and refractory mul­ ment of Melanoma. Treatment of myelodysplastic syndrome. tiple myeloma," Blood 108:3458-3464 (2006). Angiogenesis inhibitor. TNF-a production inhibitor," Drugs of the Richardson et al., "Thalidomide in multiple Myeloma," Biomed. Future, 28(5):425-431 (2003). Pharmacother. 56:115-128 (2002). Soyka et al., "Prevalence of alcohol and drug abuse in schizophrenic Richardson et al., "Thalidomide: Emerging role in cancer medi­ inpatients," Eur. Arch. Psychiatry Clin. Neurosci. 242:362-372 cine," Ann. Rev. Med. 53:629-657 (2002). (1993). Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 132 of 148 PageID: 132

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(56) References Cited Myeloma (RRMM): Outcomes Based on Prior Treatment Expo­ sure," presented at 54th ASH Annual Meeting and Exposition, OTHER PUBLICATIONS Atlanta, Georgia, Dec. 8-11, 2012, Abstract #4070. Vippagunta et al., "Crystalline solids," Adv. Drug De/iv. Rev., Srkalovic et al. "Use of melphalan, thalidomide, and 48( 1):3-26 (2001 ). dexamethasone in treatment of refractory and relapsed multiple Vogelsang et al., "Thalidomide for the treatment of chronic graft­ myeloma," Med. Oneal. 19:219-226 (2002). Steiner et al., "The assessment of refill compliance using pharmacy versus-host disease," N Engl. J Med. 326:1055-1058 (1992). records: methods, validity, and applications," J Clin. Epidemiol. Weber et al., "Thalidomide alone or with dexamethasone for mul­ 50: 105-116 (1997). tiple myeloma," Blood 94:604 (1999). Stirling et al., "Thalidomide. A surprising recovery," J Am. Pharm. Weber et al., "Thalidomide with dexamethasone of resistant mul­ Assoc. NS37:306-313 (1997). tiple myeloma," Blood 96:167 (2000). Stirling, "Thalidomide: A novel template for anticancer drugs," Welte et al., "Influence of socially desirable responding in a study Seminars Oncology 28:602-606 (2001). of stress and substance abuse," Alcohol Clin. Exp. Res. 17:758-761 Szelenyi et al., "Cyclophosphamide, adriamycin and (1993). dexamethasone (CAD) is a highly effective therapy for patients with Wilson et al., "Response to thalidomide in chemotherapy-resistant advanced multiple myeloma," Ann. Oneal. 12:105-108 (2001). mantle cell lymphoma: a case report," Br. J Haematol. 119: 128-130 THALOMID™ (thalidomide) Capsules Revised Package Insert (2002). (Jul. 15, 1998). Yuen et al., "Phase I study of an anti sense oligonucleotide to protein The Comprehensive Guide to Banff, Understanding the VIIIth kinase C-a (ISIS 3521/CGP 64128A) in patients with cancer," Clin. International Myeloma Workshop published by the International Cancer Res. 5:3357-3363 (1999). Myeloma Foundation (2001). Zangari et al., "Increased risk of deep-vein thrombosis inpatients Thomas et al., "Current role of thalidomide in cancer treatment," with multiple myeloma receiving thalidomide chemotherapy," Curr. Opin. Oneal. 12:564-573 (2000). Blood 98:1614 (2001). Transcript of the Forty-Seventh Meeting of the Dermatologic and Zangari et al., Results of phase I study of CC-5013 for the treatment Ophthalmic Drugs Advisory Committee (Sep. 4, 1997). of multiple myeloma (MM) patients who relapse after high dose Transcript of the Forty-Seventh Meeting of the Dermatologic and chemotherapy (HDT), Blood 98(11), Abstract# 3226 (2001). Ophthalmic Drugs Advisory Committee (Sep. 5, 1997). Zangari et al., "Thrombogenic activity of doxorubicin in myeloma Tseng et al., "Rediscovering thalidomide: a review of its mechanism patients receiving thalidomide: implications for therapy," Blood, of action, side effects, and potential uses," J Am. Acad. Dermatol. 100:1168-1171 (2002). 35:969-979 (1996). Zeldis et al., "S.T.E.P.S.: A comprehensive program for controlling Vacca et al., "Angiogenesis in B cell lymphoproliferative diseases. and monitoring access to thalidomide," Clin. Ther. 21:319-330 Biological and clinical studies," Leuk. Lymphoma 20:27-38 (1995). (1999). Vij et al., "Pomalidomie (POM) with Low-Dose Dexamethasone (LoDex) in Patients with Relapsed and Refractory Multiple * cited by examiner Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 133 of 148 PageID: 133

US 9,993,467 B2 1 2 FORMULATIONS OF 4-AMINO-2-(2,6- a bacterial disease, an ocular neovascular disease, a choroi­ DIOXOPIPERIDINE-3-YL)ISOINDOLINE- dal neovascular disease, a retina neovascular disease, and 1,3-DIONE rubeosis, using pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate, hydrate, or This application is a continuation of U.S. patent applica­ 5 clathrate thereof, in the dosage forms described herein. tion Ser. No. 14/447,450, filed Jul. 30, 2014, which is a continuation of U.S. patent application Ser. No. 12/783,390, 3.1. Definitions filed May 19, 2010, now U.S. Pat. No. 8,828,427, which claims priority to U.S. Provisional Application No. 61/179, As used herein and unless otherwise indicated, a compo­ 678, filed May 19, 2009, each of which are incorporated 10 sition that is "substantially free" of a compound means that herein by reference in their entireties. the composition contains less than about 20 percent by weight, more preferably less than about 10 percent by 1. FIELD weight, even more preferably less than about 5 percent by weight, and most preferably less than about 3 percent by Provided herein are formulations and dosage forms of 15 weight of the compound. pomolidomide, i.e., 4-amino-2-(2,6-dioxopiperidine-3-yl) As used herein and unless otherwise indicated, the term isoindoline-1,3-dione or CC-4047. Methods of using the "stereomerically pure" means a composition that comprises formulations and dosage forms are also provided herein. one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a 2. BACKGROUND 20 stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite Drug substances are usually administered as part of a enantiomer of the compound. A stereomerically pure com­ formulation in combination with one or more other agents position of a compound having two chiral centers will be that serve varied and specialized pharmaceutical functions. substantially free of other diastereomers of the compound. A Dosage forms of various types may be made through selec­ 25 typical stereomerically pure compound comprises greater tive use of pharmaceutical excipients. As pharmaceutical than about 80 percent by weight of one stereoisomer of the excipients have various functions and contribute to the compound and less than about 20 percent by weight of other pharmaceutical formulations in many different ways, e.g., stereoisomers of the compound, more preferably greater solubilization, dilution, thickening, stabilization, preserva­ than about 90 percent by weight of one stereoisomer of the tion, coloring, flavoring, etc. The properties that are com­ 30 compound and less than about 10 percent by weight of the monly considered when formulating an active drug sub­ other stereoisomers of the compound, even more preferably stance include bioavailability, ease of manufacture, ease of greater than about 95 percent by weight of one stereoisomer administration, and stability of the dosage form. Due to the of the compound and less than about 5 percent by weight of varying properties of the active drug substance to be for­ the other stereoisomers of the compound, and most prefer- mulated, dosage forms typically require pharmaceutical 35 ably greater than about 97 percent by weight of one stereoi­ excipients that are uniquely tailored to the active drug somer of the compound and less than about 3 percent by substance in order to achieve advantageous physical and weight of the other stereoisomers of the compound. pharmaceutical properties. As used herein and unless otherwise indicated, the term Pomolidomide, which is also known as CC-4047, is "enantiomerically pure" means a stereomerically pure com- chemically named 4-amino-2-(2,6-dioxopiperidine-3-yl) 40 position of a compound having one chiral center. isoindoline-1,3-dione. Pomolidomide is an immunomodula­ As used herein, unless otherwise specified, the term tory compound that inhibits, for example, LPS induced "pharmaceutically acceptable salt(s)," as used herein monocyte TNFa, IL-1~, IL-12, IL-6, MIP-1, MCP-1, GM­ includes, but is not limited to, salts of acidic or basic CSF, G-CSF, and COX-2 production. The compound is also moieties of thalidomide. Basic moieties are capable of known to co-stimulate the activation of T-cells. Pomolido­ 45 forming a wide variety of salts with various inorganic and mide and method of synthesizing the compound are organic acids. The acids that can be used to prepare phar­ described, e.g., in U.S. Pat. No. 5,635,517, the entirety of maceutically acceptable acid addition salts of such basic which is incorporated herein by reference. compounds are those that form non-toxic acid addition salts, Due to its diversified pharmacological properties, i.e., salts containing pharmacologically acceptable anions. pomolidomide is useful in treating, preventing, and/or man­ 50 Suitable organic acids include, but are not limited to, maleic, aging various diseases or disorders. Thus, a need exists as to fumaric, benzoic, ascorbic, succinic, acetic, formic, oxalic, dosage forms ofpomolidomide having advantageous physi­ propionic, tartaric, salicylic, citric, gluconic, lactic, man­ cal and pharmaceutical properties. delic, cinnamic, oleic, tannic, aspartic, stearic, palmitic, glycolic, glutamic, gluconic, glucaronic, saccharic, isonico- 3. SUMMARY 55 tinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic acids, or pamoic (i.e., 1,1'-methylene-bis­ Provided herein are pharmaceutical dosage forms of (2-hydroxy-3-naphthoate) acids. Suitable inorganic acids pomolidomide, or a pharmaceutically acceptable stereoiso­ include, but are not limited to, hydrochloric, hydrobromic, mer, prodrug, salt, solvate, hydrate, or clathrate thereof. Also hydroiodic, sulfuric, phosphoric, or nitric acids. Compounds provided herein are methods of treating, managing, or 60 that include an amine moiety can form pharmaceutically preventing diseases and conditions such as, but not limited acceptable salts with various amino acids, in addition to the to, cancer, pain, Macular Degeneration, a skin disease, a acids mentioned above. Chemical moieties that are acidic in pulmonary disorder, an asbestos-related disorder, a parasitic nature are capable of forming base salts with various phar­ disease, an immunodeficiency disorder, a CNS disorder, macologically acceptable cations. Examples of such salts are CNS injury, atherosclerosis, a sleep disorder, hemoglobin­ 65 alkali metal or alkaline earth metal salts and, particularly, opathy, anemia, an inflammatory disease, an autoimmune calcium, magnesium, sodium, lithium, zinc, potassium, or disease, a viral disease, a genetic disease, an allergic disease, iron salts. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 134 of 148 PageID: 134

US 9,993,467 B2 3 4 As used herein, and unless otherwise specified, the term As used herein, and unless otherwise indicated, the terms "solvate" means a compound provided herein or a salt "manage," "managing" and "management" encompass pre­ thereof, that further includes a stoichiometric or non-stoi­ venting the recurrence of the specified disease or disorder in chiometric amount of solvent bound by non-covalent inter­ a patient who has already suffered from the disease or molecular forces. Where the solvent is water, the solvate is 5 disorder, and/or lengthening the time that a patient who has a hydrate. suffered from the disease or disorder remains in remission. As used herein and unless otherwise indicated, the term The terms encompass modulating the threshold, develop­ "prodrug" means a derivative of a compound that can ment and/or duration of the disease or disorder, or changing hydrolyze, oxidize, or otherwise react under biological con­ the way that a patient responds to the disease or disorder. ditions (in vitro or in vivo) to provide the compound. 10 As used herein, and unless otherwise specified, the term Examples of prodrugs include, but are not limited to, deriva­ "about," when used in connection with doses, amounts, or tives of thalidomide that include biohydrolyzable moieties weight percent of ingredients of a composition or a dosage such as biohydrolyzable amides, biohydrolyzable esters, form, means dose, amount, or weight percent that is recog­ nized by those of ordinary skill in the art to provide a biohydrolyzable carbamates, biohydrolyzable carbonates, 15 pharmacological effect equivalent to that obtained from the biohydrolyzable ureides, and biohydrolyzable phosphate specified dose, amount, or weight percent is encompassed. analogues. Other examples of prodrugs include derivatives Specifically, the term "about" contemplates a dose, amount, of thalidomide that include -NO, -NO , -ONO, or 2 or weight percent within 30%, 25%, 20%, 15%, 10%, or 5% -ONO moieties. 2 of the specified dose, amount, or weight percent is encom­ As used herein and unless otherwise indicated, the terms 20 passed. "biohydrolyzable carbamate," "biohydrolyzable carbonate," As used herein, and unless otherwise specified, the term "biohydrolyzable ureide," "biohydrolyzable phosphate" "stable," when used in connection with a formulation or a mean a carbamate, carbonate, ureide, or phosphate, respec­ dosage form, means that the active ingredient of the formu­ tively, of a compound that either: 1) does not interfere with lation or dosage form remains solubilized for a specified the biological activity of the compound but can confer upon 25 amount of time and does not significantly degrade or aggre­ that compound advantageous properties in vivo, such as gate or become otherwise modified (e.g., as determined, for uptake, duration of action, or onset of action; or 2) is example, by HPLC). In some embodiments, about 70 per­ biologically inactive but is converted in vivo to the biologi­ cent or greater, about 80 percent or greater or about 90 cally active compound. Examples of biohydrolyzable car­ percent or greater of the compound remains solubilized after bamates include, but are not limited to, lower alkylamines, 30 the specified period. substituted ethylenediamines, aminoacids, hydroxyalkylam­ ines, heterocyclic and heteroaromatic amines, and polyether 4. DETAILED DESCRIPTION ammes. As used herein and unless otherwise indicated, the term Provided herein are pharmaceutical dosage forms of "biohydrolyzable ester" means an ester of a compound that 35 pomolidomide, or a pharmaceutically acceptable stereoiso­ either: 1) does not interfere with the biological activity of the mer, prodrug, salt, solvate, hydrate, or clathrate thereof. In compound but can confer upon that compound advantageous some embodiments, the dosage forms are suitable for oral properties in vivo, such as uptake, duration of action, or administration to a patient. In other embodiments, the dos­ onset of action; or 2) is biologically inactive but is converted age forms provided herein exhibit advantageous physical in vivo to the biologically active compound. Examples of 40 and/or pharmacological properties. Such properties include, biohydrolyzable esters include, but are not limited to, lower but are not limited to, ease of assay, content uniformity, flow alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl properties for manufacture, dissolution and bioavailability, esters, and choline esters. and stability. In certain embodiments, the dosage forms As used herein and unless otherwise indicated, the term provided herein have a shelflife of at least about 12 months, "biohydrolyzable amide" means an amide of a compound 45 at least about 24 months, or at least about 36 months without that either: 1) does not interfere with the biological activity refrigeration. of the compound but can confer upon that compound Also provided herein are kits comprising pharmaceutical advantageous properties in vivo, such as uptake, duration of compositions and dosage forms provided herein. Also pro­ action, or onset of action; or 2) is biologically inactive but vided herein are methods of treating, managing, and/or is converted in vivo to the biologically active compound. 50 preventing a disease or condition, which comprises admin­ Examples of biohydrolyzable amides include, but are not istering to a patient in need thereof a pharmaceutical com­ limited to, lower alkyl amides, a-amino acid amides, position or a dosage form provided herein. alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. As used herein, and unless otherwise specified, the terms 4.1 Compositions and Dosage Forms "treat," "treating" and "treatment" contemplate an action 55 that occurs while a patient is suffering from the specified In one embodiment, provided herein is a single unit disease or disorder, which reduces the severity of the disease dosage form suitable for oral administration to a human or disorder, or retards or slows the progression of the disease comprising: an amount equal to or greater than about 1, 5, or disorder. 10, 15, 20, 25, 30, 50, 75, 100, 150, or 200 mg of an active As used herein, and unless otherwise specified, the terms 60 ingredient; and a pharmaceutically acceptable excipient; "prevent," "preventing" and "prevention" refer to the pre­ wherein the active ingredient is pomolidomide, or a phar­ vention of the onset, recurrence or spread of a disease or maceutically acceptable stereoisomer, prodrug, salt, solvate, disorder, or of one or more symptoms thereof. The terms or clathrate thereof. In some embodiments, the amount of "prevent," "preventing" and "prevention" contemplate an active ingredient is from about 0.1 to about 100 mg, from action that occurs before a patient begins to suffer from the 65 about 0.5 to about 50 mg, from, about 0.5 to about 25 mg, specified disease or disorder, which inhibits or reduces the from about 1 mg to about 10 mg, from about 0.5 to about 5 severity of the disease or disorder. mg, or from about 1 mg to about 5 mg. In one embodiment, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 135 of 148 PageID: 135

US 9,993,467 B2 5 6 the amount of the active ingredient is about 0.5 mg. In herein can comprise excipients which are well known in the another embodiment, the amount of the active ingredient is art and are listed in the USP (XXI)/NF (XVI), which is about 1 mg. In another embodiment, the amount of the active incorporated herein by reference. ingredient is about 2 mg. In another embodiment, the In one embodiment, pomolidomide, or a pharmaceutically amount of the active ingredient is about 5 mg. 5 acceptable stereoisomer, prodrug, salt, solvate, or clathrate Pharmaceutical compositions and formulations provided thereof, comprises from about 0.1 to about 10 weight herein can be presented as discrete dosage forms, such as percent of total weight of the composition. In another capsules (e.g., gelcaps ), caplets, tablets, troches, lozenges, embodiment, pomolidomide, or a pharmaceutically accept­ dispersions, and suppositories each containing a predeter­ able stereoisomer, prodrug, salt, solvate, or clathrate thereof, mined amount of an active ingredient as a powder or in 10 comprises from about 0.1 to about 5 weight percent of total granules, a solution, or a suspension in an aqueous or weight of the composition. In another embodiment, non-aqueous liquid, an oil-in-water emulsion, or a water-in- pomolidomide, or a pharmaceutically acceptable stereoiso­ oil liquid emulsion. Because of their ease of administration, mer, prodrug, salt, solvate, or clathrate thereof, comprises tablets, caplets, and capsules represent a preferred oral from about 0.1 to about 3 weight percent of total weight of dosage unit forms. 15 the composition. In another embodiment, pomolidomide, or Tablets, caplets, and capsules typically contain from about a pharmaceutically acceptable stereoisomer, prodrug, salt, 50 mg to about 500 mg of the pharmaceutical composition solvate, or clathrate thereof, comprises from about 0.5 to (i.e., active ingredient and excipient(s)). Capsules can be of about 3 weight percent of total weight of the composition. In any size. Examples of standard sizes include #000, #00, #0, another embodiment, pomolidomide, or a pharmaceutically #1, #2, #3, #4, and #5. See, e.g., Remington's Pharmaceu­ 20 acceptable stereoisomer, prodrug, salt, solvate, or clathrate tical Sciences, page 1658-1659 (Alfonso Gennaro ed., Mack thereof, comprises from about 0.5 to about 2 weight percent Publishing Company, Easton Pa., 18th ed., 1990), which is of total weight of the composition. In another embodiment, incorporated by reference. In some embodiments, capsules pomolidomide, or a pharmaceutically acceptable stereoiso­ provided herein are of size #1 or larger, #2 or larger, or #4 mer, prodrug, salt, solvate, or clathrate thereof, comprises or larger. 25 about 1 weight percent of total weight of the composition. In Also provided herein are anhydrous pharmaceutical com­ another embodiment, pomolidomide, or a pharmaceutically positions and dosage forms including an active ingredient, acceptable stereoisomer, prodrug, salt, solvate, or clathrate since water can facilitate the degradation of some com­ thereof, comprises about 0.8 weight percent of total weight pounds. For example, the addition of water (e.g., 5 percent) of the composition. In another embodiment, pomolidomide, is widely accepted in the pharmaceutical arts as a means of 30 or a pharmaceutically acceptable stereoisomer, prodrug, salt, simulating shelf-life, i.e., long-term storage in order to solvate, or clathrate thereof, comprises about 2 weight determine characteristics such as shelf-life or the stability of percent of total weight of the composition. In another formulations over time. See, e.g., Jens T. Carstensen, Drug embodiment, pomolidomide, or a pharmaceutically accept­ Stability: Principles & Practice, 2d. Ed., Marcel Dekker, able stereoisomer, prodrug, salt, solvate, or clathrate thereof, NY, N.Y., 1995, pp. 379-80. In effect, water and heat 35 comprises about 1.7 weight percent of total weight of the accelerate decomposition. Thus, the effect of water on a composition. formulation can be of great significance since moisture In one embodiment, the active ingredient and carrier, and/or humidity are commonly encountered during manu­ diluent, binder, or filler are directly blended as described facture, handling, packaging, storage, shipment, and use of herein elsewhere. In another embodiment, the carrier, formulations. 40 diluent, binder, or filler comprises mannitol and/or starch. In An anhydrous pharmaceutical compositions should be one embodiment, the mannitol is spray dried mannitol. In prepared and stored such that the anhydrous nature is another embodiment, the starch is pregelatinized starch. maintained. Accordingly, in some embodiments, anhydrous In one embodiment, the carrier, diluent, binder, or filler compositions are packaged using materials known to pre­ comprises from about 70 to about 99 weight percent of total vent exposure to water such that they can be included in 45 weight of the composition. In another embodiment, the suitable formulary kits. Examples of suitable packaging carrier, diluent, binder, or filler comprises from about 80 to include, but are not limited to, hermetically sealed foils, about 99 weight percent of total weight of the composition. plastic or the like, unit dose containers, blister packs, and In another embodiment, the carrier, diluent, binder, or filler strip packs. comprises from about 85 to about 99 weight percent of total In this regard, also provided herein is a method of 50 weight of the composition. In another embodiment, the preparing a solid pharmaceutical formulation including an carrier, diluent, binder, or filler comprises from about 90 to active ingredient through admixing the active ingredient and about 99 weight percent of total weight of the composition. an excipient under anhydrous or low moisture/humidity In another embodiment, the carrier, diluent, binder, or filler conditions, wherein the ingredients are substantially free of comprises from about 95 to about 99 weight percent of total water. The method can further include packaging the anhy- 55 weight of the composition. In another embodiment, the drous or non-hygroscopic solid formulation under low mois­ carrier, diluent, binder, or filler comprises about 98 weight ture conditions. By using such conditions, the risk of contact percent of total weight of the composition. In another with water is reduced and the degradation of the active embodiment, the carrier, diluent, binder, or filler comprises ingredient can be prevented or substantially reduced. about 99 weight percent of total weight of the composition. Also provided herein are lactose-free pharmaceutical 60 In one embodiment, the dosage forms provided herein compositions and dosage forms. Compositions and dosage comprise both mannitol and starch. In one embodiment, forms that comprise an active ingredient that is a primary or mannitol and starch comprise from about 70 to about 99 secondary amine are preferably lactose-free. As used herein, weight percent of total weight of the composition. In another the term "lactose-free" means that the amount of lactose embodiment, mannitol and starch comprise from about 80 to present, if any, is insufficient to substantially increase the 65 about 99 weight percent of total weight of the composition. degradation rate of an active ingredient that is a primary or In another embodiment, mannitol and starch comprise from secondary amine. Lactose-free compositions provided about 85 to about 99 weight percent of total weight of the Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 136 of 148 PageID: 136

US 9,993,467 B2 7 8 composition. In another embodiment, mannitol and starch the dosage form, the dosage form comprises about 35 mg of comprise from about 90 to about 99 weight percent of total starch, and the remaining weight is filled by starch. In one weight of the composition. In another embodiment, manni­ embodiment, the mannitol is spray dried mannitol. In tol and starch comprise from about 95 to about 99 weight another embodiment, the starch is pregelatinized starch. percent of total weight of the composition. In another 5 In one embodiment where the total weight of the dosage embodiment, mannitol and starch comprise about 98 weight form is about 62.5 mg and where a lubricant is present, the percent of total weight of the composition. In another lubricant is sodium stearyl fumarate. In one embodiment, the embodiment, mannitol and starch comprise about 99 weight sodium stearyl fumarate is present at an amount of about 0.2 percent of total weight of the composition. mg. In one embodiment, the sodium stearyl fumarate is In one embodiment, the ratio of mannitol:starch in the 10 present at an amount of about 0.16 mg. dosage form is from about 1: 1 to about 1: 1.5. In one In one embodiment, provided herein is a dosage form embodiment, the ratio of mannitol:starch in the dosage form comprising: 1) pomolidomide, or a pharmaceutically accept­ is about 1: 1.3. able stereoisomer, prodrug, salt, solvate, or clathrate thereof, In another embodiment, the dosage form comprises a present at an amount that provides about 0.5 mg potency of lubricant. In one embodiment, the dosage form comprises 15 pomolidomide; 2) about 35 mg of pregelatinized starch; 3) about 0.2, 0.3, 0.5, 0.6, or 0.8 mg of lubricant. In another about 0.16 mg of sodium stearyl fumarate; and 4) spray embodiment, the dosage form comprises about 0.16, 0.32, dried mannitol at an amount that brings the total weight of 0.64, or 0.75 mg of lubricant. In one embodiment, the the dosage form to 62.5 mg. In one embodiment, the dosage lubricant is sodium stearyl fumarate (PRUV). form is suitable for administration in a size 4 or larger In one embodiment, the lubricant, e.g., PRUV, comprises 20 capsule. from about 0.01 to about 5 weight percent of total weight of In one embodiment, provided herein is a dosage form the composition. In another embodiment, the lubricant, e.g., comprising: 1) pomolidomide, or a pharmaceutically accept­ PRUV, comprises from about 0.01 to about 1 weight percent able stereoisomer, prodrug, salt, solvate, or clathrate thereof, of total weight of the composition. In another embodiment, present at an amount that provides about 1 mg potency of the lubricant, e.g., PRUV, comprises from about 0.1 to about 25 pomolidomide; and 2) a pharmaceutically acceptable excipi­ 1 weight percent of total weight of the composition. In ent. In one embodiment, the total weight of the dosage form another embodiment, the lubricant, e.g., PRUV, comprises is about 125 mg. In one embodiment, the dosage form is from about 0.1 to about 0.5 weight percent of total weight of suitable for administration in a size 4 or larger capsule. In the composition. In another embodiment, the lubricant, e.g., one embodiment, the excipient comprises a carrier, diluent, PRUV, comprises from about 0.2 to about 0.3 weight percent 30 binder, or filler. In one embodiment, the excipients comprise of total weight of the composition. In another embodiment, a carrier, diluent, binder, or filler and a lubricant. the lubricant, e.g., PRUV, comprises about 0.25 weight In one embodiment where the total weight of the dosage percent of total weight of the composition. form is about 125 mg, the carrier, diluent, binder, or filler In some embodiments, because it is typical to obtain comprises mannitol and/or starch. In one embodiment, the pomolidomide, or a pharmaceutically acceptable stereoiso­ 35 excipient comprises both mannitol and starch. In one mer, prodrug, salt, solvate, or clathrate thereof, at a purity of embodiment, where both mannitol and starch are present in less than 100%, the formulations and dosage forms provided the dosage form, the dosage form comprises about 70 mg of herein may be defined as compositions, formulations, or starch, and the remaining weight is filled by starch. In one dosage forms that comprise pomolidomide, or a pharmaceu­ embodiment, the mannitol is spray dried mannitol. In tically acceptable stereoisomer, prodrug, salt, solvate, or 40 another embodiment, the starch is pregelatinized starch. clathrate thereof, at an amount that provides the potency of In one embodiment where the total weight of the dosage a specified amount of 100% pure pomolidomide. form is about 125 mg and where a lubricant is present, the For example, in one embodiment, provided herein is a lubricant is sodium stearyl fumarate. In one embodiment, the single unit dosage form comprising: 1) pomolidomide, or a sodium stearyl fumarate is present at an amount of about 0.3 pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ 45 mg. In one embodiment, the sodium stearyl fumarate is vate, or clathrate thereof, present at an amount that provides present at an amount of about 0.32 mg. about 0.5, 1, 2, 3, 4, or 5 mg potency ofpomolidomide; and In one embodiment, provided herein is a dosage form 2) about 60, 120, 250, 180, 240, or 300 mg of a carrier, comprising: 1) pomolidomide, or a pharmaceutically accept­ diluent, binder, or filler, respectively. In one embodiment, able stereoisomer, prodrug, salt, solvate, or clathrate thereof, the amount of a carrier, diluent, binder, or filler is about 62, 50 present at an amount that provides about 1 mg potency of 124, 248, 177, 236, or 295 mg, respectively. pomolidomide; 2) about 70 mg of pregelatinized starch; 3) In one embodiment, provided herein is a dosage form about 0.32 mg of sodium stearyl fumarate; and 4) spray comprising: 1) pomolidomide, or a pharmaceutically accept­ dried mannitol at an amount that brings the total weight of able stereoisomer, prodrug, salt, solvate, or clathrate thereof, the dosage form to 125 mg. In one embodiment, the dosage present at an amount that provides about 0.5 mg potency of 55 form is suitable for administration in a size 4 or larger pomolidomide; and 2) a pharmaceutically acceptable excipi­ capsule. ent. In one embodiment, the total weight of the dosage form In one embodiment, provided herein is a dosage form is about 62.5 mg. In one embodiment, the dosage form is comprising: 1) pomolidomide, or a pharmaceutically accept­ suitable for administration in a size 4 or larger capsule. In able stereoisomer, prodrug, salt, solvate, or clathrate thereof, one embodiment, the excipient comprises a carrier, diluent, 60 present at an amount that provides about 2 mg potency of binder, or filler. In one embodiment, the excipients comprise pomolidomide; and 2) a pharmaceutically acceptable excipi­ a carrier, diluent, binder, or filler and a lubricant. ent. In one embodiment, the total weight of the dosage form In one embodiment where the total weight of the dosage is about 250 mg. In one embodiment, the dosage form is form is about 62.5 mg, the carrier, diluent, binder, or filler suitable for administration in a size 2 or larger capsule. In comprises mannitol and/or starch. In one embodiment, the 65 one embodiment, the excipient comprises a carrier, diluent, excipient comprises both mannitol and starch. In one binder, or filler. In one embodiment, the excipients comprise embodiment, where both mannitol and starch are present in a carrier, diluent, binder, or filler and a lubricant. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 137 of 148 PageID: 137

US 9,993,467 B2 9 10 In one embodiment where the total weight of the dosage is about 240 mg. In one embodiment, the dosage form is form is about 250 mg, the carrier, diluent, binder, or filler suitable for administration in a size 2 or larger capsule. In comprises mannitol and/or starch. In one embodiment, the one embodiment, the excipient comprises a carrier, diluent, excipient comprises both mannitol and starch. In one binder, or filler. In one embodiment, the excipients comprise embodiment, where both mannitol and starch are present in 5 a carrier, diluent, binder, or filler and a lubricant. the dosage form, the dosage form comprises about 140 mg In one embodiment where the total weight of the dosage of starch, and the remaining weight is filled by starch. In one form is about 240 mg, the carrier, diluent, binder, or filler embodiment, the mannitol is spray dried mannitol. In comprises mannitol and/or starch. In one embodiment, the another embodiment, the starch is pregelatinized starch. excipient comprises both mannitol and starch. In one In one embodiment where the total weight of the dosage 10 embodiment, where both mannitol and starch are present in form is about 250 mg and where a lubricant is present, the the dosage form, the dosage form comprises about 135 mg lubricant is sodium stearyl fumarate. In one embodiment, the of starch, and the remaining weight is filled by starch. In one sodium stearyl fumarate is present at an amount of about 0.6 embodiment, the marmitol is spray dried mannitol. In mg. In one embodiment, the sodium stearyl fumarate is another embodiment, the starch is pregelatinized starch. present at an amount of about 0.64 mg. 15 In one embodiment where the total weight of the dosage In one embodiment, provided herein is a dosage form form is about 240 mg and where a lubricant is present, the comprising: 1) pomolidomide, or a pharmaceutically accept­ lubricant is sodium stearyl fumarate. In one embodiment, the able stereoisomer, prodrug, salt, solvate, or clathrate thereof, sodium stearyl fumarate is present at an amount of about 0.6 present at an amount that provides about 2 mg potency of mg. pomolidomide; 2) about 140 mg of pregelatinized starch; 3) 20 In one embodiment, provided herein is a dosage form about 0.64 mg of sodium stearyl fumarate; and 4) spray comprising: 1) pomolidomide, or a pharmaceutically accept­ dried mannitol at an amount that brings the total weight of able stereoisomer, prodrug, salt, solvate, or clathrate thereof, the dosage form to 250 mg. In one embodiment, the dosage present at an amount that provides about 4 mg potency of form is suitable for administration in a size 2 or larger pomolidomide; 2) about 134.4 mg of pregelatinized starch; capsule. 25 3) about 0.6 mg of sodium stearyl fumarate; and 4) spray In one embodiment, provided herein is a dosage form dried marmitol at an amount that brings the total weight of comprising: 1) pomolidomide, or a pharmaceutically accept­ the dosage form to 240 mg. In one embodiment, the dosage able stereoisomer, prodrug, salt, solvate, or clathrate thereof, form is suitable for administration in a size 2 or larger present at an amount that provides about 3 mg potency of capsule. pomolidomide; and 2) a pharmaceutically acceptable excipi- 30 In one embodiment, provided herein is a dosage form ent. In one embodiment, the total weight of the dosage form comprising: 1) pomolidomide, or a pharmaceutically accept­ is about 180 mg. In one embodiment, the dosage form is able stereoisomer, prodrug, salt, solvate, or clathrate thereof, suitable for administration in a size 2 or larger capsule. In present at an amount that provides about 5 mg potency of one embodiment, the excipient comprises a carrier, diluent, pomolidomide; and 2) a pharmaceutically acceptable excipi- binder, or filler. In one embodiment, the excipients comprise 35 ent. In one embodiment, the total weight of the dosage form a carrier, diluent, binder, or filler and a lubricant. is about 300 mg. In one embodiment, the dosage form is In one embodiment where the total weight of the dosage suitable for administration in a size 1 or larger capsule. In form is about 180 mg, the carrier, diluent, binder, or filler one embodiment, the excipient comprises a carrier, diluent, comprises mannitol and/or starch. In one embodiment, the binder, or filler. In one embodiment, the excipients comprise excipient comprises both mannitol and starch. In one 40 a carrier, diluent, binder, or filler and a lubricant. embodiment, where both mannitol and starch are present in In one embodiment where the total weight of the dosage the dosage form, the dosage form comprises about 100 mg form is about 300 mg, the carrier, diluent, binder, or filler of starch, and the remaining weight is filled by starch. In one comprises mannitol and/or starch. In one embodiment, the embodiment, the mannitol is spray dried mannitol. In excipient comprises both mannitol and starch. In one another embodiment, the starch is pregelatinized starch. 45 embodiment, where both mannitol and starch are present in In one embodiment where the total weight of the dosage the dosage form, the dosage form comprises about 168 mg form is about 180 mg and where a lubricant is present, the of starch, and the remaining weight is filled by starch. In one lubricant is sodium stearyl fumarate. In one embodiment, the embodiment, the marmitol is spray dried mannitol. In sodium stearyl fumarate is present at an amount of about 0.5 another embodiment, the starch is pregelatinized starch. mg. In one embodiment, the sodium stearyl fumarate is 50 In one embodiment where the total weight of the dosage present at an amount of about 0.45 mg. form is about 300 mg and where a lubricant is present, the In one embodiment, provided herein is a dosage form lubricant is sodium stearyl fumarate. In one embodiment, the comprising: 1) pomolidomide, or a pharmaceutically accept­ sodium stearyl fumarate is present at an amount of about 0.8 able stereoisomer, prodrug, salt, solvate, or clathrate thereof, mg. In one embodiment, the sodium stearyl fumarate is present at an amount that provides about 3 mg potency of 55 present at an amount of about 0.75 mg. pomolidomide; 2) about 100.8 mg of pregelatinized starch; In one embodiment, provided herein is a dosage form 3) about 0.45 mg of sodium stearyl fumarate; and 4) spray comprising: 1) pomolidomide, or a pharmaceutically accept­ dried mannitol at an amount that brings the total weight of able stereoisomer, prodrug, salt, solvate, or clathrate thereof, the dosage form to 180 mg. In one embodiment, the dosage present at an amount that provides about 5 mg potency of form is suitable for administration in a size 2 or larger 60 pomolidomide; 2) about 168 mg ofpregelatinized starch; 3) capsule. about 0.75 mg of sodium stearyl fumarate; and 4) spray In one embodiment, provided herein is a dosage form dried marmitol at an amount that brings the total weight of comprising: 1) pomolidomide, or a pharmaceutically accept­ the dosage form to 300 mg. In one embodiment, the dosage able stereoisomer, prodrug, salt, solvate, or clathrate thereof, form is suitable for administration in a size 1 or larger present at an amount that provides about 4 mg potency of 65 capsule. pomolidomide; and 2) a pharmaceutically acceptable excipi­ In another embodiment, provided herein is a dosage form ent. In one embodiment, the total weight of the dosage form comprising pomolidomide, or a pharmaceutically acceptable Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 138 of 148 PageID: 138

US 9,993,467 B2 11 12 stereoisomer, prodrug, salt, solvate, or clathrate thereof, spray dried mannitol at an amount that brings the total present at an amount that provides about 0.5 mg potency of weight of the dosage form to 250 mg; wherein the dosage pomolidomide, which is stable for a period of at least about form is stable for a period of at least about 12, about 24, or 12, about 24, or about 36 months without refrigeration. In about 36 months without refrigeration. In one embodiment, some embodiments, the dosage form comprises mannitol 5 the dosage form is suitable for administration in a size 2 or and/or starch. In one embodiment where both starch and larger capsule. mannitol are present in the dosage form, starch is present at In another embodiment, provided herein is a dosage form an amount of about 35 mg, and mannitol is present at an comprising pomolidomide, or a pharmaceutically acceptable amount that brings the total weight of composition to about stereoisomer, prodrug, salt, solvate, or clathrate thereof, 62.5 mg. In some embodiments, the dosage form further 10 present at an amount that provides about 5 mg potency of comprises sodium stearyl fumarate at an amount of about 0.2 pomolidomide, which is stable for a period of at least about mg or about 0.16 mg. In some embodiments, provided 12, about 24, or about 36 months without refrigeration. In herein is a dosage form comprising: 1) pomolidomide, or a some embodiments, the dosage form comprises mannitol pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ and/or starch. In one embodiment where both starch and vate, or clathrate thereof, present at an amount that provides 15 mannitol are present in the dosage form, starch is present at about 0.5 mg potency of pomolidomide, about 35 mg an amount of about 168 mg, and mannitol is present at an pregelatinized starch; about 0.16 mg sodium stearyl fumar­ amount that brings the total weight of composition to about ate; and spray dried mannitol at an amount that brings the 300 mg. In some embodiments, the dosage form further total weight of the dosage form to 62.5 mg; wherein the comprises sodium stearyl fumarate at an amount of about 0.8 dosage form is stable for a period of at least about 12, about 20 mg or about 0.75 mg. In some embodiments, provided 24, or about 36 months without refrigeration. In one embodi­ herein is a dosage form comprising: 1) pomolidomide, or a ment, the dosage form is suitable for administration in a size pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ 4 or larger capsule. vate, or clathrate thereof, present at an amount that provides In another embodiment, provided herein is a dosage form about 5 mg potency of pomolidomide, about 168 mg prege­ comprising pomolidomide, or a pharmaceutically acceptable 25 latinized starch; about 0.75 mg sodium stearyl fumarate; and stereoisomer, prodrug, salt, solvate, or clathrate thereof, spray dried mannitol at an amount that brings the total present at an amount that provides about 1 mg potency of weight of the dosage form to 300 mg; wherein the dosage pomolidomide, which is stable for a period of at least about form is stable for a period of at least 12, about 24, or about 12, about 24, or about 36 months without refrigeration. In 36 months without refrigeration. In one embodiment, the some embodiments, the dosage form comprises mannitol 30 dosage form is suitable for administration in a size 1 or and/or starch. In one embodiment where both starch and larger capsule. mannitol are present in the dosage form, starch is present at an amount of about 70 mg, and mannitol is present at an 4.1.1 Second Active Agents amount that brings the total weight of composition to about 125 mg. In some embodiments, the dosage form further 35 In certain embodiments, provided herein are compositions comprises sodium stearyl fumarate at an amount of about 0.3 and dosage form of pomolidomide, or a pharmaceutically mg or about 0.32 mg. In some embodiments, provided acceptable stereoisomer, prodrug, salt, solvate, or clathrate herein is a dosage form comprising: 1) pomolidomide, or a thereof, which may further comprise one or more secondary pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ active ingredients. Certain combinations may work syner­ vate, or clathrate thereof, present at an amount that provides 40 gistically in the treatment of particular types diseases or about 1 mg potency of pomolidomide, about 70 mg prege­ disorders, and conditions and symptoms associated with latinized starch; about 0.32 mg sodium stearyl fumarate; and such diseases or disorders. Pomolidomide, or a pharmaceu­ spray dried mannitol at an amount that brings the total tically acceptable stereoisomer, prodrug, salt, solvate, or weight of the dosage form to 125 mg; wherein the dosage clathrate thereof, can also work to alleviate adverse effects form is stable for a period of at least about 12, about 24, or 45 associated with certain second active agents, and vice versa. about 36 months without refrigeration. In one embodiment, Specific second active compounds that can be contained the dosage form is suitable for administration in a size 4 or in the formulations and dosage forms provided herein vary larger capsule. depending on the specific indication to be treated, prevented In another embodiment, provided herein is a dosage form or managed. comprising pomolidomide, or a pharmaceutically acceptable 50 For instance, for the treatment, prevention or management stereoisomer, prodrug, salt, solvate, or clathrate thereof, of cancer, second active agents include, but are not limited present at an amount that provides about 2 mg potency of to: semaxanib; cyclosporin; etanercept; doxycycline; bort­ pomolidomide, which is stable for a period of at least about ezomib; acivicin; aclarubicin; acodazole hydrochloride; 12, about 24, or about 36 months without refrigeration. In acronine; adozelesin; aldesleukin; altretamine; ambomycin; some embodiments, the dosage form comprises mannitol 55 ametantrone acetate; amsacrine; anastrozole; anthramycin; and/or starch. In one embodiment where both starch and asparaginase; asperlin; azacitidine; azetepa; azotomycin; mannitol are present in the dosage form, starch is present at batimastat; benzodepa; bicalutamide; bisantrene hydrochlo­ an amount of about 140 mg, and mannitol is present at an ride; bisnafide dimesylate; bizelesin; bleomycin sulfate; amount that brings the total weight of composition to about brequinar sodium; bropirimine; busulfan; cactinomycin; 250 mg. In some embodiments, the dosage form further 60 calusterone; caracemide; carbetimer; carboplatin; carmus­ comprises sodium stearyl fumarate at an amount of about 0.6 tine; carubicin hydrochloride; carzelesin; cedefingol; cele­ mg or about 0.64 mg. In some embodiments, provided coxib; chlorambucil; cirolemycin; cisplatin; cladribine; cris­ herein is a dosage form comprising: 1) pomolidomide, or a natol mesylate; cyclophosphamide; cytarabine; dacarbazine; pharmaceutically acceptable stereoisomer, prodrug, salt, sol­ dactinomycin; daunorubicin hydrochloride; decitabine; vate, or clathrate thereof, present at an amount that provides 65 dexormaplatin; dezaguanine; dezaguanine mesylate; diazi­ about 2 mg potency of pomolidomide, about 140 mg prege­ quone; docetaxel; doxorubicin; doxorubicin hydrochloride; latinized starch; about 0.64 mg sodium stearyl fumarate; and droloxifene; droloxifene citrate; dromostanolone propi- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 139 of 148 PageID: 139

US 9,993,467 B2 13 14 onate; duazomycin; edatrexate; eflornithine hydrochloride; 8; cryptophycin A derivatives; curacin A; cyclopentanthra­ elsamitrucin; enloplatin; enpromate; epipropidine; epirubi­ quinones; cycloplatam; cypemycin; cytarabine ocfosfate; cin hydrochloride; erbulozole; esorubicin hydrochloride; cytolytic factor; cytostatin; dacliximab; decitabine; dehy­ estramustine; estramustine phosphate sodium; etanidazole; drodidenmin B; deslorelin; dexamethasone; dexifosfamide; etoposide; etoposide phosphate; etoprine; fadrozole hydro- 5 dexrazoxane; dexverapamil; diaziquone; didenmin B; didox; chloride; fazarabine; fenretinide; floxuridine; fludarabine diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosa­ sodium; gemcitabine; gemcitabine hydrochloride; nol; dolasetron; doxifluridine; doxorubicin; droloxifene; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmo­ dronabinol; duocarmycin SA; ebselen; ecomustine; edelfos­ fosine; iproplatin; irinotecan; irinotecan hydrochloride; Ian- 10 ine; edrecolomab; eflornithine; elemene; emitefur; epirubi­ reotide acetate; letrozole; leuprolide acetate; liarozole cin; epristeride; estramustine analogue; estrogen agonists; hydrochloride; lometrexol sodium; lomustine; losoxantrone estrogen antagonists; etanidazole; etoposide phosphate; hydrochloride; masoprocol; maytansine; mechlorethamine exemestane; fadrozole; fazarabine; fenretinide; filgrastim; hydrochloride; megestrol acetate; melengestrol acetate; mel­ finasteride; flavopiridol; flezelastine; fluasterone; fludara­ phalan; menogaril; mercaptopurine; methotrexate; metho- 15 bine; fluorodaunorunicin hydrochloride; forfenimex; form­ trexate sodium; metoprine; meturedepa; mitindomide; mito­ estane; fostriecin; fotemustine; gadolinium texaphyrin; gal­ carcin; mitocromin; mitogillin; mitomalcin; mitomycin; lium nitrate; galocitabine; ganirelix; gelatinase inhibitors; mitosper; mitotane; mitoxantrone hydrochloride; mycophe­ gemcitabine; glutathione inhibitors; hepsulfam; heregulin; nolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; hexamethylene bisacetamide; hypericin; ibandronic acid; paclitaxel; pegaspargase; peliomycin; pentamustine; peplo- 20 idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; mycin sulfate; perfosfamide; pipobroman; piposulfan; imatinib (Gleevec®), imiquimod; immunostimulant pep­ piroxantrone hydrochloride; plicamycin; plomestane; tides; insulin-like growth factor-I receptor inhibitor; inter­ porfimer sodium; porfiromycin; prednimustine; procarba­ feron agonists; interferons; interleukins; iobenguane; iodo­ zine hydrochloride; puromycin; puromycin hydrochloride; doxorubicin; ipomeanol, 4-; iroplact; irsogladine; pyrazofurin; riboprine; safingol; safingol hydrochloride; 25 isobengazole; isohomohalicondrin B; itasetron; jasplakino­ semustine; simtrazene; sparfosate sodium; sparsomycin; lide; kahalalide F; lamellarin-N triacetate; lanreotide; lein­ spirogermanium hydrochloride; spiromustine; spiroplatin; amycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; streptonigrin; streptozocin; sulofenur; talisomycin; tec­ leukemia inhibiting factor; leukocyte alpha interferon; leu­ ogalan sodium; taxotere; tegafur; teloxantrone hydrochlo­ prolide+estrogen+progesterone; leuprorelin; levamisole; ride; temoporfin; teniposide; teroxirone; testolactone; thia- 30 liarozole; linear polyamine analogue; lipophilic disaccharide miprine; thioguanine; thiotepa; tiazofurin; tirapazamine; peptide; lipophilic platinum compounds; lissoclinamide 7; toremifene citrate; trestolone acetate; triciribine phosphate; lobaplatin; lombricine; lometrexol; lonidamine; losoxan­ trimetrexate; trimetrexate glucuronate; triptorelin; tubulo­ trone; loxoribine; lurtotecan; lutetium texaphyrin; lysofyl­ zole hydrochloride; uracil mustard; uredepa; vapreotide; line; lytic peptides; maitansine; mamiostatin A; marimastat; verteporfin; vinblastine sulfate; vincristine sulfate; vin- 35 masoprocol; maspin; matrilysin inhibitors; matrix metallo­ desine; vindesine sulfate; vinepidine sulfate; vinglycinate proteinase inhibitors; menogaril; merbarone; meterelin; sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine methioninase; metoclopramide; MIF inhibitor; mifepris­ sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; tone; miltefosine; mirimostim; mitoguazone; mitolactol; and zorubicin hydrochloride. mitomycin analogues; mitonafide; mitotoxin fibroblast Other second agents include, but are not limited to: 40 growth factor-saporin; mitoxantrone; mofarotene; molgra­ 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abirater­ mostim; Erbitux, human chorionic gonadotrophin; mono­ one; aclarubicin; acylfulvene; adecypenol; adozelesin; phosphoryl lipidA+myobacterium cell wall sk; mopidamol; aldesleukin; ALL-TK antagonists; altretamine; ambamus­ mustard anticancer agent; mycaperoxide B; mycobacterial tine; amidox; amifostine; aminolevulinic acid; amrubicin; cell wall extract; myriaporone; N-acetyldinaline; N-substi­ amsacrine; anagrelide; anastrozole; andrographolide; angio- 45 tuted benzamides; nafarelin; nagrestip; naloxone+pentazo­ genesis inhibitors; antagonist D; antagonist G; antarelix; cine; napavin; naphterpin; nartograstim; nedaplatin; nemo­ anti-dorsalizing morphogenetic protein-I; antiandrogen, rubicin; neridronic acid; nilutamide; nisamycin; nitric oxide prostatic carcinoma; antiestrogen; antineoplaston; antisense modulators; nitroxide antioxidant; nitrullyn; oblimersen oligonucleotides; aphidicolin glycinate; apoptosis gene (Genasense®); O6-benzylguanine; octreotide; okicenone; modulators; apoptosis regulators; apurinic acid; ara-CDP- 50 oligonucleotides; onapristone; ondansetron; ondansetron; DL-PTBA; arginine deaminase; asulacrine; atamestane; atri­ oracin; oral cytokine inducer; ormaplatin; osaterone; oxali­ mustine; axinastatin 1; axinastatin 2; axinastatin 3; azase­ platin; oxaunomycin; paclitaxel; paclitaxel analogues; pacli­ tron; azatoxin; azatyrosine; baccatin III derivatives; balanol; taxel derivatives; palauamine; palmitoylrhizoxin; batimastat; BCR/ABL antagonists; benzochlorins; benzoyl­ pamidronic acid; panaxytriol; panomifene; parabactin; staurosporine; beta lactam derivatives; beta-alethine; beta- 55 pazelliptine; pegaspargase; peldesine; pentosan polysulfate clamycin B; betulinic acid; bFGF inhibitor; bicalutamide; sodium; pentostatin; pentrozole; perflubron; perfosfamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; perillyl alcohol; phenazinomycin; phenylacetate; phos­ bizelesin; breflate; bropirimine; budotitane; buthionine sul­ phatase inhibitors; picibanil; pilocarpine hydrochloride; foximine; calcipotriol; calphostin C; camptothecin deriva­ pirarubicin; piritrexim; placetin A; placetin B; plasminogen tives; capecitabine; carboxamide-amino-triazole; car- 60 activator inhibitor; platinum complex; platinum compounds; boxyamidotriazole; CaRest M3; CARN 700; cartilage platinum-triamine complex; porfimer sodium; porfiromycin; derived inhibitor; carzelesin; casein kinase inhibitors prednisone; propyl bis-acridone; prostaglandin 12; protea­ (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; some inhibitors; protein A-based immune modulator; pro­ chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; tein kinase C inhibitor; protein kinase C inhibitors, microal­ cladribine; clomifene analogues; clotrimazole; collismycin 65 gal; protein tyrosine phosphatase inhibitors; purine A; collismycin B; combretastatin A4; combretastatin ana­ nucleoside phosphorylase inhibitors; purpurins; pyrazolo­ logue; conagenin; crambescidin 816; crisnatol; cryptophycin acridine; pyridoxylated hemoglobin polyoxyethylene con- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 140 of 148 PageID: 140

US 9,993,467 B2 15 16 jugate; raf antagonists; raltitrexed; ramosetron; ras famesyl NMDA antagonists, and other therapeutics found, for protein transferase inhibitors; ras inhibitors; ras-GAP inhibi­ example, in the Physician's Desk Reference 2003. Specific tor; retelliptine demethylated; rhenium Re 186 etidronate; examples include, but are not limited to, salicylic acid rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide; acetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ket- roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; 5 amine, gabapentin (Neurontin®), phenytoin (Dilantin®), SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; carbamazepine (Tegretol®), oxcarbazepine (Trileptal®), semustine; senescence derived inhibitor 1; sense oligonucle­ valproic acid (Depakene®), morphine sulfate, hydromor­ otides; signal transduction inhibitors; sizofiran; sobuzoxane; phone, prednisone, griseofulvin, penthonium, alendronate, sodium borocaptate; sodium phenylacetate; solverol; dyphenhydramide, guanethidine, ketorolac (Acular®), thy- somatomedin binding protein; sonermin; sparfosic acid; 10 rocalcitonin, dimethylsulfoxide (DMSO), clonidine (Cata­ spicamycin D; spiromustine; splenopentin; spongistatin 1; press®), bretylium, ketanserin, reserpine, droperidol, atro­ squalamine; stipiamide; stromelysin inhibitors; sulfinosine; pine, phentolamine, bupivacaine, lidocaine, acetaminophen, superactive vasoactive intestinal peptide antagonist; sura­ nortriptyline (Pamelor®), amitriptyline (Elavil®), imip­ dista; suramin; swainsonine; tallimustine; tamoxifen ramine (Tofranil®), doxepin (Sinequan®), clomipramine methiodide; tauromustine; tazarotene; tecogalan sodium; 15 (Anafranil®), fluoxetine (Prozac®), sertraline (Zoloft®), tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; naproxen, nefazodone (Serzone®), venlafaxine (Effexor®), teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; trazodone (Desyrel®), bupropion (Wellbutrin®), mexi­ thiocoraline; thrombopoietin; thrombopoietin mimetic; thy­ letine, nifedipine, propranolol, tramadol, lamotrigine, vioxx, malfasin; thymopoietin receptor agonist; thymotrinan; thy­ ziconotide, ketamine, dextromethorphan, benzodiazepines, roid stimulating hormone; tin ethyl etiopurpurin; tira­ 20 baclofen, tizanidine and phenoxybenzamine. pazamine; titanocene bichloride; topsentin; toremifene; Examples of second active agents that may be used for the translation inhibitors; tretinoin; triacetyluridine; triciribine; treatment, prevention and/or management of macular degen­ trimetrexate; triptorelin; tropisetron; turosteride; tyrosine eration and related syndromes include, but are not limited to, kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; a steroid, a light sensitizer, an integrin, an antioxidant, an urogenital sinus-derived growth inhibitory factor; urokinase 25 interferon, a xanthine derivative, a growth hormone, a receptor antagonists; vapreotide; variolin B; velaresol; neutrotrophic factor, a regulator of neovascularization, an veramine; verdins; verteporfin; vinorelbine; vinxaltine; anti-VEGF antibody, a prostaglandin, an antibiotic, a phy­ vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and toestrogen, an anti-inflammatory compound or an antiangio­ zinostatin stimalamer. genesis compound, or a combination thereof. Specific Yet other second active agents include, but are not limited 30 examples include, but are not limited to, verteporfin, purly­ to, 2-methoxyestradiol, telomestatin, inducers of apoptosis tin, an angiostatic steroid, rhuFab, interferon-2a, pentoxif­ in multiple myeloma cells (such as, for example, TRAIL), ylline, tin etiopurpurin, motexafin, lucentis, lutetium, statins, semaxanib, cyclosporin, etanercept, doxycycline, 9-fluoro-11,21-dihydroxy-16, 17-1-methylethylidinebis bortezomib, oblimersen (Genasense®), remicade, docetaxel, (oxy)pregna-l,4-diene-3,20-dione, latanoprost (see U.S. celecoxib, melphalan, dexamethasone (Decadron®), ste­ 35 Pat. No. 6,225,348), tetracycline and its derivatives, rifamy­ roids, gemcitabine, cisplatinum, temozolomide, etoposide, cin and its derivatives, macrolides, metronidazole (U.S. Pat. cyclophosphamide, temodar, carboplatin, procarbazine, Nos. 6,218,369 and 6,015,803), genistein, genistin, 6'-O­ gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, Mal genistin, 6'-O-Ac genistin, daidzein, daidzin, 6'-O­ taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT- Mal daidzin, 6'-O-Ac daidzin, glycitein, glycitin, 6'-O-Mal 11, interferon alpha, pegylated interferon alpha (e.g., PEG 40 glycitin, biochanin A, formononetin (U.S. Pat. No. 6,001, INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, 368), triamcinolone acetomide, dexamethasone (U.S. Pat. carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. pacilitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinore­ 5,632,984), basic fibroblast growth factor (bFGF), trans­ lbine, zoledronic acid, palmitronate, biaxin, busulphan, forming growth factor b (TGF-b ), brain-derived neuro- prednisone, bisphosphonate, arsenic trioxide, vincristine, 45 trophic factor (BDNF), plasminogen activator factor type 2 doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 estramustine sodium phosphate (Emcyt®), sulindac, and (Eli Lilly), Miravant, and RETISERT implant (Bausch & etoposide. Lomb). All of the references cited herein are incorporated in In another embodiment, examples of specific second their entireties by reference. agents according to the indications to be treated, prevented, 50 Examples of second active agents that may be used for the or managed can be found in the following references, all of treatment, prevention and/or management of skin diseases which are incorporated herein in their entireties: U.S. Pat. include, but are not limited to, keratolytics, retinoids, a-hy­ Nos. 6,281,230 and 5,635,517; U.S. publication nos. 2004/ droxy acids, antibiotics, collagen, botulinum toxin, inter­ 0220144, 2004/0190609, 2004/0087546, 2005/0203142, feron, steroids, and immunomodulatory agents. Specific 2004/0091455, 2005/0100529, 2005/0214328, 2005/ 55 examples include, but are not limited to, 5-fluorouracil, 0239842, 2006/0154880, 2006/0122228, and 2005/ masoprocol, trichloroacetic acid, salicylic acid, lactic acid, 0143344; and U.S. provisional application No. 60/631,870. ammonium lactate, urea, tretinoin, isotretinoin, antibiotics, Examples of second active agents that may be used for the collagen, botulinum toxin, interferon, corticosteroid, tran­ treatment, prevention and/or management of pain include, sretinoic acid and collagens such as human placental colla- but are not limited to, conventional therapeutics used to treat 60 gen, animal placental collagen, Dermalogen, AlloDerm, or prevent pain such as antidepressants, anticonvulsants, Fascia, Cymetra, Autologen, Zyderm, Zyplast, Resoplast, antihypertensives, anxiolytics, calcium channel blockers, and Isolagen. muscle relaxants, non-narcotic analgesics, opioid analge­ Examples of second active agents that may be used for the sics, anti-inflammatories, cox-2 inhibitors, immunomodula­ treatment, prevention and/or management of pulmonary tory agents, alpha-adrenergic receptor agonists or antago­ 65 hepertension and related disorders include, but are not nists, immunosuppressive agents, corticosteroids, limited to, anticoagulants, diuretics, cardiac glycosides, cal­ hyperbaric oxygen, ketamine, other anesthetic agents, cium channel blockers, vasodilators, prostacyclin analogues, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 141 of 148 PageID: 141

US 9,993,467 B2 17 18 endothelin antagonists, phosphodiesterase inhibitors ( e.g., clorgyline, phenelzine and isocarboxazid; a COMT inhibi­ PDE V inhibitors), endopeptidase inhibitors, lipid lowering tor, such as, but not limited to, tolcapone and entacapone; a agents, thromboxane inhibitors, and other therapeutics cholinesterase inhibitor, such as, but not limited to, phys- known to reduce pulmonary artery pressure. Specific ostigmine saliclate, physostigmine sulfate, physostigmine examples include, but are not limited to, warfarin (Couma- 5 bromide, meostigmine bromide, neostigmine methylsulfate, din®), a diuretic, a cardiac glycoside, digoxin-oxygen, dil­ ambenonim chloride, edrophonium chloride, tacrine, prali- tiazem, nifedipine, a vasodilator such as prostacyclin ( e.g., doxime chloride, obidoxime chloride, trimedoxime bro­ prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), mide, diacetyl monoxim, endrophonium, pyridostigmine, treprostinil (Remodulin®), nitric oxide (NO), bosentan (Tra­ and demecarium; an anti-inflammatory agent, such as, but cleer®), amlodipine, epoprostenol (Florae), treprostinil (Re- 10 not limited to, naproxen sodium, diclofenac sodium, modulin®), prostacyclin, tadalafil (Cialis®), simvastatin diclofenac potassium, celecoxib, sulindac, oxaprozin, (Zocor®), omapatrilat (Vanlev®), irbesartan (Avapro®), diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, pravastatin (Pravachol®), digoxin, L-arginine, iloprost, nabumetone, refecoxib, methotrexate, leflunomide, sul­ betaprost, and sildenafil (Viagra®). fasalazine, gold salts, Rho-D Immune Globulin, mycophe­ Examples of second active agents that may be used for the 15 nylate mofetil, cyclosporine, azathioprine, tacrolimus, basil­ treatment, prevention and/or management of asbestos-re­ iximab, daclizumab, salicylic acid, acetylsalicylic acid, lated disorders include, but are not limited to, anthracycline, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasala­ platinum, alkylating agent, oblimersen (Genasense®), cis­ zine, acetaminophen, indomethacin, sulindac, mefenamic platinum, cyclophosphamide, temodar, carboplatin, procar­ acid, meclofenamate sodium, tolmetin, ketorolac, bazine, gliadel, tamoxifen, topotecan, methotrexate, taxo- 20 dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxi­ tere, mnotecan, capecitabine, cisplatin, thiotepa, cam, ampiroxicam, droxicam, pivoxicam, tenoxicam, phe- fludarabine, carboplatin, liposomal daunorubicin, cytara­ nylbutazone, oxyphenbutazone, antipyrine, aminopyrine, bine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF, apazone, zileuton, aurothioglucose, gold sodium thiomalate, dacarbazine, vinorelbine, zoledronic acid, palmitronate, auranofin, methotrexate, colchicine, allopurinol, probenecid, biaxin, busulphan, prednisone, bisphosphonate, arsenic, tri- 25 sulfinpyrazone and benzbromarone or betamethasone and oxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganci­ other glucocorticoids; and an antiemetic agent, such as, but clovir, adriamycin, bleomycin, hyaluronidase, mitomycin C, not limited to, metoclopromide, domperidone, prochlorpera­ mepacrine, thiotepa, tetracycline and gemcitabine. zine, promethazine, chlorpromazine, trimethobenzamide, Examples of second active agents that may be used for the ondansetron, granisetron, hydroxyzine, acetylleucine treatment, prevention and/or management of parasitic dis- 30 monoethanolamine, alizapride, azasetron, benzquinamide, eases include, but are not limited to, chloroquine, quinine, bietanautine, bromopride, buclizine, clebopride, cyclizine, quinidine, pyrimethamine, sulfadiazine, doxycycline, clin­ dimenhydrinate, diphenidol, dolasetron, meclizine, methal­ damycin, mefloquine, halofantrine, primaquine, hydroxy­ latal, metopimazine, nabilone, oxyperndyl, pipamazine, sco­ chloroquine, proguanil, atovaquone, azithromycin, suramin, polamine, sulpiride, tetrahydrocannabinol, thiethylperazine, pentamidine, melarsoprol, nifurtimox, benznidazole, 35 thioproperazine, tropisetron, and a mixture thereof. amphotericin B, pentavalent antimony compounds (e.g., Examples of second active agents that may be used for the sodium stiboglucuronate ), interfereon gamma, itraconazole, treatment, prevention and/or management of CNS injuries a combination of dead promastigotes and BCG, leucovorin, and related syndromes include, but are not limited to, corticosteroids, sulfonamide, spiramycin, IgG (serology), immunomodulatory agents, immunosuppressive agents, trimethoprim, and sulfamethoxazole. 40 antihypertensives, anticonvulsants, fibrinolytic agents, anti­ Examples of second active agents that may be used for the platelet agents, antipsychotics, antidepressants, benzodiaz­ treatment, prevention and/or management of immunodefi­ epines, buspirone, amantadine, and other known or conven­ ciency disorders include, but are not limited to: antibiotics tional agents used in patients with CNS injury/damage and (therapeutic or prophylactic) such as, but not limited to, related syndromes. Specific examples include, but are not ampicillin, tetracycline, penicillin, cephalosporins, strepto- 45 limited to: steroids (e.g., glucocorticoids, such as, but not mycin, kanamycin, and erythromycin; antivirals such as, but limited to, methylprednisolone, dexamethasone and betame- not limited to, amantadine, rimantadine, acyclovir, and riba­ thasone); an anti-inflanimatory agent, including, but not virin; immunoglobulin; plasma; immunologic enhancing limited to, naproxen sodium, diclofenac sodium, diclofenac drugs such as, but not limited to, levami sole and isoprinos­ potassium, celecoxib, sulindac, oxaprozin, diflunisal, etod­ ine; biologics such as, but not limited to, ganimaglobulin, 50 olac, meloxicam, ibuprofen, ketoprofen, nabumetone, refe­ transfer factor, interleukins, and interferons; hormones such coxib, methotrexate, leflunomide, sulfasalazine, gold salts, as, but not limited to, thymic; and other immunologic agents RHo-D Immune Globulin, mycophenylate mofetil, such as, but not limited to, B cell stimulators (e.g., BAFF/ cyclosporine, azathioprine, tacrolimus, basiliximab, dacli­ BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growth factors zumab, salicylic acid, acetylsalicylic acid, methyl salicylate, (e.g., TGF-a), antibodies (e.g., anti-CD40 and IgM), oligo- 55 diflunisal, salsalate, olsalazine, sulfasalazine, acetamino­ nucleotides containing urnnethylated CpG motifs, and vac­ phen, indomethacin, sulindac, mefenamic acid, meclofena- cines ( e.g., viral and tumor peptide vaccines). mate sodium, tolmetin, ketorolac, dichlofenac, flurbinpro­ Examples of second active agents that may be used for the fen, oxaprozin, piroxicam, meloxicam, ampiroxicam, treatment, prevention and/or management of CNS disorders droxicam, pivoxicam, tenoxicam, phenylbutazone, oxy­ include, but are not limited to: opioids; a dopamine agonist 60 phenbutazone, antipyrine, aminopyrine, apazone, zileuton, or antagonist, such as, but not limited to, Levodopa, aurothioglucose, gold sodium thiomalate, auranofin, metho- L-DOPA, cocaine, a-methyl-tyrosine, reserpine, tetra­ trexate, colchicine, allopurinol, probenecid, sulfinpyrazone benazine, benzotropine, pargyline, fenodolpam mesylate, and benzbromarone; a cAMP analog including, but not cabergoline, pramipexole dihydrochloride, ropinorole, limited to, db-cAMP; an agent comprising a methylpheni­ amantadine hydrochloride, selegiline hydrochloride, carbi- 65 date drug, which comprises 1-threo-methylphenidate, dopa, pergolide mesylate, Sinemet CR, and Symmetrel; a d-threo-methylphenidate, dl-threo-methylphenidate, MAO inhibitor, such as, but not limited to, iproniazid, 1-erythro-methylphenidate, d-erythro-methylphenidate, di- Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 142 of 148 PageID: 142

US 9,993,467 B2 19 20 erythro-methylphenidate, and a mixture thereof; and a sions of blood, or of a blood substitute such as Hemospan™ diuretic agent such as, but not limited to, mannitol, furo­ or Hemospan™ PS (Sangart). semide, glycerol, and urea. Examples of second active agent that may be used for the 4.2. Process for Making Dosage Forms treatment, prevention and/or management of dysfunctional 5 Dosage forms provided herein can be prepared by any of sleep and related syndromes include, but are not limited to, the methods of pharmacy, but all methods include the step a tricyclic antidepressant agent, a selective serotonin of bringing the active ingredient into association with the reuptake inhibitor, an antiepileptic agent (gabapentin, pre­ excipient, which constitutes one or more necessary ingredi­ gabalin, carbamazepine, oxcarbazepine, levitiracetam, topi­ ents. In general, the compositions are prepared by uniformly ramate), an antiaryhthmic agent, a sodium channel blocking 10 admixing ( e.g., direct blend) the active ingredient with agent, a selective inflammatory mediator inhibitor, an opioid liquid excipients or finely divided solid excipients or both, agent, a second immunomodulatory compound, a combina­ and then, if necessary, shaping the product into the desired tion agent, and other known or conventional agents used in presentation ( e.g., compaction such as roller-compaction). If sleep therapy. Specific examples include, but are not limited desired, tablets can be coated by standard aqueous or non­ 15 aqueous techniques. to, Neurontin, oxycontin, morphine, topiramate, amitrypti­ A dosage form provided herein can be prepared by line, nortryptiline, carbamazepine, Levodopa, L-DOPA, compression or molding, optionally with one or more acces­ cocaine, a-methyl-tyrosine, reserpine, tetrabenazine, benzo­ sory ingredients. Compressed tablets can be prepared by tropine, pargyline, fenodolpam mesylate, cabergoline, compressing in a suitable machine the active ingredient in a pramipexole dihydrochloride, ropinorole, amantadine 20 free-flowing form such as powder or granules, optionally hydrochloride, selegiline hydrochloride, carbidopa, per­ mixed with an excipient as above and/or a surface active or golide mesylate, Sinemet CR, Symmetrel, iproniazid, clor­ dispersing agent. Molded tablets can be made by molding in gyline, phenelzine, isocarboxazid, tolcapone, entacapone, a suitable machine a mixture of the powdered compound physostigmine saliclate, physostigmine sulfate, physostig­ moistened with an inert liquid diluent. Encapsulation of the dosage forms provided herein can be done using capsules of mine bromide, meostigmine bromide, neostigmine methyl- 25 methylcellulose, calcium alginate, or gelatin. sulfate, ambenonim chloride, edrophonium chloride, tacrine, In some embodiments, the active ingredients and excipi­ pralidoxime chloride, obidoxime chloride, trimedoxime bro­ ents are directly blended and loaded into, for example, a mide, diacetyl monoxim, endrophonium, pyridostigmine, capsule, or compressed directly into tablets. A direct­ demecarium, naproxen sodium, diclofenac sodium, blended dosage form may be more advantageous than a diclofenac potassium, celecoxib, sulindac, oxaprozin, 30 compacted (e.g., roller-compacted) dosage form in certain diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, instances, since direct-blending can reduce or eliminate the nabumetone, refecoxib, methotrexate, leflunomide, sul­ harmful health effects that may be caused by airborne fasalazine, gold salts, RHo-D Immune Globulin, mycophe­ particles of ingredients during the manufacture using com­ nylate mofetil, cyclosporine, azathioprine, tacrolimus, basil- paction process. 35 Direct blend formulations may be advantageous in certain iximab, daclizumab, salicylic acid, acetylsalicylic acid, instances because they require only one blending step, that methyl salicylate, diflunisal, salsalate, olsalazine, sulfasala­ of the active and excipients, before being processed into the zine, acetaminophen, indomethacin, sulindac, mefenamic final dosage form, e.g., tablet or capsule. This can reduce the acid, meclofenamate sodium, tolmetin, ketorolac, production of airborne particle or dust to a minimum, while dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxi- 40 roller-compaction processes may be prone to produce dust. cam, ampiroxicam, droxicam, pivoxicam, tenoxicam, phe­ In roller-compaction process, the compacted material is nylbutazone, oxyphenbutazone, antipyrine, aminopyrine, often milled into smaller particles for further processing. apazone, zileuton, aurothioglucose, gold sodium thiomalate, The milling operation can produce significant amounts of auranofin, methotrexate, colchicine, allopurinol, probenecid, airborne particles, since the purpose for this step in manu­ facturing is to reduce the materials particle size. The milled sulfinpyrazone, benzbromarone, betamethasone and other 45 material is then blended with other ingredients prior to glucocorticoids, metoclopromide, domperidone, prochlo­ manufacturing the final dosage form. rperazine, promethazine, chlorpromazine, trimethobenz­ For certain active ingredients, in particular for a com­ amide, ondansetron, granisetron, hydroxyzine, acetylleucine pound with a low solubility, the active ingredient's particle monoethanolamine, alizapride, azasetron, benzquinamide, size is reduced to a fine powder in order to help increase the bietanautine, bromopride, buclizine, clebopride, cyclizine, 50 active ingredient's rate of solubilization. The increase in the dimenhydrinate, diphenidol, dolasetron, meclizine, methal­ rate of solubilization is often necessary for the active ingre­ latal, metopimazine, nabilone, oxyperndyl, pipamazine, sco­ dient to be effectively absorbed in the gastrointestinal tract. polamine, sulpiride, tetrahydrocannabinol, thiethylperazine, However for fine powders to be directly-blended and loaded thioproperazine, tropisetron, and a mixture thereof. onto capsules, the excipients should preferably provide 55 certain characteristics which render the ingredients suitable Examples of second active agents that may be used for the for the direct-blend process. Examples of such characteris­ treatment, prevention and/or management of hemoglobin­ tics include, but are not limited to, acceptable flow charac­ opathy and related disorders include, but are not limited to: teristics. In one embodiment, therefore, provided herein is interleukins, such as IL-2 (including recombinant IL-II the use of, and compositions comprising, excipients which ("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; 60 may provide characteristics, which render the resulting interferons, such as interferon alfa-2a, interferon alfa-2b, mixture suitable for direct-blend process, e.g., good flow interferon alfa-nl, interferon alfa-n3, interferon beta-I a, and characteristics. interferon gannna-I b; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrous oxide; hydroxy urea; 4.2.1. Screening HEMOXIN™ (NIPRISAWM; see U.S. Pat. No. 5,800,819); 65 Gardos channel antagonists such as clotrimazole and triaryl The process for making the pharmaceutical compositions methane derivatives; Deferoxamine; protein C; and transfu- of the invention preferably includes the screening of the Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 143 of 148 PageID: 143

US 9,993,467 B2 21 22 active ingredient and the excipient(s). In one embodiment, Examples of diseases or disorders include, but are not the active ingredient is passed through a screen having limited to, cancer, disorders associated with angiogenesis, openings of about 200 microns to about 750 microns. In pain including, but not limited to, Complex Regional Pain another embodiment, the active ingredient is passed through Syndrome ("CRPS"), Macular Degeneration ("MD") and a screen with openings of about 200 microns to about 400 5 related syndromes, skin diseases, pulmonary disorders, microns. In one embodiment, the active ingredient is passed asbestos-related disorders, parasitic diseases, immunodefi­ through a screen having openings of about 300 to about 400 ciency disorders, CNS disorders, CNS injury, atherosclero­ microns. Depending on the excipient(s) used, the screen sis and related disorders, dysfunctional sleep and related openings vary. For example, disintegrants and binders are disorders, hemoglobinopathy and related disorders (e.g., 10 anemia), TNFa related disorders, and other various diseases passed through openings of about 430 microns to about 7 50 and disorders. microns, from about 600 microns to about 720 microns, or Examples of cancer and precancerous conditions include, about 710 microns. Lubricants are typically passed through but are not limited to, those described in U.S. Pat. Nos. smaller openings, e.g., about 150 microns to about 250 6,281,230 and 5,635,517 to Muller et al., in various U.S. microns screen. In one embodiment, the lubricant is passed 15 patent publications to Zeldis, including publication nos. through a screen opening of about 210 microns. 2004/0220144Al, published Nov. 4, 2004 (Treatment of Myelodysplastic Syndrome); 2004/0029832Al, published 4.2.2. Pre-Blending Feb. 12, 2004 (Treatment of Various Types of Cancer); and 2004/0087546, published May 6, 2004 (Treatment of After the ingredients are screened, the exc1p1ent and 20 Myeloproliferative Diseases). Examples also include those active ingredient are mixed in a diffusion mixer. In one described in WO 2004/103274, published Dec. 2, 2004. All embodiment, the mixing time is from about 1 minute to of these references are incorporated herein in their entireties about 50 minutes, from about 5 minutes to about 45 minutes, by reference. from about 10 minutes to about 40 minutes, or from about Certain examples of cancer include, but are not limited to, 10 minutes to about 25 minutes. In another embodiment, the 25 cancers of the skin, such as melanoma; lymph node; breast; mixing time is about 15 minutes. cervix; uterus; gastrointestinal tract; lung; ovary; prostate; When more than one excipients are used, the excipients colon; rectum; mouth; brain; head and neck; throat; testes; may be admixed in a tumble blender for about 1 minute to kidney; pancreas; bone; spleen; liver; bladder; larynx; nasal about 20 minutes, or for about 5 minutes to about 10 passages; and AIDS-related cancers. The compounds are minutes, prior to mixing with the active ingredient. 30 also useful for treating cancers of the blood and bone marrow, such as multiple myeloma and acute and chronic 4.2.3. Roller Compaction leukemias, for example, lymphoblastic, myelogenous, lym­ phocytic, and myelocytic leukemias. The compounds pro­ In one embodiment, the pre-blend may optionally be vided herein can be used for treating, preventing or manag- passed through a roller compactor with a hammer mill 35 ing either primary or metastatic tumors. attached at the discharge of the compactor. Other cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, 4.2.4. Final Blend hemangiopericytoma, multiple brain metastase, glioblas­ toma multiforms, glioblastoma, brain stem glioma, poor When a lubricant, e.g., sodium stearyl fumarate, is used, 40 prognosis malignant brain tumor, malignant glioma, recur­ the lubricant is mixed with the pre-blend at the end of the rent malignant glioma, anaplastic astrocytoma, anaplastic process to complete the pharmaceutical composition. This oligodendroglioma, neuroendocrine tumor, rectal adenocar­ additional mixing is from about 1 minute to about 10 cinoma, Dukes C & D colorectal cancer, unresectable col­ minutes, or from about 3 minutes to about 5 minutes. orectal carcinoma, metastatic hepatocellular carcinoma, 45 Kaposi's sarcoma, karotype acute myeloblastic leukemia, 4.2.5. Encapsulation chronic lymphocytic leukemia (CLL), Hodgkin's lym­ phoma, non-Hodgkin's lymphoma, cutaneous T-Cell lym­ The formulation mixture is then encapsulated into the phoma, cutaneous B-Cell lymphoma, diffuse large B-Cell desired size capsule shell using, for example, a capsule lymphoma, low grade follicular lymphoma, metastatic mela- filling machine or a rotary tablet press. 50 noma (localized melanoma, including, but not limited to, ocular melanoma), malignant mesothelioma, malignant 4.3. Kits pleural effusion mesothelioma syndrome, peritoneal carci­ noma, papillary serous carcinoma, gynecologic sarcoma, Pharmaceutical packs or kits which comprise pharmaceu­ soft tissue sarcoma, scleroderma, cutaneous vasculitis, tical compositions or dosage forms provided herein are also 55 Langerhans cell histiocytosis, leiomyosarcoma, fibrodyspla­ provided. An example of a kit comprises notice in the form sia ossificans progressive, hormone refractory prostate can­ prescribed by a govermnental agency regulating the manu­ cer, resected high-risk soft tissue sarcoma, unrescectable facture, use or sale of pharmaceuticals or biological prod­ hepatocellular carcinoma, Waldenstrom's macroglobuline­ ucts, which notice reflects approval by the agency of manu­ mia, smoldering myeloma, indolent myeloma, fallopian tube facture, use or sale for human administration. 60 cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hor­ 4.4. Methods of Treatment, Prevention, and mone-insensitive prostate cancer, chemotherapy-insensitive Management prostate cancer, papillary thyroid carcinoma, follicular thy­ roid carcinoma, medullary thyroid carcinoma, and leio- Provided herein are methods of treating, preventing, and/ 65 myoma. In a specific embodiment, the cancer is metastatic. or managing certain diseases or disorders using the formu­ In another embodiment, the cancer is refractory or resistance lations, compositions, or dosage forms provided herein. to chemotherapy or radiation. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 144 of 148 PageID: 144

US 9,993,467 B2 23 24 In one embodiment, the diseases or disorders are various sympathetically maintained pain syndrome, causalgia, forms of leukemias such as chronic lymphocytic leukemia, Sudeck atrophy of bone, algoneurodystrophy, shoulder hand chronic myelocytic leukemia, acute lymphoblastic leuke­ syndrome, post-traumatic dystrophy, trigeminal neuralgia, mia, acute myelogenous leukemia and acute myeloblastic post herpetic neuralgia, cancer related pain, phantom limb leukemia, including leukemias that are relapsed, refractory 5 pain, fibromyalgia, chronic fatigue syndrome, spinal cord or resistant, as disclosed in U.S. publication no. 2006/ injury pain, central post-stroke pain, radiculopathy, diabetic 0030594, published Feb. 9, 2006, which is incorporated in neuropathy, post-stroke pain, luetic neuropathy, and other its entirety by reference. painful neuropathic conditions such as those induced by The term "leukemia" refers malignant neoplasms of the drugs such as vincristine and velcade. blood-forming tissues. The leukemia includes, but is not 10 As used herein, the terms "complex regional pain syn- limited to, chronic lymphocytic leukemia, chronic myelo­ drome," "CRPS" and "CRPS and related syndromes" mean cytic leukemia, acute lymphoblastic leukemia, acute myel­ a chronic pain disorder characterized by one or more of the ogenous leukemia and acute myeloblastic leukemia. The following: pain, whether spontaneous or evoked, including leukemia can be relapsed, refractory or resistant to conven­ allodynia (painful response to a stimulus that is not usually tional therapy. The term "relapsed" refers to a situation 15 painful) and hyperalgesia (exaggerated response to a stimu­ where patients who have had a remission of leukemia after lus that is usually only mildly painful); pain that is dispro­ therapy have a return of leukemia cells in the marrow and a portionate to the inciting event (e.g., years of severe pain decrease in normal blood cells. The term "refractory or after an aukle sprain); regional pain that is not limited to a resistant" refers to a circumstance where patients, even after single peripheral nerve distribution; and autonomic dysregu- intensive treatment, have residual leukemia cells in their 20 lation (e.g., edema, alteration in blood flow and hyperhidro­ marrow. sis) associated with trophic skin changes (hair and nail In another embodiment, the diseases or disorders are growth abnormalities and cutaneous ulceration). various types oflymphomas, including Non-Hodgkin's lym­ Examples of MD and related syndromes include, but are phoma (NHL). The term "lymphoma" refers a heterogenous not limited to, those described in U.S. patent publication no. group of neoplasms arising in the reticuloendothelial and 25 2004/0091455, published May 13, 2004, which is incorpo­ lymphatic systems. "NHL" refers to malignant monoclonal rated herein by reference. Specific examples include, but are proliferation of lymphoid cells in sites of the immune not limited to, atrophic (dry) MD, exudative (wet) MD, system, including lymph nodes, bone marrow, spleen, liver age-related maculopathy (ARM), choroidal neovascularisa­ and gastrointestinal tract. Examples of NHL include, but are tion (CNVM), retinal pigment epithelium detachment not limited to, mantle cell lymphoma (MCL), lymphocytic 30 (PED), and atrophy of retinal pigment epithelium (RPE). lymphoma of intermediate differentiation, intermediate lym­ Examples of skin diseases include, but are not limited to, phocytic lymphoma (ILL), diffuse poorly differentiated lym­ those described in U.S. publication no. 2005/0214328Al, phocytic lymphoma (PDL), centrocytic lymphoma, diffuse published Sep. 29, 2005, which is incorporated herein by small-cleaved cell lymphoma (DSCCL), follicular lym­ reference. Specific examples include, but are not limited to, phoma, and any type of the mantle cell lymphomas that can 35 keratoses and related symptoms, skin diseases or disorders be seen under the microscope (nodular, diffuse, blastic and characterized with overgrowths of the epidermis, acne, and mentle zone lymphoma). wrinkles. Examples of diseases and disorders associated with, or As used herein, the term "keratosis" refers to any lesion characterized by, undesired angiogenesis include, but are not on the epidermis marked by the presence of circumscribed limited to, inflammatory diseases, autoimmune diseases, 40 overgrowths of the horny layer, including but not limited to viral diseases, genetic diseases, allergic diseases, bacterial actinic keratosis, seborrheic keratosis, keratoacanthoma, diseases, ocular neovascular diseases, choroidal neovascular keratosis follicularis (Darier disease), inverted follicular diseases, retina neovascular diseases, and rubeosis (neovas­ keratosis, palmoplantar keratoderma (PPK, keratosis pal­ cularization of the angle). Specific examples of the diseases maris et plantaris), keratosis pilaris, and stucco keratosis. and disorders associated with, or characterized by, undesired 45 The term "actinic keratosis" also refers to senile keratosis, angiogenesis include, but are not limited to, arthritis, endo­ keratosis senilis, verruca senilis, plana senilis, solar kerato- metriosis, Crohn's disease, heart failure, advanced heart sis, keratoderma or keratoma. The term "seborrheic kerato­ failure, renal impairment, endotoxemia, toxic shock syn­ sis" also refers to seborrheic wart, senile wart, or basal cell drome, osteoarthritis, retrovirus replication, wasting, men­ papilloma. Keratosis is characterized by one or more of the ingitis, silica-induced fibrosis, asbestos-induced fibrosis, 50 following symptoms: rough appearing, scaly, erythematous veterinary disorder, malignancy-associated hypercalcemia, papules, plaques, spicules or nodules on exposed surfaces stroke, circulatory shock, periodontitis, gingivitis, macro­ (e.g., face, hands, ears, neck, legs and thorax), excrescences cytic anemia, refractory anemia, and Sq-deletion syndrome. of keratin referred to as cutaneous horns, hyperkeratosis, Examples of pain include, but are not limited to those telangiectasias, elastosis, pigmented lentigines, acanthosis, described in U.S. patent publication no. 2005/0203142, 55 parakeratosis, dyskeratoses, papillomatosis, hyperpigmenta­ published Sep. 15, 2005, which is incorporated herein by tion of the basal cells, cellular atypia, mitotic figures, reference. Specific types of pain include, but are not limited abnormal cell-cell adhesion, dense inflammatory infiltrates to, nociceptive pain, neuropathic pain, mixed pain of noci­ and small prevalence of squamous cell carcinomas. ceptive and neuropathic pain, visceral pain, migraine, head­ Examples of skin diseases or disorders characterized with ache and post-operative pain. 60 overgrowths of the epidermis include, but are not limited to, Examples of nociceptive pain include, but are not limited any conditions, diseases or disorders marked by the presence to, pain associated with chemical or thermal burns, cuts of of overgrowths of the epidermis, including but not limited the skin, contusions of the skin, osteoarthritis, rheumatoid to, infections associated with papilloma virus, arsenical arthritis, tendonitis, and myofascial pain. keratoses, sign of Leser-Trelat, warty dyskeratoma (WD), Examples of neuropathic pain include, but are not limited 65 trichostasis spinulosa (TS), erythrokeratodermia variabilis to, CRPS type I, CRPS type II, reflex sympathetic dystrophy (EKV), ichthyosis fetalis (harlequin ichthyosis), knuckle (RSD), reflex neurovascular dystrophy, reflex dystrophy, pads, cutaneous melanoacanthoma, porokeratosis, psoriasis, Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 145 of 148 PageID: 145

US 9,993,467 B2 25 26 squamous cell carcinoma, confluent and reticulated papillo­ Examples of immunodeficiency disorders include, but are matosis (CRP), acrochordons, cutaneous horn, cowden dis­ not limited to, those described in U.S. application Ser. No. ease (multiple hamartoma syndrome), dermatosis papulosa 11/289,723, filed Nov. 30, 2005. Specific examples include, nigra (DPN), epidermal nevus syndrome (ENS), ichthyosis but not limited to, adenosine deaminase deficiency, antibody vulgaris, molluscum contagiosum, prurigo nodularis, and 5 deficiency with normal or elevated Igs, ataxia-tenlangiecta­ acanthosis nigricans (AN). sia, bare lymphocyte syndrome, common variable immuno­ Examples of pulmonary disorders include, but are not deficiency, lg deficiency with hyper-IgM, lg heavy chain limited to, those described in U.S. publication no. 2005/ deletions, IgA deficiency, immunodeficiency with thymoma, 0239842Al, published Oct. 27, 2005, which is incorporated reticular dysgenesis, Nezelof syndrome, selective IgG sub- 10 class deficiency, transient hypoganimaglobulinemia of herein by reference. Specific examples include pulmonary infancy, Wistcott-Aldrich syndrome, X-linked agamma­ hypertension and related disorders. Examples of pulmonary globulinemia, X-linked severe combined immunodefi­ hypertension and related disorders include, but are not ciency. limited to: primary pulmonary hypertension (PPH); second­ Examples of CNS disorders include, but are not limited ary pulmonary hypertension (SPH); familial PPH; sporadic 15 to, those described in U.S. publication no. 2005/0143344, PPH; precapillary pulmonary hypertension; pulmonary arte­ published Jun. 30, 2005, which is incorporated herein by rial hypertension (PAH); pulmonary artery hypertension; reference. Specific examples include, but are not limited to, idiopathic pulmonary hypertension; thrombotic pulmonary include, but are not limited to, Amyotrophic Lateral Scle­ arteriopathy (TPA); plexogenic pulmonary arteriopathy; rosis, Alzheimer Disease, Parkinson Disease, Huntington's functional classes I to IV pulmonary hypertension; and 20 Disease, Multiple Sclerosis other neuroimmunological dis­ pulmonary hypertension associated with, related to, or sec­ orders such as Tourette Syndrome, delerium, or disturbances ondary to, left ventricular dysfunction, mitral valvular dis­ in consciousness that occur over a short period of time, and ease, constrictive pericarditis, aortic stenosis, cardiomyopa­ amnestic disorder, or discreet memory impairments that thy, mediastinal fibrosis, anomalous pulmonary venous occur in the absence of other central nervous system impair­ drainage, pulmonary venoocclusive disease, collagen vasu- 25 ments. lar disease, congenital heart disease, HIV virus infection, Examples of CNS injuries and related syndromes include, drugs and toxins such as fenfluramines, congenital heart but are not limited to, those described in U.S. publication no. disease, pulmonary venous hypertension, chronic obstruc­ 2006/0122228, published Jun. 8, 2006, which is incorpo- tive pulmonary disease, interstitial lung disease, sleep-dis­ rated herein by reference. Specific examples include, but are ordered breathing, alveolar hypoventilation disorder, 30 not limited to, CNS injury/damage and related syndromes, chronic exposure to high altitude, neonatal lung disease, include, but are not limited to, primary brain injury, second- alveolar-capillary dysplasia, sickle cell disease, other coagu­ ary brain injury, traumatic brain injury, focal brain injury, lation disorder, chronic thromboemboli, connective tissue diffuse axonal injury, head injury, concussion, post-concus­ disease, lupus including systemic and cutaneous lupus, sion syndrome, cerebral contusion and laceration, subdural schistosomiasis, sarcoidosis or pulmonary capillary heman- 35 hematoma, epidermal hematoma, post-traumatic epilepsy, giomatosis. chronic vegetative state, complete SCI, incomplete SCI, Examples of asbestos-related disorders include, but not acute SCI, subacute SCI, chronic SCI, central cord syn­ limited to, those described in U.S. publication no. 2005/ drome, Brown-Sequard syndrome, anterior cord syndrome, 0100529, published May 12, 2005, which is incorporated conus medullaris syndrome, cauda equina syndrome, neu­ herein by reference. Specific examples include, but are not 40 rogenic shock, spinal shock, altered level of consciousness, limited to, mesothelioma, asbestosis, malignant pleural effu­ headache, nausea, emesis, memory loss, dizziness, diplopia, sion, benign exudative effusion, pleural plaques, pleural blurred vision, emotional !ability; sleep disturbances, irrita­ calcification, diffuse pleural thickening, rounded atelectasis, bility, inability to concentrate, nervousness, behavioral fibrotic masses, and lung cancer. impairment, cognitive deficit, and seizure. Examples of parasitic diseases include, but are not limited 45 Other disease or disorders include, but not limited to, to, those described in U.S. publication no. 2006/0154880, viral, genetic, allergic, and autoimmune diseases. Specific published Jul. 13, 2006, which is incorporated herein by examples include, but not limited to, HIV, hepatitis, adult reference. Parasitic diseases include diseases and disorders respiratory distress syndrome, bone resorption diseases, caused by human intracellular parasites such as, but not chronic pulmonary inflammatory diseases, dermatitis, cystic limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L. 50 fibrosis, septic shock, sepsis, endotoxic shock, hemody­ donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. namic shock, sepsis syndrome, post ischemic reperfusion mexicana, L. braziliensis, TGondii, B. microti, B. divergens, injury, meningitis, psoriasis, fibrotic disease, cachexia, graft B. coli, C. parvum, C. cayetanensis, E. histolytica, I. belli, S. versus host disease, graft rejection, auto-immune disease, mansonii, S. haematobium, Trypanosoma ssp., Toxoplasma rheumatoid spondylitis, Crohn's disease, ulcerative colitis, ssp., and 0. volvulus. Other diseases and disorders caused by 55 inflammatory-bowel disease, multiple sclerosis, systemic non-human intracellular parasites such as, but not limited to, lupus erythrematosus, ENL in leprosy, radiation damage, Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia cancer, asthma, or hyperoxic alveolar injury. darlingi, Cytauxzoon fells, Eimeria ssp., Hammondia ssp., Examples of atherosclerosis and related conditions and Theileria ssp., are also encompassed. Specific examples include, but are not limited to, those disclosed in U.S. include, but are not limited to, malaria, babesiosis, trypano- 60 publication no. 2002/0054899, published May 9, 2002, somiasis, leishmaniasis, toxoplasmosis, meningoencephali- which is incorporated herein by reference. Specific tis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isospo­ examples include, but are not limited to, all forms of nas1s, cyclosporiasis, microsporidiosis, ascariasis, conditions involving atherosclerosis, including restenosis trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, after vascular intervention such as angioplasty, stenting, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, 65 atherectomy and grafting. All forms of vascular intervention schistosomiasis, and dermatitis caused by animal schisto- are contemplated herein, including diseases of the cardio- sames. vascular and renal system, such as, but not limited to, renal Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 146 of 148 PageID: 146

US 9,993,467 B2 27 28 angioplasty, percutaneous coronary intervention (PCI), per­ supranuclear palsy; corticobasal degeneration; frontotempo­ cutaneous transluminal coronary angioplasty (PTCA), ral dementia; amyloid pathology disorders; mild cognitive carotid percutaneous transluminal angioplasty (PTA), coro­ impairment; Alzheimer disease with parkinsonism; Wilson nary by-pass grafting, angioplasty with stent implantation, disease; Hallervorden-Spatz disease; Chediak-Hagashi dis- peripheral percutaneous transluminal intervention of the 5 ease; SCA-3 spinocerebellar ataxia; X-linked dystonia par­ iliac, femoral or popliteal arteries, and surgical intervention kinsonism; prion disease; hyperkinetic disorders; chorea; using impregnated artificial grafts. The following chart ballismus; dystonia tremors; Amyotrophic Lateral Sclerosis provides a listing of the major systemic arteries that may be (ALS); CNS trauma and myoclonus. in need of treatment, all of which are contemplated herein: Examples of hemoglobinopathy and related disorders 10 include, but are not limited to, those described in U.S. publication no. 2005/0143420Al, published Jun. 30, 2005, Artery Body Areas Supplied which is incorporated herein by reference. Specific Axillary Shoulder and axilla examples include, but are not limited to, hemoglobinopathy, Brachia! Upper arm sickle cell anemia, and any other disorders related to the Brachiocephalic Head, neck, and arm 15 differentiation of CD34+ cells. Celiac Divides into left gastric, splenic, and hepatic arteries Examples ofTNFa related disorders include, but are not Common carotid Neck Common iliac Divides into external and internal iliac arteries limited to, those described in WO 98/03502 and WO Coronary Heart 98/54170, both of which are incorporated herein in their Deep femoral Thigh entireties by reference. Specific examples include, but are Digital Fingers 20 not limited to: endotoxemia or toxic shock syndrome; Dorsalis pedis Foot External carotid Neck and external head regions cachexia; adult respiratory distress syndrome; bone resorp­ External iliac Femoral artery tion diseases such as arthritis; hypercalcemia; Graft versus Femoral Thigh Host Reaction; cerebral malaria; inflammation; tumor Gastric Stomach growth; chronic pulmonary inflammatory diseases; reperfu- Hepatic Liver, gallbladder, pancreas, and duodenwn Inferior mesenteric Descending colon, rectum, and pelvic wall 25 sion injury; myocardial infarction; stroke; circulatory shock; Internal carotid Neck and internal head regions rheumatoid arthritis; Crohn's disease; HIV infection and Internal iliac Rectum, urinary bladder, external genitalia, buttocks AIDS; other disorders such as rheumatoid arthritis, rheuma­ muscles, uterus and vagina Left gastric Esophagus and stomach toid spondylitis, osteoarthritis, psoriatic arthritis and other Middle sacral Sacrum arthritic conditions, septic shock, septic, endotoxic shock, Ovarian Ovaries 30 graft versus host disease, wasting, Crohn's disease, ulcer­ Palmar arch Hand ative colitis, multiple sclerosis, systemic lupus erythroma­ Peroneal Calf tosis, ENL in leprosy, HIV, AIDS, and opportunistic infec­ Popliteal Knee Posterior tibial Calf tions in AIDS; disorders such as septic shock, sepsis, Pulmonary Lungs endotoxic shock, hemodynamic shock and sepsis syndrome, Radial Forearm 35 post ischemic reperfusion injury, malaria, mycobacterial Renal Kidney infection, meningitis, psoriasis, congestive heart failure, Splenic Stomach, pancreas, and spleen Subclavian Shoulder fibrotic disease, cachexia, graft rejection, oncogenic or can­ Superior mesenteric Pancreas, small intestine, ascending and cerous conditions, asthma, autoimmune disease, radiation transverse colon damages, and hyperoxic alveolar injury; viral infections, Testicblar Testes 40 such as those caused by the herpes viruses; viral conjunc­ Ulnar Forearm tivitis; or atopic dermatitis. In other embodiments, the use of formulations, composi­ Examples of dysfunctional sleep and related syndromes tions or dosage forms provided herein in various immuno­ include, but are not limited to, those disclosed in U.S. logical applications, in particular, as vaccine adjuvants, publication no. 2005/0222209Al, published Oct. 6, 2005, 45 particularly anticancer vaccine adjuvants, as disclosed in which is incorporated herein by reference. Specific U.S. Publication No. 2007 /0048327, published Mar. 1, 2007, examples include, but are not limited to, snoring, sleep which is incorporated herein in its entirety by reference, is apnea, insonmia, narcolepsy, restless leg syndrome, sleep also encompassed. These embodiments also relate to the terrors, sleep walking sleep eating, and dysfunctional sleep uses of the compositions, formulations, or dosage forms associated with chronic neurological or inflammatory con­ 50 provided herein in combination with vaccines to treat or ditions. Chronic neurological or inflammatory conditions, prevent cancer or infectious diseases, and other various uses include, but are not limited to, Complex Regional Pain such as reduction or desensitization of allergic reactions. Syndrome, chronic low back pain, musculoskeletal pain, arthritis, radiculopathy, pain associated with cancer, fibro­ 5. EXAMPLES myalgia, chronic fatigue syndrome, visceral pain, bladder 55 pain, chronic pancreatitis, neuropathies (diabetic, post-her­ Embodiments provided herein may be more fully under­ petic, traumatic or inflammatory), and neurodegenerative stood by reference to the following examples. These disorders such as Parkinson's Disease, Alzheimer's Disease, examples are meant to be illustrative of pharmaceutical amyotrophic lateral sclerosis, multiple sclerosis, Hunting­ compositions and dosage forms provided herein, but are not ton's Disease, bradykinesia; muscle rigidity; parkinsonian 60 in any way limiting. tremor; parkinsonian gait; motion freezing; depression; defective long-term memory, Rubinstein-Taybi syndrome 5.1 Example 1: 0.5 mg Strength Pomolidomide (RTS); dementia; postural instability; hypokinetic disorders; Dosage Capsule synuclein disorders; multiple system atrophies; striatonigral degeneration; olivopontocerebellar atrophy; Shy-Drager 65 Table 1 illustrates a batch formulation and single dosage syndrome; motor neuron disease with parkinsonian features; formulation for a 0.5 mg strength pomolidomide single dose Lewy body dementia; Tau pathology disorders; progressive unit in a size #4 capsule. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 147 of 148 PageID: 147

US 9,993,467 B2 29 30 TABLE 1 TABLE 3

Formulation for 0.5 mg strength pomolidomide capsule Formulation for 2 mg strength pomolidomide capsule

Percent By Quantity 5 Percent By Quantity Material Weight (mg/capsule) Material Weight (mg/capsule)

Pomolidomide ~1% 0.5* Pomolidomide ~1% 2* Starch 1500 56% 35 Starch 1500 56% 140 Sodium Stearyl Fumarate (PRUV) ~0.3% 0.16 Sodium Stearyl Fumarate (PRUV) ~0.3% 0.64 Spray Dried Mannitol (Mannogem EZ) remainder remainder 10 Spray Dried Mannitol (Mannogem EZ) remainder remainder

Total 100.0% 62.5 Total 100.0% 250

*Denotes amount of pomolidomide that corresponds to the amount that provides the *Denotes amount of pomolidomide that corresponds to the amount that provides the potency of0.5 mg ofpomolidomide. potency of 2 mg of pomolidomide. 15 Pomolidomide was passed through a 35-mesh screen. Pomolidomide was passed through a 35-mesh screen. Mannitol and starch were each separately passed through a Mannitol and starch were each separately passed through a 25-mesh screen. Pomolidomide was pre-blended with a 25-mesh screen. Pomolidomide was pre-blended with a portion of mannitol and starch. The pre-blend was milled portion of mannitol and starch. The pre-blend was milled 20 through a 0.039 inch screen. The remainder of the mannitol through a 0.039 inch screen. The remainder of the mannitol and starch was also milled through a 0.039 inch screen. The and starch was also milled through a 0.039 inch screen. The pre-blend was blended with the reminder of mannitol and pre-blend was blended with the reminder of mannitol and starch. To this blend, sodium fumarate, which was passed starch. To this blend, sodium fumarate, which was passed through a 60 mesh screen, was further blended. The final 25 through a 60 mesh screen, was further blended. The final blend was encapsulated into a size #4 capsule. blend was encapsulated into a size #2 capsule.

5.2 Example 2: 1 mg Strength Pomolidomide 5.4 Example 4: 3 mg Strength Pomolidomide Dosage Capsule Dosage Capsule 30

Table 2 illustrates a batch formulation and single dosage Table 4 illustrates a batch formulation and single dosage formulation for a 1 mg strength pomolidomide single dose formulation for a 0.5 mg strength pomolidomide single dose unit in a size #4 capsule. unit in a size #2 capsule. 35 TABLE 2 TABLE 4

Formulation for 1 mg strength pomolidomide capsule Formulation for 3 mg strength pomolidomide capsule

Percent By Quantity Percent By Quantity Material Weight (mg/capsule) 40 Material Weight (mg/capsule)

Pomolidomide ~1% 1* Pomolidomide ~l.6% 3* Starch 1500 56% 70 Starch 1500 56% 100.8 Sodium Stearyl Fumarate (PRUV) ~0.3% 0.32 Sodium Stearyl Fumarate (PRUV) ~0.3% 0.45 Spray Dried Mannitol (Mannogem EZ) remainder remainder Spray Dried Mannitol (Mannogem EZ) remainder remainder 45 Total 100.0% 125 Total 100.0% 180

*Denotes amount of pomolidomide that corresponds to the amount that provides the *Denotes amount of pomolidomide that corresponds to the amount that provides the potency of 1 mg of pomolidomide. potency of 3 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Pomolidomide was passed through a 35-mesh screen. 50 Mannitol and starch were each separately passed through a Mannitol and starch were each separately passed through a 25-mesh screen. Pomolidomide was pre-blended with a 25-mesh screen. Pomolidomide was pre-blended with a portion of mannitol and starch. The pre-blend was milled portion of mannitol and starch. The pre-blend was milled through a 0.039 inch screen. The remainder of the mannitol through a 0.039 inch screen. The remainder of the mannitol and starch was also milled through a 0.039 inch screen. The 55 and starch was also milled through a 0.039 inch screen. The pre-blend was blended with the reminder of mannitol and pre-blend was blended with the reminder of mannitol and starch. To this blend, sodium fumarate, which was passed starch. To this blend, sodium fumarate, which was passed through a 60 mesh screen, was further blended. The final through a 60 mesh screen, was further blended. The final blend was encapsulated into a size #4 capsule. blend was encapsulated into a size #2 capsule. 60 5.3 Example 3: 2 mg Strength Pomolidomide 5.5 Example 5: 4 mg Strength Pomolidomide Dosage Capsule Dosage Capsule

Table 3 illustrates a batch formulation and single dosage 65 Table 5 illustrates a batch formulation and single dosage formulation for a 2 mg pomolidomide single dose unit in a formulation for a 0.5 mg strength pomolidomide single dose size #2 capsule. unit in a size #2 capsule. Case 2:19-cv-15343 Document 1 Filed 07/12/19 Page 148 of 148 PageID: 148

US 9,993,467 B2 31 32 TABLE 5 months. For determination of the level of impurities, an HPLC gradient method was employed using the following Formulation for 4 mg strength pomolidomide capsule conditions: Colunm: Zorbax SB-CN, 150 mmx4.6 mm id, 5 µm Percent By Quantity 5 particle size Material Weight (mg/capsule) Temperature: Ambient Pomolidomide ~l.6% 4* Mobile Phase: A: 10/90 methanol/0.1 % trifluoroacetic Starch 1500 56% 134.4 acid Sodium Stearyl Fumarate (PRUV) ~0.3% 0.6 B: 80/20 methanol/0.1 % trifluoroacetic acid Spray Dried Mannitol (Mannogem EZ) remainder remainder 10 Total 100.0% 240 Time (min) %A %B *Denotes amount of pomolidomide that corresponds to the amount that provides the potency of 4 mg of pomolidomide. Gradient Profile: 0 90 10 5 90 10 Pomolidomide was passed through a 35-mesh screen. 50 20 80 15 Mannitol and starch were each separately passed through a 51 90 10 25-mesh screen. Pomolidomide was pre-blended with a 60 90 10 portion of mannitol and starch. The pre-blend was milled through a 0.039 inch screen. The remainder of the mannitol Flow Rate: 1.0 mL/min and starch was also milled through a 0.039 inch screen. The Injection Volume: 25 µL 20 pre-blend was blended with the reminder of mannitol and Detection: UV, 240 nm starch. To this blend, sodium fumarate, which was passed Run Time: 60 minutes. through a 60 mesh screen, was further blended. The final From the experiments, it was observed that the impurities blend was encapsulated into a size #2 capsule. in the formulation provided herein stayed negligent through­ out the time period investigated. The performance charac- 5.6 Example 6: 5 mg Strength Pomolidomide 25 teristics of the dosage also maintained throughout the time Dosage Capsule period investigated. These results show that the formulations provided herein have adequate stability for clinical and other Table 6 illustrates a batch formulation and single dosage uses. While examples of certain particular embodiments are formulation for a 5 mg pomolidomide single dose unit in a 30 size #1 capsule. provided herein, it will be apparent to those skilled in the art that various changes and modifications may be made. Such TABLE 4 modifications are also intended to fall within the scope of the appended claims. Formulation for 5 mg strength pomolidomide capsule What is claimed is: 35 1. An oral dosage form in the form of a capsule which Percent By Quantity comprises: 1) pomalidomide at an amount of0.1 to 3 weight Material Weight (mg/capsule) percent of the total weight of the composition; 2) a binder or Pomolidomide ~2% 5* filler at an amount of 90 to 99 weight percent of total weight Starch 1500 56% 168 of the composition, wherein the binder or filler is a mixture Sodium Stearyl Fumarate (PRUV) ~0.3% 0.75 40 Spray Dried Mannitol (Mannogem EZ) remainder remainder of starch and mannitol; and wherein the ratio ofmannitol:starch in the dosage form is Total 100.0% 300 from about 1:1 to about 1:1.5. 2. The oral dosage form of claim 1, wherein pomalido­ *Denotes amount of pomolidomide that corresponds to the amount that provides the potency of 5 mg of pomolidomide. mide is present at an amount of 0.5 to 2 weight percent of 45 total weight of the composition. Pomolidomide was passed through a 35-mesh screen. 3. The oral dosage form of claim 1, wherein the binder or Mannitol and starch were each separately passed through a filler is present at an amount of 95 to 99 weight percent of 25-mesh screen. Pomolidomide was pre-blended with a total weight of the composition. portion of mannitol and starch. The pre-blend was milled 4. The oral dosage form of claim 1, wherein the starch is through a 0.039 inch screen. The remainder of the mannitol 50 pregelatinized starch. and starch was also milled through a 0.039 inch screen. The 5. The oral dosage form of claim 1, wherein the mannitol pre-blend was blended with the reminder of mannitol and is spray dried mannitol. starch. To this blend, sodium fumarate, which was passed 6. The oral dosage form of claim 1 further comprising a through a 60 mesh screen, was further blended. The final lubricant at an amount of 0.01 to 1 weight percent of total blend was encapsulated into a size #1 capsule. 55 weight of the composition. 5.7 Example 7: Stability of Formulation 7. The oral dosage form of claim 6, wherein the lubricant is present at an amount of0.1 to 0.5 weight percent of total Accelerated stability was assessed under 40° C./75% RH, weight of the composition. 8. The oral dosage form of claim 7, wherein the lubricant and levels of impurities over the time period of initial, 1 60 month, 3 months, and 6 months were determined. Long term is sodium stearyl fumarate. stability under 25° C./60% RH is also assessed during 0-24 * * * * *