Case: 19-1364 Document: 32 Page: 1 Filed: 04/15/2019
No. 19-1364
In the United States Court of Appeals For the Federal Circuit ______
BIOGEN, INC., Appellant, v.
UNITED STATES Intervenor. ______ON APPEAL FROM THE U.S. PATENT AND TRADEMARK OFFICE Case No. IPR2017-01168 ______
APPELLANT’S OPENING BRIEF ______
Rachelle H. Thompson Brian D. Schmalzbach MCGUIREWOODS LLP Lyle D. Kossis 434 Fayetteville Street MCGUIREWOODS LLP Suite 2600 Gateway Plaza Raleigh, NC 27601 800 East Canal Street Telephone: (919) 775-6572 Richmond, VA 23219 Facsimile: (919) 775-6591 Telephone: (804) 775-4746 [email protected] Facsimile: (804) 698-2304 [email protected] [email protected]
Counsel for Appellant Biogen, Inc.
Case: 19-1364 Document: 32 Page: 2 Filed: 04/15/2019
FORM 9. Certificate of Interest Form 9 Rev. 10/17 UNITED STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
Biogen, Inc.v. Pfizer, Inc.
Case No. 19-1364
CERTIFICATE OF INTEREST
Counsel for the: (petitioner) (appellant) (respondent) (appellee) (amicus) (name of party)
Biogen, Inc. certifies the following (use “None” if applicable; use extra sheets if necessary):
2. Name of Real Party in interest 3. Parent corporations and 1. Full Name of Party (Please only include any real party publicly held companies Represented by me in interest NOT identified in that own 10% or more of Question 3) represented by me is: stock in the party For Biogen, Inc.: None. For Genentech, Inc.: Genentech, Inc. is a wholly owned subsidiary of Roche Holdings Inc. Roche Holdings Inc.’s ultimate parent, Roche Holdings Ltd., is a publicly held Swiss corporation traded on the Swiss Stock Exchange. Upon information and belief, more than Biogen, Inc. Genentech, Inc. 10% of Roche Holdings Ltd.’s voting shares are held either directly or indirectly by Novartis AG, a publicly held Swiss corporation.
4. The names of all law firms and the partners or associates that appeared for the party or amicus now represented by me in the trial court or agency or are expected to appear in this court (and who have not or will not enter an appearance in this case) are: Irell & Manella LLP - Michael R. Fleming, Gary N. Frischling, Keith A. Orso, Yite John Lu, David I. Gindler Case: 19-1364 Document: 32 Page: 3 Filed: 04/15/2019
FORM 9. Certificate of Interest Form 9 Rev. 10/17
5. The title and number of any case known to counsel to be pending in this or any other court or agency that will directly affect or be directly affected by this court’s decision in the pending appeal. See Fed. Cir. R. 47. 4(a)(5) and 47.5(b). (The parties should attach continuation pages as necessary). None
4/15/2019 /s/ Rachelle H. Thompson Date Signature of counsel
Please Note: All questions must be answered Rachelle H. Thompson Printed name of counsel cc: Counsel of Record
Reset Fields Case: 19-1364 Document: 32 Page: 4 Filed: 04/15/2019
TABLE OF CONTENTS PAGE
STATEMENT OF RELATED CASES ...... vii INTRODUCTION ...... 1 JURISDICTION ...... 5 STATEMENT OF THE ISSUES ...... 5 STATEMENT OF THE CASE ...... 6 I. The ’873 patent describes an innovative treatment combination specifically designed for DLCL patients older than 60...... 6 II. As of the priority date, a POSA knew that a patient’s age and type of lymphoma were critical prognostic factors...... 10 III. The Board determined that the challenged claims are unpatentable as obvious over a five-reference combination...... 12 SUMMARY OF ARGUMENT ...... 17 STANDARD OF REVIEW ...... 19 ARGUMENT ...... 20 I. A POSA would not have been motivated to combine the prior art to make the claimed invention...... 21 A. A POSA would not have combined all three treatments together without evidence that any two of the treatments were better in combination than either one given individually...... 22 B. The foundational reference—Moreau—provides no evidence that the tested combination therapy was better than either treatment individually...... 26 C. The other prior art contains no evidence or data that any combination of two therapies was more effective than the individual treatments alone...... 28
-i-
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D. The Board’s determination that a POSA would have combined the references is legal error and separately lacks substantial evidence...... 35 i. The Board erred as a matter of law by not viewing the prior art from the POSA’s perspective...... 36 ii. The Board’s decision lacks substantial evidence because it disregarded uncontroverted evidence about what would have motivated a POSA...... 37 iii. The Board’s decision lacks substantial evidence because the Board did not explain how a POSA would have combined the references to arrive at the claimed invention...... 39 II. A POSA would not have had a reasonable expectation of success in treating DLCL patients older than 60 with the claimed invention...... 45 A. As a factual matter, a reasonable expectation of success as of the priority date required evidence that a combination therapy improved the prognosis of DLCL patients older than 60...... 46 B. The prior art contained no evidence or data that any combination therapy, let alone all three treatments combined, successfully improved prognoses for elderly DLCL patients...... 49 C. The Board’s conclusion that there was a reasonable expectation of success lacks substantial evidence and constitutes legal error...... 55 i. The Board erred by relying on conclusory expert testimony...... 55 ii. The Board’s decision lacks substantial evidence because it misread the prior art...... 57
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iii. The Board erred as a matter of law by not viewing the prior art from the POSA’s perspective...... 60 III. The Board erred in finding claim 4 obvious because the prior art did not disclose treatment outcomes for DLCL patients older than 60 with bone marrow involvement...... 61 CONCLUSION ...... 63
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TABLE OF AUTHORITIES PAGE Cases
Arendi S.A.R.L. v. Apple Inc., 832 F.3d 1355 (Fed. Cir. 2016) ...... 35, 57, 64
Arkie Lures, Inc. v. Gene Larew Tackle, Inc., 119 F.3d 953 (Fed. Cir. 1997) ...... 37, 61
Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331 (Fed. Cir. 2016) ...... 19
In re Brimonidine Patent Litig., 643 F.3d 1366 (Fed. Cir. 2011) ...... passim
CRFD Research, Inc. v. Matal, 876 F.3d 1330 (Fed. Cir. 2017) ...... 39
Cutsforth, Inc. v. MotivePower, Inc., 636 F. App’x 575 (Fed. Cir. 2016) ...... 57
Dickinson v. Zurko, 527 U.S. 150 (1999) ...... 19
DSS Tech. Mgmt., Inc. v. Apple Inc., 885 F.3d 1367 (Fed. Cir. 2018) ...... 63
Ecolochem, Inc. v. S. California Edison Co., 227 F.3d 1361 (Fed. Cir. 2000) ...... 55
Envtl. Designs, Ltd. v. Union Oil Co. of California, 713 F.2d 693 (Fed. Cir. 1983) ...... 45
Genzyme Corp. v. Dr. Reddy’s Labs., Ltd., 716 F. App’x 1006 (Fed. Cir. 2017) ...... 30
Hagmeyer v. Dep’t of Treasury, 757 F.2d 1281 (Fed. Cir. 1985) ...... 41
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Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A. DE C.V., 865 F.3d 1348 (Fed. Cir. 2017) ...... 46
Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino, 738 F.3d 1337 (Fed. Cir. 2013) ...... 53
Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359 (Fed. Cir. 2016) ...... 59
Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376 (Fed. Cir. 2015) ...... 19
KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007) ...... 20
L.A. Biomedical Research Inst. v. Eli Lilly & Co., 849 F.3d 1049 (Fed. Cir. 2017) ...... 34, 53
In re Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364 (Fed. Cir. 2016) ...... 35, 56, 57, 63
Motor Vehicle Mfrs. Ass’n of U.S., Inc. v. State Farm, 463 U.S. 29 (1983) ...... 38, 60
Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461 (Fed. Cir. 1997)……………………………………………….37
In re Nuvasive, Inc., 842 F.3d 1376 (Fed. Cir. 2016) ...... 20
PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186 (Fed. Cir. 2014) ...... 38
Pers. Web Techs., LLC v. Apple, Inc., 848 F.3d 987 (Fed. Cir. 2017) ...... 19, 44
Pozen Inc. v. Par Pharm., Inc., 696 F.3d 1151 (Fed. Cir. 2012) ...... 38, 48
-v-
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Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d 989 (Fed. Cir. 2009) ...... 27
Regents of University of California v. Broad Institute, Inc., 903 F.3d 1286 (Fed. Cir. 2018) ...... 20
Sanofi-Aventis Deutschland GmbH v. Glenmark Pharm. Inc., USA, 748 F.3d 1354 (Fed. Cir. 2014) ...... 46, 54
In re Schweickert, 676 F. App’x 988 (Fed. Cir. 2017) ...... 44
Star Sci., Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d 1364 (Fed. Cir. 2011) ...... 29, 36, 50 , 60
Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313 (Fed. Cir. 2002) ...... 21
Universal Camera Corp. v. NLRB, 340 U.S. 474 (1951) ...... 19
Upjohn Co. v. Mova Pharm. Corp., 225 F.3d 1306 (Fed. Cir. 2000) ...... 43
Wasica Fin. GmbH v. Cont’l Auto. Sys., Inc., 853 F.3d 1272 (Fed. Cir. 2017) ...... 55
In re Zurko, 258 F.3d 1379 (Fed. Cir. 2001) ...... 39
Statutes
28 U.S.C. § 1295(a)(4)(A) ...... 5
35 U.S.C. § 141(c) ...... 5
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STATEMENT OF RELATED CASES
The appellant is unaware of any related cases under Federal Circuit
Rules 28(a) or 47.5.
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INTRODUCTION
There is no reasonable expectation that all medical treatments attempted in cancer patients will succeed. The invention here relates to a treatment for elderly patients with Diffuse Large Cell Lymphoma (DLCL), an aggressive form of non-Hodgkin’s lymphoma. Despite the unpredictability in the prior art, U.S. Patent No. 8,821,873 (the ’873 patent) describes an innovative treatment combination for elderly DLCL patients.
The combination includes (i) a chemotherapy regimen, (ii) a monoclonal antibody that targets the CD20 antigen on the surface of normal and cancerous B cells, and (iii) a stem cell transplantation regimen. The inventors combined these three therapies together to improve the prognosis of DLCL patients older than 60. That improvement was a substantial advance because prior DLCL treatments did not work well in elderly patients.
The Board determined that the patented treatment combination was obvious. Why then—given the desire to improve treatment outcomes—had no one used that treatment combination before the ’873 patent? Tellingly, no single prior art reference anticipates the claims. The Board instead relied
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on a five-reference combination that supposedly would have motivated a
POSA to make the claimed invention.1
Several of those references, however, would have been of no use to a
POSA seeking to treat elderly DLCL patients. Some references disclosed studies with DLCL patients younger than 60 or patients with less aggressive lymphomas than DLCL. A POSA knew, though, that the patient’s age and type of lymphoma were critical factors to consider in designing treatments and predicting survival outcomes. All experts here agreed that patients older than 60 responded to treatment differently than younger patients, and that treatments shown to be effective for younger patients did not necessarily work as well in elderly patients. All experts also agreed that successful treatments for weaker lymphomas did not necessarily work on aggressive lymphomas. Prior art that studied patient populations younger than 60 or less aggressive lymphomas could not have motivated a POSA to make the claimed invention or provide a reasonable expectation of success.
The Final Written Decision largely tracks Pfizer’s briefs below and concludes that the claims are obvious, but the Board’s motivation-to-
1 “POSA” refers to a Person of Ordinary Skill in the Art at the time of the invention claimed in the ’873 patent.
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combine analysis is flawed. The Board failed to recognize that several pieces
of prior art did not focus on, or report positive results for, DLCL patients
older than 60. The Board also ignored undisputed evidence showing that if more testing were needed to determine whether a two-treatment combination was better than either treatment individually, then a POSA would not have been motivated to add a third therapy to the mix to arrive at the three-treatment combination claimed in the ’873 patent. That oversight was crucial because no reference reported data showing that a two-treatment combination was better than the individual treatments alone, let alone that all three treatments recited in the claimed method could work together. When pushed to explain the motivation to combine, all Pfizer’s expert could muster is that a POSA “might” have taken a “leap of faith” to add all three treatments together. Appx1798, 142:5–9 (emphasis added).
The Board separately concluded that a POSA would have had a reasonable expectation of success. Yet, neither Pfizer’s petition nor its expert declarations meaningfully addressed the reasonable expectation of success.
The Board attempted to fill the gap by improperly relying on conclusory expert testimony. Further, the prior art did not disclose that any two- treatment combination improved patient outcomes over either treatment
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individually. That missing evidence negates any expectation of success, as
even Pfizer described the problem facing a POSA as “whether new therapies would have improved prognosis for patients over 60 years.” Appx120.
Without evidence that a two-treatment combination worked better, a POSA would not have reasonably expected to treat patients successfully with the claimed three-treatment combination.
The Board erred as a matter of law by not viewing the evidence from the POSA’s perspective. Undisputed evidence shows that a POSA would not have been motivated to combine all three treatments together without evidence that any combination treatment was better than the individual treatments alone. Undisputed evidence also shows that a POSA would not have had a reasonable expectation of success without evidence that a combination treatment improved the prognoses of DLCL patients over 60.
The Board did not consider this evidence when reviewing the prior art.
The Board also erred in ruling that claim 4 is obvious. Claim 4 recites the three-treatment combination for patients with bone marrow involvement. Only two references reported treatment results for patients with bone marrow involvement. In one reference, the only two DLCL patients in that study did not respond to treatment. In the other, the study
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did not report the ages or type of lymphoma for the positive responders.
Without that information, a POSA would not have reasonably expected to successfully treat elderly DLCL patients with bone marrow involvement using the claimed treatment combination.
JURISDICTION
The PTAB issued its Final Written Decision on October 31, 2018.
Appx1. Biogen timely filed a notice of appeal on January 2, 2019. Appx2042.
This Court has jurisdiction under 35 U.S.C. § 141(c) and 28 U.S.C.
§ 1295(a)(4)(A).
STATEMENT OF THE ISSUES
1. Whether the Board erred as a matter of law by not viewing the
prior art from the perspective of a POSA.
2. Whether the Board’s determination that there was motivation to
combine the cited references lacks substantial evidence because it
(i) disregarded expert testimony that a POSA would not have combined
multiple treatments without evidence that the combination therapy was
more effective than the treatments given individually, and (ii) failed to
explain in detail how and why a POSA would have combined the teachings
of five disparate references.
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3. Whether the Board’s determination that there was a reasonable
expectation of success lacks substantial evidence because it (i) relied on
conclusory expert testimony and (ii) misread the prior art.
4. Whether the Board erred in concluding that claim 4 of the ’873
patent was obvious when the prior art did not address treatment outcomes
for DLCL patients older than 60 with bone marrow involvement.
STATEMENT OF THE CASE
I. The ’873 patent describes an innovative treatment combination specifically designed for DLCL patients older than 60.
Lymphomas are cancers that involve the uncontrolled growth of B cells or T cells. Appx1099, ¶27. As Pfizer’s expert, Dr. Ozer, explained,
“[e]ach lymphoma has its own distinct genetic, immunologic, and molecular characteristics.” Appx170–171, ¶33. To account for such differences, physicians classify lymphomas as low, intermediate, or high grade.
Appx1099–1100, ¶29. The patent explains that intermediate- and high-grade lymphomas “are much more aggressive at the time of diagnosis than are low-grade lymphomas.” Appx53, 1:33–35. While patients with low-grade lymphoma may survive 5-7 years after diagnosis, the survival rate for high- grade lymphoma is only “6 months to 2 years.” Appx53, 1:32–36.
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POSAs understood that DLCL was an aggressive form of cancer.
Appx54, 3:5–14. The patent explains that there are several “classification
systems for the different types of lymphoma.” Appx53, 2:46–48. Under the
“Working Formulation,” DLCL is an intermediate-grade lymphoma
identified as “Type G.”2 Appx53, 2:52–58; Appx1100, ¶33. Under the
Revised European American Lymphoma (REAL) classification, DLCL is an
“aggressive” form of lymphoma. Appx54, 3:5–14. There is no dispute that
“a POSA would classify DLCL as an intermediate- or high-grade” lymphoma. Appx171–172, ¶35.
As of the priority date, chemotherapy was the standard of care for treating DLCL patients. After a physician diagnosed a patient with DLCL, the initial treatment (also called the “upfront” or “first-line” treatment)
“consisted of administering one or more chemotherapy drugs.” Appx1101,
¶36. Although there were several known chemotherapy regimens, “[t]he most preferred chemotherapeutic regimen is CHOP.” Appx54, 3:43–44.
CHOP is an acronym for the constituent drugs: cyclophosphamide (C),
2 At the time of the claimed invention, the Working Formulation system classified lymphoma subtypes on a scale of “A” to “J.” Appx171–172, ¶35.
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hydroxydaunorubicin (H), Oncovin (O), and prednisone/prednisolone (P).
Appx1101, ¶37.
An alternative to CHOP was stem cell transplantation. Autologous stem cell transplantation involved harvesting the patient’s own stem cells, while allogenic transplantation used stem cells from a donor with matching bone marrow. Appx1103, ¶¶42–43. Peripheral blood stem cell transplantation (PBSCT) harvested the patient’s own stem cells from his circulating blood. Appx1103, ¶41. Although the ’873 patent discusses transplantation, it nowhere states that physicians used stem cell transplantation to treat elderly DLCL patients. In fact, one of the references the Board used in support of its unpatentability decision explains that stem cell transplantation “is usually restricted to patients aged ≤60 years, partly due to the anticipated poor tolerance of intensive treatment in elderly patients.”
Appx265 (emphasis added).
The ’873 patent explains that while “patients often respond to conventional therapies,” “they usually relapse within several months.”
Appx53, 1:44–46. As of the priority date, a “relatively new approach” for treating non-Hodgkin’s lymphoma “has been to treat patients with a monoclonal antibody directed to a protein on the surface of cancerous B
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cells.” Appx53, 1:47–49. The ’873 patent explains that it would be advantageous if researchers developed “alternative therapies and other monoclonal antibodies” to “decrease the frequency of relapse.” Appx53,
2:8–12.
The inventors disclose a combination treatment to improve the prognosis of elderly DLCL patients. Claim 1 recites:
A method of treating a patient with diffuse large cell lymphoma comprising administering anti-CD20 antibody and chemo- therapy to the patient, wherein the patient is >60 years old, wherein the chemotherapy comprises CHOP . . ., and wherein the anti-CD20 antibody is administered to the patient in combination with stem cell transplantation regimen.
Appx56, 8:37–44.
Claim 2 depends from claim 1 and recites a chimeric anti-CD20 antibody. Appx56, 8:45–46. Claim 3 depends from claim 2 and further recites rituximab, which the patent describes as a “new generation of monoclonal antibodies.” Appx54, 3:52–55. Claim 4 recites the method of claim 1 “wherein the lymphoma is accompanied by bone marrow involvement.” Appx56, 8:49–50. And independent claim 5 recites the same elements as claim 1 but replaces the anti-CD20 antibody with “rituximab.”
Appx56, 8:51–56.
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II. As of the priority date, a POSA knew that a patient’s age and type of lymphoma were critical prognostic factors.
As the Board held, a POSA had at least an M.D. degree, with more than one year of experience treating patients with non-Hodgkin’s lymphoma as a practicing oncologist or hematologist, and was familiar with research and clinical trials about treating lymphoma patients. Appx10–11. A POSA knew
that two factors were critical to designing a patient’s course of treatment and
assessing the likely outcome: the patient’s age and the type of lymphoma.
All of the experts agreed that age affects the survival rates of
lymphoma patients. Biogen’s expert, Dr. Kahl, explained that “[a]s of the
priority date, a person having ordinary skill in the art knew that age was a
critical prognostic factor for [non-Hodgkin’s lymphoma].” Appx1105–1106,
¶49. A leading international study of prognostic indicators for lymphomas found that “age—being over age 60—was the most important factor
independently associated with poorer survival in patients with
intermediate- and high-grade lymphoma.” Appx1105–1106, ¶49 (emphasis
added). Not only did elderly patients process drugs differently, but they
were also more susceptible to certain drug toxicities. Appx1106, ¶50.
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Pfizer’s experts agreed that age was a critical prognostic factor. Dr.
Ozer explained that age was a “significant prognostic factor” in treating lymphomas. Appx979, 19:4–6. Dr. Ozer also acknowledged that the leading international study of prognostic indicators for lymphomas found age to be the most important factor. Appx980, 20:12–18. Dr. Soiffer likewise admitted that age was “[a] prognostic factor” to consider. Appx1766, 110:20–22. He stated it was “likely true” that “DLCL patients over 60 had worse response
[rates] to treatment than younger DLCL patients.” Appx1769, 113:8–14.
Apart from age, the experts agreed that a POSA would have known the type of lymphoma dictated treatment design, and that the higher the grade of lymphoma, the lower the chance of survival. Dr. Kahl explained that “the person having ordinary skill in the art would have known that determining what kind of lymphoma a patient had was important because it impacted the patient’s treatment and treatment outcomes.” Appx1099,
¶28. A POSA therefore paid careful attention to whether the lymphoma was low, intermediate, or high-grade. Appx1099, ¶¶28–29.
Pfizer’s experts agreed. Dr. Ozer confirmed that “[o]ne of the central determining factors for a patient’s prognosis was the patient’s grade of lymphoma.” Appx977, 17:2–6. He conceded that “doctors use different
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treatments for different grades of lymphoma.” Appx978, 18:3–8 (emphasis added). Dr. Soiffer likewise agreed that “the characteristics of a given
lymphoma w[ere] important for determining the appropriate treatment.”
Appx1689, 33:4–8. He admitted “the patient’s grade of lymphoma” was
“one of the central determining factors for a patient’s prognosis.”
Appx1689–1690, 33:25–34:3.
III. The Board determined that the challenged claims are unpatentable as obvious over a five-reference combination.
Pfizer petitioned for inter partes review, arguing that the claims of the
’873 patent are obvious in view of the combined disclosures of the cited
references: Moreau, Link, McNeil, Maloney, and Coiffier. Appx111–117.
The Moreau study treated fourteen patients older than 60 who had
intermediate- or high-grade non-Hodgkin’s lymphoma. Appx265. The
patients received CHOP and PBSCT as upfront treatment. Appx265.
Moreau did not utilize a control group that received only CHOP, so Moreau
did not compare the efficacy of CHOP alone to CHOP plus PBSCT.
Appx265. Moreau reported that half the patients died seven to twenty-eight
months after treatment. Appx265. Moreau further reported that all patients
experienced high levels of toxicity. Appx267; see also Appx1007, 47:1–4;
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Appx184, ¶63 (Dr. Ozer’s declaration, stating high levels of toxicity reported in Moreau “was expected in an elderly population”).
Link reports the abstract of a pilot study that treated patients with
CHOP plus rituximab, but as Pfizer admits, “Link did not study patients over 60.” Appx101. The study included 31 patients with intermediate- or high-grade non-Hodgkin’s lymphoma. Appx257. The patients’ median age was 49. Appx257. Link reported that the treatment “represents a tolerable therapy” for these younger patients with intermediate- or high-grade lymphoma. Appx257.
McNeil is a news article discussing treatments for elderly patients with non-Hodgkin’s lymphoma. McNeil cited an ongoing phase III clinical trial comparing “CHOP alone to CHOP plus [a] new monoclonal antibody.”
Appx249. McNeil reported that the study would include “630 patients age
60 and over,” but did not explain how many (if any) of those patients had
DLCL. Appx249. McNeil discloses that in this study, and other studies focusing on the elderly, “data on length of disease-free and overall survival will be key.” Appx250. McNeil did not report any data or results from the trial.
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Maloney studied the efficacy of Rituxan® (the brand name for rituximab) in patients with non-Hodgkin’s lymphoma. Appx273. The study included only 20 patients divided into three dosing groups, and the median age of each dosing group was 48, 59, and 59.5, respectively. Appx273. Only two patients in the study had DLCL, and Maloney did not report their ages.
Appx271. Further, neither DLCL patient responded to rituximab therapy.
Appx271; see also Appx1013, 53:15–25 (Dr. Ozer’s deposition, confirming that the two DLCL patients in Maloney did not respond). Neither did three other patients with intermediate- or high-grade lymphoma. Appx1013, 53:15–25.
Based on this data, Maloney concluded that the monoclonal antibody was
“safe” and “well-tolerated . . . in patients with relapsed, low-grade B-cell lymphoma.” Appx279 (emphasis added).
Coiffier studied the efficacy of using rituximab alone to treat patients with intermediate- or high-grade lymphoma. Appx258. The median patient age in Coiffier was greater than 60. Appx259. Coiffier concluded that rituximab “has significant anti-lymphoma activity in DLCL and MCL patients,” but Coiffier did not identify any positive responders older than
60. Appx263; see also Appx1014–1015, 54:7–55:15 (Dr. Ozer’s deposition, confirming that Coiffier does not disclose whether any patients responding
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to rituximab were older than 60). Coiffier did not study the antibody’s effect in combination with CHOP or stem cell transplantation, and did not report adverse events for all patients older than 60. Appx261.
The Board concluded that the challenged claims are unpatentable as obvious. In its Final Written Decision, the Board adopted Pfizer’s description of the prior art. Appx15–18. The Board stated that “Link and
McNeil would have provided” a POSA with a reason “to add rituximab to
CHOP in Moreau’s method.” Appx19. The Board also stated that “Moreau
would have suggested to the artisan that rituximab would be suitable for use
in stem cell transplantation” even though Moreau did not mention or study
the monoclonal antibody. Appx19. The Board credited the unsupported
statement from Pfizer’s experts that Maloney would have likewise
motivated a POSA to make the claimed invention. Appx19–20.
The Board did not consider whether a POSA would have combined three treatments without evidence that any combination therapy was better or safer than the individual treatments alone. Biogen explained that a POSA
would not have added rituximab to the regimen in Moreau because “no two of those therapies had been shown to be better than the individual therapies
alone.” Appx20. Biogen also cited Pfizer’s expert, Dr. Ozer’s admission that
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“if more testing was needed though to determine whether the combination
therapy was more effective and still safe, then a person of ordinary skill in
the art would test the combination therapy further before trying to add a third
drug.” Appx793, Appx818–819 (emphasis added). The Board disregarded
this evidence and refused to recognize “such a standard for establishing a
motivation to combine known elements.” Appx20.
The Board also ignored Biogen’s argument that Pfizer failed to submit
evidence of a “reasonable expectation of success.” Appx28. Dr. Ozer barely
discussed the concept in his declaration beyond a “throwaway conclusion,”
and Dr. Soiffer said nothing about it. Appx795; see also Appx193, ¶89. The
Board held that the prior art teachings “serve not only as motivation for combining rituximab with Moreau’s method . . . but also serve to demonstrate why a [POSA] would have had a reasonable expectation of success[].” Appx30.
The Board similarly concluded that the dependent claims are obvious.
With respect to claim 4, Biogen explained that Maloney did not “report success in any DLCL patients without bone marrow involvement.” Appx32.
The Board disagreed and ruled that a POSA would have considered
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“Maloney’s teaching that rituximab does not impact marrow reserves.”
Appx32–33.
SUMMARY OF ARGUMENT
I. The Board wrongly determined that a POSA would have been
motivated to combine the cited prior art to make the claimed invention. All
experts agreed that a POSA would not have added a third therapy to a
combination treatment without evidence that the combination treatment
was better than the treatments given individually. The prior art did not
show that any two-treatment combination was better than the individual
treatments alone. Indeed, several references did not even test combination
therapies. Further, several references did not study the relevant population:
DLCL patients older than 60.
The Board did not address whether any combination therapies were
better than the individual treatments alone even though all experts opined
that a POSA would have needed such confirmation before combining all
three treatments together. The Board also did not explain how a POSA would
have combined five disparate references together to make the claimed
invention. The Board’s determination that there was a motivation to
combine thus lacks substantial evidence.
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II. The Board wrongly determined that a POSA would have had a reasonable expectation of success. All experts agreed, as a factual matter, that a reasonable expectation of success in this context meant evidence that the claimed invention would improve the prognosis of elderly DLCL patients. No reference showed that any two-treatment combination improved patient prognoses. Without such information, a POSA could not have reasonably expected to successfully treat elderly DLCL patients with the claimed three-treatment combination.
The Board relied on a single conclusory statement in Pfizer’s expert’s declaration to find that a POSA would have had a reasonable expectation of success. The Board’s reliance on conclusory expert testimony is not substantial evidence. On top of that, none of the cited references showed that any two-treatment combination improved patient prognoses for elderly
DLCL patients. A POSA therefore would not have had a reasonable expectation of success in using a three-treatment combination, and the
Board’s contrary ruling lacks substantial evidence.
III. The Board erroneously concluded that claim 4 is obvious. Only two of the cited references address patients with bone marrow involvement.
Neither reference reported that the bone-marrow patients who responded to
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treatment were DLCL patients older than 60. Without this information, a
POSA would not have had a motivation to combine or a reasonable expectation of success in treating elderly DLCL patients with bone marrow involvement using the claimed three-treatment combination.
STANDARD OF REVIEW
“[O]bviousness under § 103 is a question of law based on underlying findings of fact.” Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376,
1381 (Fed. Cir. 2015). This Court “review[s] the Board’s ultimate determination of obviousness de novo and its underlying factual determinations for substantial evidence.” Pers. Web Techs., LLC v. Apple, Inc.,
848 F.3d 987, 991 (Fed. Cir. 2017). “Substantial evidence is more than a mere scintilla. It means such relevant evidence as a reasonable mind might accept as adequate to support a conclusion.” Blue Calypso, LLC v. Groupon, Inc., 815
F.3d 1331, 1337 (Fed. Cir. 2016). “The substantiality of evidence must take into account whatever in the record fairly detracts from its weight.”
Universal Camera Corp. v. NLRB, 340 U.S. 474, 488 (1951).
The Supreme Court “has stressed the importance of not simply rubber- stamping agency factfinding.” Dickinson v. Zurko, 527 U.S. 150, 162 (1999).
“The APA requires meaningful review; and its enactment meant stricter
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judicial review of agency factfinding than Congress believed some courts had previously conducted.” Id. This Court adopts the same approach:
“Although we review [] factual finding[s] for substantial evidence, the factual inquiry whether to combine references must be thorough and searching, and the need for specificity pervades our authority on the PTAB’s findings on motivation to combine.” In re Nuvasive, Inc., 842 F.3d 1376, 1381–
82 (Fed. Cir. 2016).
ARGUMENT
“[C]laimed discoveries almost of necessity will be combinations of what, in some sense, is already known.” KSR Int’l Co. v. Teleflex Inc., 550 U.S.
398, 418–19 (2007). “An obviousness determination requires finding that a person of ordinary skill in the art would have been motivated to combine or modify the teachings in the prior art and would have had a reasonable expectation of success in doing so.” Regents of University of California v. Broad
Institute, Inc., 903 F.3d 1286, 1291 (Fed. Cir. 2018).
For each claim in the ’873 patent, both criteria are missing. A POSA would not have combined all three treatments together absent more testing to determine whether combination therapies were better than the treatments given individually. Likewise, a POSA would not have had a reasonable
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expectation that combining CHOP, rituximab, and stem cell transplantation would improve patient prognoses because the prior art did not show that any combination therapy was better than the individual treatments alone.
By disregarding the undisputed evidence that fleshed out the POSA’s viewpoint, the Board did not view the prior art from the POSA’s perspective and thus erred as a matter of law.
Moreover, claim 4 is not obvious because the prior art did not report positive treatment results for DLCL patients older than 60 with bone marrow involvement. Only Maloney and Coiffier involved patients with bone marrow involvement. The DLCL patients in Maloney did not respond to treatment, and Coiffier did not identify the positive responders as DLCL patients older than 60. Those references provide no motivation to combine or reasonable expectation of success.
I. A POSA would not have been motivated to combine the prior art to make the claimed invention.
The Board’s finding of a motivation to combine lacks substantial evidence. “The showing of a motivation to combine must be clear and particular, and it must be supported by actual evidence.” Teleflex, Inc. v.
Ficosa N. Am. Corp., 299 F.3d 1313, 1334 (Fed. Cir. 2002) (emphasis added).
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The record shows that a POSA would not have combined all three treatments together because he did not even know whether a two-treatment combination was better than either treatment given individually. The Board reached the contrary conclusion by disregarding record evidence and misreading the prior art.
A. A POSA would not have combined all three treatments together without evidence that any two of the treatments were better in combination than either one given individually.
Biogen’s expert, Dr. Kahl, explained that a POSA would not have
combined the prior art to make the claimed invention. The prior art did not
show that any combination of two therapies “was better” than the therapies
given individually. Appx1126, ¶117. Dr. Kahl explained that “as of the
priority date in August 1999, no two of those therapies had been shown to
be better together than each alone—even in lymphoma patients generally,
let alone in the claimed DLCL patients >60 years old.” Appx1125, ¶116.
Given the lack of evidence on the improved efficacy of combination
therapies, “more testing was needed to determine whether administering
any two of CHOP chemotherapy, an anti-CD20 antibody, and a stem cell
transplantation regimen was more effective (and still safe) as compared to
each treatment alone.” Appx1126, ¶118.
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Pfizer’s expert, Dr. Ozer, agreed. Dr. Ozer explained that if a
“combination therapy proved more effective” than the individual
treatments, researchers would “add[] another drug to that combination to
see if the triple combination would be more effective.” Appx987, 27:7–11.
But “if more testing was needed” to see if the combination therapy “was
more effective and still safe, then a [POSA] would test the combination
therapy further before trying to add a third drug.” Appx987, 27:12–18
(emphasis added).
Biogen’s expert, Dr. Kahl, also explained that a POSA would have been careful not to combine treatments that made it difficult to assess chemosensitivity. Patients typically underwent CHOP before stem cell transplantation. Appx1103–1104, ¶45; see also Appx174–175, ¶43 (Dr. Ozer’s declaration). A POSA would have ensured that the patient responded positively to chemotherapy (i.e., was chemosensitive) before starting transplantation because “[i]f a patient’s disease was not chemosensitive . . . then a physician would potentially be putting the patient through the stem cell transplantation regimen unnecessarily.” Appx1103–1104, ¶45. If a
POSA treated the patient first with rituximab plus CHOP, then any positive response could be due to rituximab, not CHOP. The presence of other
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treatments would have thus made it difficult for POSAs to tell whether the patient responded to chemotherapy or something else. Appx1103–1105,
¶¶45–48. That uncertainty would have discouraged a POSA from combining treatments because a patient who did not respond to chemotherapy “was not a good candidate to begin a stem cell transplantation regimen.” Appx1104–1105, ¶46.
Apart from chemosensitivity, a POSA would have also been hesitant to combine treatments due to toxicity concerns. Pfizer’s expert, Dr. Ozer, agreed that CHOP was more toxic to patients older than 60. Appx990–991,
30:15–31:1. He conceded that “stem cell transplantation was known to be potentially lethal.” Appx998, 38:11–14. And he explained that “the total toxicity associated with using multiple drugs together can be too high even if the toxicities of those individual drugs do not overlap.” Appx985, 25:15–
19. A POSA therefore would have looked for evidence that a combination therapy improved patient outcomes before adding a third drug to the mix that could make the combination unacceptably toxic.
This Court has recognized that potentially increased toxicity is a powerful motivation not to combine treatments. In In re Brimonidine Patent
Litig., 643 F.3d 1366 (Fed. Cir. 2011), the patents at issue claimed an eye drop
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formula used to treat glaucoma. The patents claimed a drug combination that included “CMC as a solubility-enhancing component.” Id. at 1372
(discussing ’873 patent). The defendant argued that the use of CMC was obvious over the prior art because “Alphagan® and Refresh Tears®, which contains CMC, were routinely prescribed together.” Id. at 1373–74. The
Court held that just because a POSA could have combined these drugs does not mean he would have done so. “Two ingredients might be therapeutically effective when used separately as part of an overall treatment regimen, yet be incompatible or ineffective when combined in a single solution.” Id. at 1374
(emphasis added). A POSA would not have combined treatments
haphazardly without some evidence that they worked well together.
Both the expert testimony here and the reasoning in Brimonidine show why there was motivation not to combine. A POSA would not have combined CHOP, rituximab, and stem cell transplantation into a single treatment regimen without evidence that any combination of two of the three therapies was more effective than each individual therapy.
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B. The foundational reference—Moreau—provides no evidence that the tested combination therapy was better than either treatment individually.
The Moreau reference has significant shortcomings. Moreau was a pilot study that examined the feasibility of using CHOP and PBSCT as upfront therapy for DLCL patients older than 60. Appx265. The study’s 14 patients first received three courses of CHOP and then a round of PBSCT if they responded positively to CHOP. Appx265. All experts agree that
Moreau did not study or address any monoclonal antibody, let alone rituximab. Appx1114, ¶73; Appx182–183, ¶61; Appx1382, ¶25.
Moreau did not include a control group that received only CHOP.
Appx265. As Biogen’s expert, Dr. Kahl, explained, a POSA “can’t tell whether the strategy that they [Moreau] are employing is a therapeutic advance or not.” Appx1259, 60:6–8. The long-term positive results in some patients “might have been achieved with a standard approach” of CHOP alone. Appx1259, 60:16–19. Even Dr. Ozer admitted “Moreau did not conclude that its first line treatment [CHOP + PBSCT] was better than a standard regimen of CHOP.” Appx1008, 48:12–15.
Moreau itself did not suggest that CHOP plus PBSCT worked better than each treatment given individually. The study simply concluded that
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“patients with intermediate- or high-grade disseminated [non-Hodgkin’s lymphoma] should not be excluded from trials evaluating the role of
[transplantation] as part of initial treatment.” Appx268 (emphasis added).
Far from showing that a combination therapy improved efficacy, Moreau expressly acknowledges that more testing was essential to figure out whether
CHOP plus PBSCT was better than CHOP alone. That is why Pfizer’s expert,
Dr. Ozer, conceded “Moreau does not say that any patient should receive any particular treatment.” Appx1022–1023, 62:23–63:1.
At most, Moreau offered only general guidance about transplantation, but indicated that the jury is still out on whether the combination of CHOP and PBSCT works better than CHOP. Appx268. Yet “patents are not barred just because it was obvious to explore a new technology or general approach that seemed to be a promising field of experimentation.” Procter & Gamble
Co. v. Teva Pharm. USA, Inc., 566 F.3d 989, 996–97 (Fed. Cir. 2009). “[W]here the prior art gave only general guidance as to the particular form of the claimed invention,” it did not supply a motivation to combine. Id.
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C. The other prior art contains no evidence or data that any combination of two therapies was more effective than the individual treatments alone.
No combination of the other prior art would have motivated a POSA to make the claimed invention. To fill the gaps left by Moreau, the Board relied on four other references. But all of them suffer from the same limitation as Moreau: They did not examine whether any combination of
CHOP, stem cell transplantation, and the monoclonal antibody was more effective or less toxic than the treatments given individually. More still, many of these references did not focus on DLCL patients older than 60.
Without studying the relevant patient population, the other references add nothing further.
Link: Link reports the abstract for a small pilot study that examined 31 patients with intermediate- or high-grade lymphoma. Appx257. The patients received CHOP and a monoclonal antibody as upfront treatment.
Appx257. The median patient age in Link was 49, not greater than 60.
Appx257. As Pfizer’s expert, Dr. Ozer, admitted, Link did not state that any of the patients in the study were older than 60. Appx1009–1010, 49:25–50:2; see also Appx101 (Pfizer’s Petition, admitting that “Link did not study patients over 60”).
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Nor did Link compare a combination treatment to the individual
treatments alone. Link reports that the patients received CHOP plus
rituximab, but the study did not include a control group that received either
treatment individually. Appx257. During his deposition, Pfizer’s expert, Dr.
Soiffer, admitted that Link “did not compare R-CHOP and CHOP in a head-
to-head comparison.”3 Appx1803, 147:22–24. A POSA would not have added stem cell transplantation to Link because “more testing was needed” to see if R-CHOP “was more effective and still safe” compared to CHOP alone. Appx987, 27:12–18 (Dr. Ozer’s deposition).
Link’s speculation about R-CHOP would not have motivated a POSA to combine treatments. Link reported that CHOP plus rituximab “represents a tolerable therapy” in younger patients with similar toxicity to CHOP alone
“and may offer higher response rates.” Appx257 (emphasis added). But a reference’s “speculative and tentative disclosure of what ‘might’ or ‘may’ lead to [the relevant result] does not sufficiently direct or instruct one of skill in th[e] art.” Star Sci., Inc. v. R.J. Reynolds Tobacco Co., 655 F.3d 1364, 1376 (Fed.
Cir. 2011) (emphasis added); see also Genzyme Corp. v. Dr. Reddy’s Labs., Ltd.,
3 The “R” in “R-CHOP” refers to Rituxan® or rituximab. R-CHOP means a treatment consisting of both CHOP and the monoclonal antibody.
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716 F. App’x 1006, 1010 (Fed. Cir. 2017) (no motivation to combine despite reference’s “hypothesi[s] in an isolated sentence, without explanation, that plerixafor may cause stem cell mobilization” (emphasis added)).
McNeil: McNeil is a news article that reports the initiation of two
studies. Appx249. One study was a phase III trial that compared “CHOP
alone to CHOP plus the monoclonal antibody.” Appx249. Pfizer’s expert,
Dr. Soiffer, explained that the trial in McNeil was necessary because, as of the priority date, “we didn’t have clear evidence of the benefit of CHOP
Rituxan over CHOP.” Appx1796, 140:11–12. Although the trial included
“elderly” patients, McNeil did not report the median age for the study.
Appx249. On top of that, McNeil did not report the trial’s results. Appx249; see also Appx1003, 43:18–21 (agreeing that McNeil did not provide results).
The clinical trial that McNeil describes underscores that POSAs would have
needed “more testing” to see if combination therapies “w[ere] more effective
and still safe” than either treatment individually. Appx987, 27:12–18
(Dr. Ozer’s deposition).
McNeil also reported a separate study that was examining the efficacy
of CHOP plus PBSCT. Appx250. But McNeil never reported the target
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patient population, the type of lymphoma the patients had, or whether there was a control group that received CHOP alone. Appx250.
Maloney: Maloney is a small 20-patient study that examined the efficacy of the monoclonal antibody alone. Appx271. The median patient age in Maloney was 59, and only two patients had DLCL. Appx273. Pfizer’s expert, Dr. Ozer, agreed that Maloney did not state that those two DLCL patients were older than 60. Appx1012, 52:5–10.
Maloney did not show that any combination therapy was more effective than the treatments given individually because Maloney studied rituximab as a monotherapy. Worse still, the DLCL patients in Maloney did not respond to treatment. Dr. Ozer admitted “none of the patients with intermediate or high grade lymphoma,” including the two DLCL patients,
“responded to the therapy” in Maloney. Appx1013, 53:15–25. Because the only DLCL patients in Maloney did not respond to rituximab treatment
alone, Maloney provides no suggestion that rituximab, much less rituximab
plus something else, can treat elderly DLCL patients.
Coiffier: Like Maloney, Coiffier studied the efficacy of rituixmab alone.
The median age was greater than 60, and the patients had aggressive
lymphomas. Appx259–262. While Coiffier concluded that rituximab
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showed “significant anti-lymphoma activity in DLCL and MCL patients,”
Coiffier did not study a combination therapy and did not report results for patients older than 60. Appx263. Like Maloney, Coiffier would not have motivated a POSA to combine all three therapies together because “more testing was needed” to see if rituximab plus something else “was more effective and still safe” than the treatments individually. Appx987, 27:12–
18.
When viewed as a whole, the references do not teach or suggest to a
POSA combining CHOP, stem cell transplantation, and rituximab to treat elderly DLCL patients. The chart below highlights that no reference reported that any two-treatment combination was better than the treatments given alone, which underscores that even when viewed as a whole, the references would not have motivated a POSA to combine all three treatments to treat a single elderly patient.
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Teaching or Data Showing Combination Suggestion to that Combo was Therapy Combine All More Effective Reported Three than Treatments Therapies? Individually? Moreau CHOP + PBSCT No No
Link R-CHOP No No R-CHOP and McNeil No No CHOP + PBSCT Maloney None No No
Coiffier None No No
Critically, Link, McNeil, Maloney, and Coiffier, singly or in combination, would have been of no use to a POSA seeking to treat DLCL patients over age 60 with the claimed three-treatment regimen. As explained above, the patient’s age and type of lymphoma were critical prognostic factors to consider in designing treatments. A POSA here could not have relied on studies of younger patients or treatment results for less aggressive lymphomas because “[i]f you looked at all patients over 60 versus all patients under 60, both response and tolerability of treatment would be different between those groups.” Appx1768, 112:22–25 (Dr. Soiffer’s deposition)
(emphasis added). Link, McNeil, Maloney, and Coiffier did not study
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patients over 60, or did not report positive results for elderly DLCL patients.
References that do not focus on the relevant patient population would not have motivated a POSA. See L.A. Biomedical Research Inst. v. Eli Lilly & Co.,
849 F.3d 1049, 1065 (Fed. Cir. 2017) (claims not obvious over prior art because one reference “was not limited to a population of patients suffering from [the relevant condition],” and another reference did not report studies “expressly limited to atherosclerotic, or even aging, patient populations” (emphasis
added)).
A POSA reading the prior art may have thought that combination
therapies could possibly improve on individual treatments. The recently- launched trial cited in McNeil, for example, sought to answer whether R-
CHOP was better than CHOP alone. But the possibility that a two-treatment combination could prove effective did not mean that a POSA would have been motivated to combine all three treatments of rituximab, CHOP, and stem cell transplantation together. As explained above, supra at 24–25, a POSA would have known that both CHOP and stem cell transplantation individually carried serious side effects—and could prove fatal—for elderly patients. A POSA also would have known that “[t]wo ingredients might be therapeutically effective when used separately as part of an overall
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treatment regimen, yet be incompatible or ineffective when combined in a single solution.” See Brimonidine, 643 F.3d at 1374. Given all this uncertainty, it should be unsurprising that Pfizer’s expert, Dr. Soiffer, thought combining all three therapies would have been taking a “leap of faith.” Appx1798,
142:5–9. Because ordinary artisans need more than faith before exposing elderly patients to potentially lethal treatment, there was no motivation to combine.
D. The Board’s determination that a POSA would have combined the references is legal error and separately lacks substantial evidence.
The Board’s motivation-to-combine analysis: (i) erred as a matter of law by failing to view the evidence from the POSA’s perspective,
(ii) improperly disregarded the uncontroverted evidence about what motivated a POSA, and (iii) did not explain in detail how a POSA would have combined five disparate references. Because the record does not support the
Board’s ruling, this Court should reverse. See Arendi S.A.R.L. v. Apple Inc.,
832 F.3d 1355, 1367 (Fed. Cir. 2016) (reversing obviousness ruling because the Board’s rulings were “unsupported by substantial evidence”); In re
Magnum Oil Tools Int’l, Ltd., 829 F.3d 1364, 1381 (Fed. Cir. 2016) (reversing
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obviousness ruling because “the Board’s factual findings regarding the alleged motivation to combine lacked substantial evidence”).
i. The Board erred as a matter of law by not viewing the prior art from the POSA’s perspective.
“Whether prior art invalidates a patent claim as obvious is determined from the perspective of one of ordinary skill in the art.” Star Sci., Inc., 655
F.3d at 1374. As explained above, the undisputed evidence before the Board
shows that a POSA would not have been motivated to combine all three
claimed treatments together without evidence that any two-treatment
combination worked better than either treatment individually. See
Argument §§ I.A, I.D.ii. But the Board did not view the prior art through the
lens of a POSA. Rather, the Board improperly adopted a view of the prior
art based on what it thought would have motivated a POSA. Appx20. The
Board dismissed the contrary evidence by claiming there was no “standard”
for considering that testimony, Appx20, even though Biogen was arguing
about the undisputed facts, not the law, see Argument § I.D.ii.
By not viewing the prior art from the POSA’s perspective, the Board violated the cardinal rule that “[t]he decision of obviousness” must be made
“from the viewpoint of a person of ordinary skill in the field of the
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invention.” Arkie Lures, Inc. v. Gene Larew Tackle, Inc., 119 F.3d 953, 956 (Fed.
Cir. 1997). While the prior art need not provide an explicit suggestion to
combine elements, this Court has consistently held that the prior art must be
“filtered through the knowledge of one skilled in the art.” Motorola, Inc. v.
Interdigital Tech. Corp., 121 F.3d 1461, 1472 (Fed. Cir. 1997). By disregarding the undisputed evidence that fleshed out the POSA’s viewpoint, the Board viewed the claims without reference to an ordinary artisan’s perspective.
The Board therefore erred as a matter of law.
ii. The Board’s decision lacks substantial evidence because it disregarded uncontroverted evidence about what would have motivated a POSA.
Pfizer’s expert, Dr. Ozer, admitted that if more testing were essential
to evaluate a two-treatment combination, then a POSA would not have
added a third treatment to the mix. Appx987, 27:12–18. The Board did not
consider that evidence when reviewing the prior art because there was
supposedly “no authority for applying such a standard for establishing a
motivation to combine known elements according to their established
functions.” Appx20 (emphasis added).
The Board’s reasoning confused questions of law with questions of fact. “The presence or absence of a motivation to combine references in an
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obviousness determination is a pure question of fact.” PAR Pharm., Inc. v.
TWI Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014). Biogen did not argue that a certain legal standard applied, but that as a factual matter, in view of the
uncontroverted evidence on a POSA’s perspective, there was no motivation
to combine here. All experts agreed that a POSA would not have been
motivated to combine all three treatments together without data showing
that any combination treatment was more effective or less toxic than the
treatments given individually. See Argument § I.A. The Board did not cite
any contrary factual evidence. Because the Board’s determination that a
POSA would have been motivated to combine all three treatments “r[an] counter to the evidence before the agency,” its decision lacked substantial evidence. Motor Vehicle Mfrs. Ass’n of U.S., Inc. v. State Farm, 463 U.S. 29, 43
(1983).
When the asserted claims require some consideration of the added benefits or potential drawbacks of combination therapies, the Board cannot
bypass that inquiry. Like the patentee in Pozen Inc. v. Par Pharmaceuticals,
Biogen argued that the claims were not obvious because the prior art did not
“disclose the combination therapy has any added benefits over any of the components given individually.” 696 F.3d 1151, 1163 (Fed. Cir. 2012). And
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as in Brimonidine, Biogen argued that there was no motivation to combine because while “[t]wo ingredients might be therapeutically effective when used separately as part of an overall treatment regimen,” a POSA would have known they may be “incompatible or ineffective when combined in a single solution.” 643 F.3d at 1374. The same considerations in Pozen and
Brimonidine apply here. The Board improperly disregarded undisputed
testimony, and reached a conclusion that was contradicted by all the
evidence of record.
iii. The Board’s decision lacks substantial evidence because the Board did not explain how a POSA would have combined the references to arrive at the claimed invention.
The Board also found a motivation to combine by misreading the prior
art and thus erred in concluding that the claims are obvious. See, e.g., CRFD
Research, Inc. v. Matal, 876 F.3d 1330, 1349 (Fed. Cir. 2017) (holding that the
Board’s “misreading” of a reference “led it to err in its obviousness determination”); In re Zurko, 258 F.3d 1379, 1386 (Fed. Cir. 2001) (reversing decision because “[t]he Board’s conclusion of obviousness was based on a misreading of the references relied upon and, therefore, lacks substantial evidence support”).
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The Board’s misreading began with Moreau. The Board incorrectly concluded that the only difference between Moreau and claims 1 and 5 of the ’873 patent is the addition of rituximab. Appx16. But, as Pfizer’s expert,
Dr. Ozer, concedes, “Moreau does not say that any patient should receive any particular treatment.” Appx1022, 62:23–63:1. Thus, contrary to the
Board’s finding, Moreau does not teach or suggest a method of treating
DLCL patients over the age of 60 with CHOP and stem cell transplantation.
The Board likewise misread Maloney. The Board stated Maloney would have motivated a POSA to add rituximab to CHOP and stem cell transplantation. Appx19–20. But in Maloney, the only two DLCL patients did not respond to treatment, and Maloney does not disclose that those two
DLCL patients were over 60. See supra at 31. To get around this fact, the
Board credited Pfizer’s expert’s testimony that “a POSA would not have understood [Maloney’s] teaching . . . to have been limited by this fact.”
Appx20. That conclusory assertion runs headfirst into the uncontroverted evidence that the type of lymphoma is a critical prognostic factor to consider in designing treatments and predicting patient outcomes. See Background
§ II. The Board in effect claimed that a POSA would have designed a treatment regimen for DLCL patients over 60 based on a study where the
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only DLCL patients did not respond to treatment and where their ages were unknown. That finding lacks substantial evidence because “the testimony accepted is inherently improbable [and] discredited by undisputed evidence.” Hagmeyer v. Dep’t of Treasury, 757 F.2d 1281, 1284 (Fed. Cir. 1985).
The Board likewise claimed that Link would have motivated a POSA to combine CHOP, rituximab, and stem cell transplantation to treat elderly
DLCL patients. Appx21–22. But, as Pfizer’s expert, Dr. Ozer, admits, Link
did not study patients over 60. Appx1009–1010, 49:25–50:2; see also Appx101
(Pfizer’s Petition, admitting that “Link did not study patients over 60”). The
Board nonetheless credited Dr. Ozer’s assertion that age did not matter.
Appx21. That assertion not only contradicts the unrebutted testimony that
age was the most critical prognostic factor, see Background § II, but also
contradicts Dr. Ozer’s own testimony on this point. Appx979, 19:4–6 (Dr.
Ozer agreeing that age was a “significant prognostic factor” in treating
lymphomas). Because a POSA would not have relied on studies that did not
examine the relevant patient population, Dr. Ozer’s assertion that age did not matter was “inherently improbable [and] discredited by undisputed evidence.” Hagmeyer, 757 F.2d at 1284.
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The Board’s reading of McNeil similarly missed the mark. The Board contends that McNeil would have motivated a POSA to combine rituximab with CHOP. Appx19–22. But McNeil did not report results from the clinical trial that compared R-CHOP to CHOP alone. The Board does not explain why McNeil supposedly would have led a POSA to combine rituximab with both CHOP and stem cell transplantation when McNeil did not even show that R-CHOP worked at all. As Pfizer’s expert, Dr. Ozer, testified, a POSA would not have combined all three treatments before there was evidence that R-CHOP was better than either treatment individually. Appx987, 27:12–
18.
The Board concluded by discussing Coiffier. Appx22. Coiffier addressed only rituximab, though, and did not suggest or teach that any combination therapy was better than the individual treatments alone.
Coiffier further did not teach or suggest to a POSA adding rituximab to
CHOP and stem cell transplantation for elderly DLCL patients because
Coiffier did not teach or suggest that rituximab was effective in elderly
DLCL patients. Indeed, Coiffier fails to identify a single responder to rituximab as a patient over 60. See supra at 31–32. Given that Coiffier does not disclose that rituximab has efficacy in patients over 60, there would have
42 Case: 19-1364 Document: 32 Page: 53 Filed: 04/15/2019
been no reason to combine rituximab with CHOP to treat elderly DLCL patients despite Coiffier’s teaching that the efficacy responses were achieved without the toxicity commonly observed with combination chemotherapy regimens. Appx263.
The Board also erroneously disregarded the POSA’s desire not to confound the chemosensitivity analysis. As explained, a POSA would not have wanted to combine treatments with CHOP because that would have
made it difficult to assess whether the patient’s response was due to CHOP or something else. See supra at 23–24. The Board credited Pfizer’s expert,
Dr. Soiffer, who stated that any treatment that decreased the volume of cancer cells—whether CHOP or R-CHOP—made the patient a better transplant candidate. Appx24–25. But Dr. Soiffer did not cite any references or prior art to support that assertion of the POSA’s background knowledge.
The Board simply repeated what Dr. Soiffer said in his declaration and declared him “more credible.” Appx25. Yet, an expert’s assertion of
“general scientific knowledge[] require[s] support by documentary evidence in order to receive probative weight.” Upjohn Co. v. Mova Pharm. Corp., 225
F.3d 1306, 1311 (Fed. Cir. 2000). Without any documentary evidence to
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support Dr. Soiffer’s testimony on chemosensitivity, the Board wrongly credited his statements.
Overall, the Board nowhere explained why or how a POSA supposedly
would have combined all three treatments together despite no evidence that
any two-treatment combination was better than either treatment given individually. As elsewhere, “the Board nowhere clearly explained, or cited evidence showing, how the combination of the [] references was supposed to work.” Pers. Web Techs., LLC, 848 F.3d at 994 (emphasis in original). The
PTAB wrongly divorced the prior art from the POSA’s key motivation: whether there was evidence that treatment combinations were better than each treatment individually in DLCL patients older than 60. “The Board, at best, merely posits that a skilled artisan could combine [the references] . . . and would do so because these references were within the knowledge of a skilled artisan.” In re Schweickert, 676 F. App’x 988, 996 (Fed. Cir. 2017)
(rejecting such showing as based on hindsight bias). The Board wrongly concluded that the combination of Moreau (not disclosing that any patient should receive any treatment outcome), Maloney (disclosing that DLCL patients did not respond to rituximab treatment), Link (disclosing ritxumab and CHOP for younger patients), McNeil (disclosing no results for rituximab
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and CHOP), and Coiffier (disclosing no rituximab responses for patients over 60) would have motivated a POSA to add rituximab to Moreau to treat elderly DLCL patients.
Although CHOP, rituximab, and stem cell transplantation were known individual treatments for DLCL, the inventors of the ’873 patent combined them to make an innovative and more effective treatment for patients over 60 years old. “Virtually all inventions are combinations and virtually all are combinations of old elements.” Envtl. Designs, Ltd. v. Union
Oil Co. of California, 713 F.2d 693, 698 (Fed. Cir. 1983). Because there was no motivation to combine rituximab, CHOP, and stem cell transplantation to treat elderly DLCL patients, the challenged claims are not obvious based on the five-reference combination.
II. A POSA would not have had a reasonable expectation of success in treating DLCL patients older than 60 with the claimed invention.
The patent explains that the problem it addressed was improving treatment outcomes for DLCL patients older than 60. As of the priority date, the prior art contained no evidence that combination therapies predictably improved treatment outcomes for that patient population. That missing evidence is crucial because “in the medical arts[,] potential solutions are less
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likely to be genuinely predictable.” Sanofi-Aventis Deutschland GmbH v.
Glenmark Pharm. Inc., USA, 748 F.3d 1354, 1360 (Fed. Cir. 2014).
“Unpredictability of results equates more with nonobviousness rather than obviousness.” Honeywell Int’l Inc. v. Mexichem Amanco Holding S.A. DE C.V.,
865 F.3d 1348, 1356 (Fed. Cir. 2017). Without evidence that improved
outcomes were likely, a POSA would have had no reasonable expectation of
success.
A. As a factual matter, a reasonable expectation of success as of the priority date required evidence that a combination therapy improved the prognosis of DLCL patients older than 60.
The ’873 patent explains that the problem confronting a POSA was improving treatment outcomes for elderly lymphoma patients. “While patients often respond to conventional therapies, they usually relapse within several months.” Appx53, 1:44–46. A POSA would have been looking for
“alternative therapies and other monoclonal antibodies” that “circumvent some of the deficiencies associated with current treatments and decrease the frequency of relapse.” Appx53, 2:8–12. Unsurprisingly, Pfizer itself described the problem facing a POSA as “whether new therapies would have improved prognosis for patients over 60 years.” Appx120 (emphasis added).
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All experts agreed that a reasonable expectation of success meant
improving the prognosis of the relevant patient population. Biogen’s expert,
Dr. Kahl, explained that “[i]n this context I think success would mean that
the treatment is proven to be better than what is already available.”
Appx1257, 58:1–4. When asked again, he reiterated that “my definition of
success would mean that the outcome was improved over what would have
been achieved with a standard approach.” Appx1257, 58:21–24.
Pfizer’s expert, Dr. Soiffer, agreed that success meant achieving better treatment outcomes than conventional therapies. Dr. Soiffer agreed that head-to-head clinical studies “are necessary to show whether a novel therapy . . . ha[s] better outcomes than the standard of care.” Appx1704,
48:4–9. Dr. Soiffer explained that “if we just talk about patients over the age of 60, successful treatment would mean improving the prognosis for patients over the age of 60.” Appx1786, 130:10–19 (emphasis added).
Pfizer’s other expert, Dr. Ozer, also conceded that success meant improving treatment outcomes. Dr. Ozer agreed that “using multiple therapies together can result in an unacceptable total level of toxicity.”
Appx984, 24:15–18. He explained that “if more testing was needed [] to determine whether the combination therapy was more effective and still safe,
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then a [POSA] would test the combination therapy further before trying to add a third drug.” Appx987, 27:12–18 (emphases added). A three-treatment
combination no better (or more toxic) than a two-treatment combination was not a successful treatment.
When confronting combination therapies, this Court has focused on whether there was evidence that a combination therapy proved more effective than the individual treatments alone. In Pozen, the court considered obviousness challenges to several patents for treating migraines. The patents claimed drug combinations that “produce longer lasting efficacy compared to the administration” of the drugs individually. 696 F.3d at 1158.
The Court held the claims were not obvious over the prior art partly because the art did not “disclose the combination therapy has any added benefits over any of the components given individually.” Id. at 1163 (emphasis added).
While the claims here do not expressly require that the three-therapy combination must have greater efficacy than any of the individual therapies, all experts agreed that a reasonable expectation of success in this context meant improved prognoses. The improved-prognosis standard here mirrors the improved-efficacy standard that this Court confronted in Pozen.
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Given the undisputed evidence here, a reasonable expectation of success for a three-treatment combination has a straightforward meaning: improving the prognoses of DLCL patients older than 60 with the claimed invention. That definition requires evidence that a POSA would have reasonably expected the claimed three-treatment combination would have improved the prognosis of the relevant patient population. There is no such evidence.
B. The prior art contained no evidence or data that any combination therapy, let alone all three treatments combined, successfully improved prognoses for elderly DLCL patients.
The Board relied on the same prior art described above to supply a
reasonable expectation of success. But none of the prior art reported
evidence or data suggesting that combination treatments improved
prognoses for DLCL patients older than 60.
Moreau: Moreau studied the use of CHOP plus PBSCT as upfront
treatment for DLCL patients older than 60. Appx265. As explained above,
supra at 26–27, Moreau did not compare CHOP alone to CHOP plus PBSCT.
Moreau also did not advise that any particular patient should receive a
certain kind of treatment. Appx265. In fact, half of the DLCL patients
treated with the Moreau combination died, and all patients experienced high
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toxicities. Appx267; see also Appx1007, 47:1–4; Appx184, ¶63. As a result,
Moreau did not show that the tested combination improved patient prognoses over the “standard of care.” Appx1704, 48:4-9.
Link: Link reports the abstract of a study that used R-CHOP to treat patients with intermediate- or high-grade lymphoma. Appx257. As explained above, Link did not study elderly DLCL patients. See supra at 28–
30. Link did not compare R-CHOP to CHOP alone, and did not conclude that the tested combination therapy worked better than the individual treatments alone. The researchers’ speculation about what “may” be true cannot supply a reasonable expectation of success. See Star Sci., Inc., 655 F.3d at 1376.
McNeil: As explained above, McNeil is a news article that reported the initiation of a study comparing R-CHOP to CHOP alone. Appx249. But
McNeil did not report the age or type of lymphoma for the patients in either study, limiting their utility in this context. See Background § II. McNeil also did not report results from either study and did not tell a POSA whether either combination therapy worked at all or improved patient prognoses compared to the standard of care. Appx249–250. A trial that provides no
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indication of success necessarily provides no reasonable expectation of success.
Maloney: Maloney studied rituximab as a monotherapy. Appx271.
The only two DLCL patients in Maloney did not respond to treatment.
Appx271. Maloney also did not report whether the DLCL patients were older than 60. Appx273. Far from showing that a combination therapy could be effective, Maloney did not even show that rituximab by itself could successfully treat DLCL patients older than 60.
Coiffier: Coiffier tested rituximab on patients with aggressive lymphoma. Appx258. Although Coiffier reported that the antibody appeared effective, it did not combine rituximab with any other treatment.
See supra at 31–32. Coiffier also did not report treatment results for patients older than 60 individually or as a group. See supra at 32. Like Maloney,
Coiffier did not supply a reasonable expectation of success for the claimed invention because it studied only rituximab.
As the chart below highlights, the Board’s prior art suffers from fundamental limitations.
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Data Showing Positive Results that Combination Median Patient for DLCL Patients Therapy Age >60 of Any Age? Improved Prognosis? Moreau Yes Yes No
Link No Yes4 No
McNeil Not reported Not reported No
Maloney No No No
Coiffier Yes Yes No
Link, McNeil, Maloney, and Coiffier, which do not disclose singly or in combination the efficacy of rituximab in DLCL patients over 60, do not suggest a reasonable expectation of success. The patient’s age and type of lymphoma were the most critical prognostic factors that POSAs considered.
See Background § II. A POSA would have known that “[i]f you looked at all patients over 60 versus all patients under 60, both response and tolerability of treatment would be different between those groups.” Appx1768, 112:22–
25 (emphasis added). A POSA could not have reasonably relied on art that
4 Though Link reported positive results for some DLCL patients, it did not identify any positive responders as older than 60. Appx257.
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did not study the claimed patient population. See L.A. Biomedical Research,
849 F.3d at 1065.
Putting aside the patient subpopulations, the prior art provided no data on which basis a POSA would have reasonably expected to have improved an elderly DLCL patient’s prognosis with any combination therapy, let alone the claimed invention. That distinction is crucial because “the expectation-of-success analysis must match the highly desired goal [a three- treatment combo], not switch to a different goal [a two-treatment combo] that may be a less challenging but also less worthwhile pursuit.” Institut
Pasteur & Universite Pierre Et Marie Curie v. Focarino, 738 F.3d 1337, 1346 (Fed.
Cir. 2013). None of the prior art reported results from studies pitting two- treatment combinations against either treatment individually.
Importantly, the combination of the prior art—Moreau (disclosing half
the DLCL patients died and all patients experienced high toxicities),
Maloney (disclosing that DLCL patients did not respond to rituximab
treatment), Link (disclosing ritxumab and CHOP for younger patients),
McNeil (disclosing no results for rituximab and CHOP), and Coiffier
(disclosing no rituximab responses for patients over 60)—provides a POSA no data from which to conclude that the treatment combination was better
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than the individual treatment or that the treatment worked at all in elderly
DLCL patients. A POSA would have therefore hesitated before mixing and matching treatments, especially because the procedures could be deadly.
Appx990–991, 30:15–31:1. As Pfizer’s expert, Dr. Ozer, admitted, “the total toxicity associated with using multiple drugs together can be too high even if the toxicities of those individual drugs do not overlap.” Appx985, 25:15–
19.
Given the state of the prior art, an ordinary artisan could not have predicted successful treatment of this particular subset of patients. Cf.
Sanofi-Aventis, 748 F.3d at 1360 (explaining that medical solutions “are less likely to be genuinely predictable”). Despite a fragile patient population, despite the toxicity of the underlying treatments, and despite the lack of evidence that any two-treatment therapy worked better than solo treatments, the Board determined that a POSA still would have thought that all three therapies together would improve prognoses. That finding has no evidentiary support in the prior art, and ignores sound medical judgment
that counsels against putting patients through a “[treatment] regimen
unnecessarily.” See Appx999, 39:18–20; Appx1103–1104, ¶45. Because there
was no evidence as of the priority date of the claimed invention that any
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combination therapy improved the prognosis of DLCL patients older than
60, there was no reasonable expectation of success.
C. The Board’s conclusion that there was a reasonable expectation of success lacks substantial evidence and constitutes legal error.
The Board made three errors in finding a reasonable expectation of success: (i) the Board relied on conclusory testimony, (ii) the Board misread the prior art, and (iii) the Board failed to view the prior art from the POSA’s perspective.
i. The Board erred by relying on conclusory expert testimony.
The Board improperly relied on conclusory expert testimony. “Broad conclusory statements regarding the teaching of multiple references, standing alone, are not evidence.” Ecolochem, Inc. v. S. California Edison Co.,
227 F.3d 1361, 1372 (Fed. Cir. 2000). “As we have stated, obviousness determinations cannot be sustained by merely conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.” Wasica Fin.
GmbH v. Cont’l Auto. Sys., Inc., 853 F.3d 1272, 1286 (Fed. Cir. 2017).
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It was Pfizer’s burden to produce evidence of a reasonable expectation
of success. In re Magnum Oil Tools Int’l, Ltd., 829 F.3d at 1375–76. Yet, Pfizer’s
experts barely said a word on this topic. Dr. Soiffer’s declaration does not
address the reasonable expectation of success at all. Dr. Ozer’s declaration
addresses the expectation of success once in a conclusory sentence. Appx193
(“[A] POSA would have found it obvious to combine the teachings of Link
and Moreau to arrive at the invention of claim 1—the method of using
rituximab and CHOP in combination with stem cell transplantation to treat
patients over 60 years old with DLCL—and would have had a reasonable
expectation of success.”); see also Appx838–842 (highlighting dearth of
evidence to the Board).
The Board only briefly analyzed the reasonable expectation of success.
Appx28–31. The Board stated that the prior art supplied a reasonable expectation of success in adding rituximab to the treatment regimen disclosed in Moreau. Appx30. To support its conclusion, the Board cited
Dr. Ozer’s passing analysis of Link and his conclusory assertions. Appx30
(citing ¶89 of Dr. Ozer’s declaration). The Board also cited Dr. Ozer’s discussion of Maloney, but Dr. Ozer there did not say anything about reasonable expectation of success. Appx30.
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This Court has consistently reversed the Board’s rulings when they rely on conclusory expert statements. E.g., In re Magnum, 829 F.3d at 1380;
Arendi, 832 F.3d at 1366; Cutsforth, Inc. v. MotivePower, Inc., 636 F. App’x 575,
577–79 (Fed. Cir. 2016). The determination here warrants the same result.
ii. The Board’s decision lacks substantial evidence because it misread the prior art.
The Board erred by misreading the prior art. The Board claimed that
Moreau “disclosed a successful method of treating DLCL patients over 60 years of age.” Appx29–30. But as explained above, supra at 26–27, Moreau did not recommend any particular treatment for individual patients. Half the patients died, and all patients experienced high toxicities. Appx265.
Moreau also did not compare the tested combination therapy to CHOP alone. Appx265. Moreau thus does not disclose that CHOP plus PBSCT improved patient prognoses compared to CHOP alone.
The Board also misread the other references. See Appx30. None of
Link, McNeil, Maloney, or Coiffier reported results that any combination therapy improved prognoses. See supra at 33–34. Several references did not focus on the relevant patient population or report positive results for elderly
DLCL patients. Id. Those shortcomings were of paramount concern because
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all the record evidence before the Board showed that age and type of lymphoma were the most important prognostic factors. See Background § II.
Because a POSA could not have extrapolated a study’s results to every other patient population, the Board erred by not considering the limited utility of
Link, McNeil, Maloney, and Coiffier.
Even under the Board’s own claim construction, the prior art did not supply a reasonable expectation of success. The Board construed the claim language “in combination with stem cell transplantation” to mean the administration of rituximab during transplantation “for the purpose of improving the survival rate of transplant patients.” Appx8 (emphasis added).
Pfizer introduced no evidence that any single treatment or treatment combination disclosed in the prior art improved the survival rate of transplant patients. Only Moreau studied transplant patients, and Moreau did not conclude that CHOP plus PBSCT improved patient outcomes over alternative therapies. Appx265. The Board’s own claim construction underscores that the record was devoid of evidence that combination therapies improved patient outcomes.
The Board compounded its misreading of the prior art by conflating a motivation to combine with a reasonable expectation of success. After
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summarizing the prior art, the Board stated “[t]hose combined teachings serve not only as motivation for combining rituximab with Moreau’s method, as discussed above, but also serve to demonstrate why a person of ordinary skill would have had a reasonable expectation of successfully treating a 60 year old DLCL patient.” Appx30. The Board never explained why it treated two distinct concepts as mirror images of one another.
Without a clarifying explanation, the Board impermissibly commingled the obviousness criteria. See Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
821 F.3d 1359, 1367 (Fed. Cir. 2016) (faulting Board for “conflat[ing] two different legal concepts—reasonable expectation of success and motivation to combine”).
The Board may have conflated the concepts by disregarding undisputed evidence. After briefly discussing the expectation of success, the
Board contended in a footnote that the claimed treatment does not require a
“particular result” or an improved outcome. Appx31 n.11. But as explained above, Argument § II.A, the patent explains that the problem confronting the POSA was improving treatment outcomes by reducing the frequency of relapses. Appx53, 2:8–12. Even Pfizer described the problem as “whether new therapies would have improved prognosis for patients over 60 years.”
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Appx120. And all experts agreed that a reasonable expectation of success meant improving treatment outcomes for DLCL patients older than 60. See
Argument § II.A. The Board’s opinion identifies no contrary record
evidence.
Because the Board “offered an explanation for its decision that runs counter to the evidence before the agency,” its ruling lacked substantial evidence. Motor Vehicle Mfrs., 463 U.S. at 43.
iii. The Board erred as a matter of law by not viewing the prior art from the POSA’s perspective.
“Whether prior art invalidates a patent claim as obvious is determined from the perspective of one of ordinary skill in the art.” Star Sci., Inc., 655
F.3d at 1374. As explained above, the undisputed evidence before the Board
shows that a POSA would not have had a reasonable expectation of success
without some evidence that the claimed invention improved the prognoses
of elderly DLCL patients. See Argument § II.A. Once more, the Board did
not view the prior art through the lens of a POSA. Rather, the Board adopted
a view of the prior art based on what it thought would have motivated a
POSA. Appx29–30. The Board did not consider evidence of improved
prognoses because it thought the claims did not require a particular result,
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Appx31 n.11, even though all experts agreed that success meant improved prognoses, see Argument § II.A.
The Board erred again as a matter of law. “The decision of obviousness” must be made “from the viewpoint of a person of ordinary skill in the field of the invention.” Arkie Lures, Inc., 119 F.3d at 956. By failing
to apply the POSA’s viewpoint in resolving the reasonable expectation of
success, the Board failed to view the prior art as a POSA would have. The
Board therefore made an error of law.
III. The Board erred in finding claim 4 obvious because the prior art did not disclose treatment outcomes for DLCL patients older than 60 with bone marrow involvement.
Claim 4 recites the method of claim 1 “wherein the lymphoma is
accompanied by bone marrow involvement.” Appx56, 8:49–50. Bone
marrow involvement means cancer in the patient’s bone marrow. See
Appx53, 2:27–39. Claim 4 is not obvious for all the reasons discussed above.
See Argument §§ I–II. In addition, the prior art did not disclose treatment
outcomes for DLCL patients older than 60 with bone marrow involvement.
Maloney did not provide evidence of successful treatment outcomes.
While Maloney reported that some patients showed tumor responses in
“bone marrow,” none were DLCL patients. Appx271; see supra at 31–32.
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Maloney also did not report the ages of the patients who exhibited tumor responses in their bone marrow. Appx275–276. Because Maloney does not tell a POSA whether DLCL patients older than 60 exhibited bone marrow responses, Maloney would not have motivated a POSA to use the claimed invention to treat elderly DLCL patients with bone marrow involvement.
Coiffier did not provide evidence of successful treatment outcomes.
Only seven of the 52 patients in Coiffier had bone marrow involvement, and only three of those patients responded to treatment. Appx260. Coiffier did not report the age of the bone-marrow responders or whether they had
DLCL. Appx260. Because age and type of lymphoma are critical prognostic factors to consider, Coiffier did not provide evidence that the monoclonal antibody could successfully treat elderly DLCL patients with bone marrow involvement.
The Board’s contrary analysis ignored the critical prognostic factors of age and type of lymphoma, as well as its own claim construction. The Board claimed that “a person having ordinary skill in the art would have considered Maloney’s teaching that rituximab does not impact marrow reserves, in combination with the teachings and suggestions of Moreau,
Link, McNeil and Coiffier” to recreate claim 4. Appx32–33. But the Board
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failed to consider that the DLCL patients in Maloney did not respond to treatment. See supra at 31–32. Without evidence of efficacy for treating
DLCL patients, Maloney could not have motivated a POSA to use any combination therapy to treat elderly DLCL patients with bone marrow involvement, let alone to use all three treatments together for bone-marrow patients. Likewise, Coiffier would not have motivated a POSA to use any combination therapy to treat elderly DLCL patients because it provides no evidence that the bone-marrow responders were DLCL patients older than
60. Appx260.
Because the Board did not wrestle with the dearth of information on bone-marrow responders, the Board’s determination as to claim 4 lacks substantial evidence.
CONCLUSION
Because the Board “failed to articulate a sufficient rationale for why a skilled artisan would have sought to combine the asserted prior art” and erred in concluding that the claims of the ’873 patent are obvious, this Court should reverse. In re Magnum Oil Tools Int’l, Ltd., 829 F.3d at 1381; see also
DSS Tech. Mgmt., Inc. v. Apple Inc., 885 F.3d 1367, 1377 (Fed. Cir. 2018)
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(reversing PTAB obviousness ruling not supported by the record); Arendi,
832 F.3d at 1366–67 (same).
Dated: April 15, 2019 Respectfully Submitted,
/s/ Rachelle H. Thompson Rachelle H. Thompson MCGUIREWOODS LLP 434 Fayetteville Street Suite 2600 Raleigh, NC 27601 Telephone: (919) 775-6572 Facsimile: (919) 775-6591 [email protected]
Brian D. Schmalzbach Lyle D. Kossis MCGUIREWOODS LLP Gateway Plaza 800 East Canal Street Richmond, VA 23219 Telephone: (804) 775-4746 Facsimile: (804) 698-2304 [email protected] [email protected]
Counsel for Appellant Biogen, Inc.
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CERTIFICATE OF SERVICE
I certify that on April 15, 2019, I filed the foregoing with the Clerk of this Court using the CM/ECF System, which will send notice of such filing to all registered CM/ECF users.
/s/ Rachelle H. Thompson Rachelle H. Thompson
Counsel for Appellant Biogen, Inc.
65 Case: 19-1364 Document: 32 Page: 76 Filed: 04/15/2019
CERTIFICATE OF COMPLIANCE
This brief complies with the type-volume limitation of Federal Circuit Rule 32(a) because:
This brief contains 12,254 words, excluding the parts of the brief exempted by Appellate Rule 32(f) and Federal Circuit Rule 32(b).
This brief complies with the typeface and type style requirements of Appellate Rule 32(a)(5) because:
This brief has been prepared in a proportionally spaced 14-point Book Antiqua font using Microsoft Word.
/s/ Rachelle H. Thompson Rachelle H. Thompson
Counsel for Appellant Biogen, Inc.
66 Case: 19-1364 Document: 32 Page: 77 Filed: 04/15/2019
ADDENDUM Case: 19-1364 Document: 32 Page: 78 Filed: 04/15/2019
TABLE OF CONTENTS
Page
Final Written Decision (Paper 59) ...... Appx1
U.S. Patent No. 8,821,873 B2 ...... Appx40
Ai
Case: 19-1364 Document: 32 Page: 79 Filed: 04/15/2019 [email protected] Paper No. 59 571-272-7822 Entered: October 31, 2018
UNITED STATES PATENT AND TRADEMARK OFFICE ______
BEFORE THE PATENT TRIAL AND APPEAL BOARD ______
PFIZER, INC., Petitioner,
v.
BIOGEN, INC., Patent Owner. ______
Case IPR2017-01168 Patent 8,821,873 B2 ______
Before ERICA A. FRANKLIN, SHERIDAN K. SNEDDEN, and JACQUELINE T. HARLOW, Administrative Patent Judges.
FRANKLIN, Administrative Patent Judge.
FINAL WRITTEN DECISION 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
Appx1 Case: 19-1364 Document: 32 Page: 80 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2
I. INTRODUCTION Pfizer, Inc. (“Petitioner”) filed a Petition requesting an inter partes review of claims 1–5 of U.S. Patent No. 8,821,873 B2 (Ex. 1001, “the ’873 patent”). Paper 2 (“Pet.”). Biogen, Inc. (“Patent Owner”) did not file a Preliminary Response to the Petition. On November 6, 2017, we instituted an inter partes review of all challenged claims and consolidated Petitioner’s two grounds into one ground.1 Paper 6 (“Dec. Inst.”). On February 26, 2018, Patent Owner filed a Patent Owner Response to the Petition. Paper 24 (“PO Resp.”). On May 24, 2018, Petitioner filed a Reply to the Patent Owner Response. Paper 29 (“Reply”). Petitioner and Patent Owner each filed a Motion to Exclude Evidence. Papers 38 and 42. Each party filed an Opposition to the other party’s motion. Papers 45 and 47. Each party also filed a Reply to the other party’s Opposition. Papers 48 and 49. Patent Owner filed a Motion for Observation on Cross-Examination Testimony. Paper 41. Petitioner filed a Response to Patent Owner’s Motion for Observation. Paper 46. On July 24, 2018, the parties presented arguments at an oral hearing. The hearing transcript has been entered in the record. Paper 57 (“Tr.”).
1 The Board has determined that this consolidation of grounds satisfies the requirements of SAS Inst., Inc. v. Iancu, 138 S. Ct. 1348 (2018), and Office Guidance on the Impact of SAS on AIA Trial Proceedings (https://www.uspto.gov/patents-application-process/patent-trial-and-appeal- board/trials/guidance-impact-sas-aia-trial), as the consolidation reflects all claims and all grounds presented in the Petition. 2
Appx2 Case: 19-1364 Document: 32 Page: 81 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2
We issue this Final Written Decision pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. Having considered the record before us, we determine that Petitioner has shown by a preponderance of the evidence that claims 1–5 are unpatentable. See 35 U.S.C. § 316(e). Additionally, the Motions to Exclude Evidence by Petitioner and Patent Owner have been decided, as discussed below in Section III. A. Related Proceedings Petitioner and Patent Owner have not identified any other pending proceedings involving the ’873 patent. Pet. 7; Paper 5, 2. Petitioner filed petitions for inter parties review of claims in related U.S. Patent Nos. 8,329,172 B2 (IPR2017-01166) and 8,557,244 B1 (IPR2017-01167). Both of those petitions were denied. See IPR2017-01166, Papers 9 (denying institution); IPR2017-01167, Papers 8 (denying institution) and 12 (denying rehearing). B. The ’873 Patent The ’873 patent relates to methods for treating a patient who is greater than 60 years old and has diffuse large cell lymphoma (“DLCL”), and in one embodiment, wherein the lymphoma is accompanied by bone marrow involvement. Ex. 1001, 1:17–21. DLCL refers to an aggressive form of non-Hodgkin’s lymphoma (“NHL”). Id. at 3:1–9. The treatment comprises administering a chimeric anti-CD20 antibody, i.e., “RITUXAN® rituximab,” and CHOP (cyclophosphamide, hydroxydaunorubicin/doxo- rubicin, vincristine, and prednisone/prednisolone) chemotherapy, wherein the antibody is administered in combination with stem cell transplantation. Id. at 3:49–50; 6:8–17. Transplant regimens include autologous bone marrow transplant, allogeneic bone marrow transplant, or peripheral blood
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Appx3 Case: 19-1364 Document: 32 Page: 82 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 stem cell transplant (PBSCT). Id. at 2:34–39. According to the Specification, when there is bone marrow involvement accompanying the lymphoma, patients may benefit from prior treatment with the anti-CD20 antibody before bone marrow harvesting because doing so may decrease the quantity of tumor cells in the bone marrow or stem cell preparation. Id. at 6:8–13. C. Illustrative Claims Claims 1 and 4 are illustrative and are reproduced below: 1. A method of treating a patient with diffuse large cell lymphoma comprising administering anti-CD20 antibody and chemotherapy to the patient, wherein the patient is >60 years old, wherein the chemotherapy comprises CHOP (cyclophosphamide, hydroxydaunorubicin/doxorubicin, vin- cristine, and prednisone/prednisolone), and wherein the anti- CD20 antibody is administered to the patient in combination with stem cell transplantation regimen.
4. The method of claim 1, wherein the lymphoma is accompanied by bone marrow involvement.
D. The Instituted Ground of Unpatentability Petitioner challenges the patentability of claims 1–5 of the ’873 patent
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Appx4 Case: 19-1364 Document: 32 Page: 83 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 under 35 U.S.C. § 103(a) as obvious over Moreau, 2 Link,3 McNeil,4 Maloney,5 and Coiffier.6 Petitioner also relies upon the Declarations of Howard Ozer, M.D., Ph.D. (Ex. 1002), Scott Bennett, Ph.D. (Ex. 1016), and Dr. Robert J. Soiffer, M.D. (Ex. 1035). Patent Owner relies upon the declaration of Dr. Brad S. Kahl, M.D. (Ex. 2011). II. ANALYSIS A. Claim Construction In an inter partes review, the Board interprets claim terms in an unexpired patent according to the broadest reasonable construction in light of the specification of the patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2142 (2016) (affirming the Board’s application of the broadest reasonable construction standard in inter partes review proceedings). Under that standard, and
2 Moreau et al., Peripheral blood stem cell transplantation as front-line therapy in patients aged 61 to 65 years: a pilot study, 21 BONE MARROW TRANSPLANTATION 1193–96 (1998) (Ex. 1007). 3 Link et al., Phase II Pilot Study of the Safety and Efficacy of Rituximab in Combination with CHOP Chemotherapy in Patients with Previously Untreated Intermediate- or High-Grade NHL, Program/Proceedings, 17 AM. SOC. CLIN. ONCOL. 3a (Abstract 7) (1998) (Ex. 1005). 4 McNeil, Non-Hodgkin’s Lymphoma Trials In Elderly Look Beyond CHOP, 90 J. NAT. CANCER INST. 266–67 (1998) (Ex. 1003). 5 Maloney et al., IDEC-C2B8: Results of a Phase I Multiple-Dose Trial in Patients with Relapsed Non-Hodgkin’s Lymphoma, 15 J. Clin. Oncology 3266–3274 (1997) (Ex. 1008). 6 Coiffier et al., Rituximab (Anti-CD20 Monoclonal Antibody) for the Treatment of Patients with Relapsing or Refractory Aggressive Lymphoma: A Multicenter Phase II Study, 92 BLOOD 1927–32 (1998) (Ex. 1006). 5
Appx5 Case: 19-1364 Document: 32 Page: 84 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 absent any special definitions, we give claim terms their ordinary and customary meaning, as would be understood by one of ordinary skill in the art at the time of the invention. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007); Trivascular, Inc. v. Samuels, 812 F.3d 1056, 1062 (Fed. Cir. 2016) (“Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification and prosecution history.”). Any special definitions for claim terms must be set forth with reasonable clarity, deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Petitioner assert that the broadest reasonable interpretation of the terms of the ’873 patent is their plain and ordinary meaning. Pet. 30. In particular, Petitioner asserts that the claim term “in combination with” recited in claims 1 and 5 includes “the administration of the anti-CD20 antibody (e.g., rituximab) at the ‘induction’ of CHOP chemotherapy but before the actual collecting or transplanting of stem cells.” Id. As support, Petitioner refers to the Specification description that “rituximab can be administered at induction, in vivo purging, mobilization, conditioning, post- transplant reinfusion and at any other time during bone marrow or stem cell transplant for the purpose of improving the survival rate of transplant recipients.” Id. at 30–31 (quoting Ex. 1001, 6:13–17). Additionally, Petitioner refers to the discussion in the Specification explaining that “induction” refers to “the initial therapies aimed at achieving induction of remission,” wherein the induction typically involves “the administration of some type of chemotherapy, i.e., CHOP.” Id. at 31 (quoting Ex. 1001, 6:17– 20).
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Referring to the same Specification descriptions, Patent Owner asserts that a person of ordinary skill in the art would have understood that “the anti-CD20 antibody is administered at any time during bone marrow or stem cell transplantation, including at the listed times—or any other time—during a stem cell transplantation regimen.” PO Resp. 17–18 (citing Ex. 1001, 6:13–17 and Ex. 2011 ¶ 57). According to Patent Owner, the claim recitation of “in combination with” is not met by administering rituximab “before stem cell transplantation” because the Specification describes “rituximab treatment at the various stages of transplantation,” which a person of ordinary skill in the art would understand to mean “rituximab treatment during the transplantation regimen.” Id. at 18–19 (citing Ex. 1001, 6:54–58). In the Reply, Petitioner asserts that there is no real dispute as to the construction of the claim phrase “in combination with.” Reply 7–8. Petitioner explains that it “does not argue that claim 1 includes administration of rituximab before all phases of the entire stem cell transplantation regimen.” Id. at 8. Instead, Petitioner explains that its position is that “in combination with stem cell transplantation” includes administering rituximab in the “induction phase” of the stem cell transplantation regimen, “which indisputably is part of the stem cell transplantation regimen [and] precedes the actual stem cell transplantation, which is conducted in the harvest phase of the regimen.” Id. In other words, Petitioner asserts that induction is a phase or stage of the stem cell transplantation regimen. Having considered the evidence and arguments, we determine that, in light of the Specification, the broadest reasonable construction of the claim
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Appx7 Case: 19-1364 Document: 32 Page: 86 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 phrase directed to administering rituximab “in combination with stem cell transplantation,”7 means that the rituximab may be administered “at induction, in vivo purging, mobilization, conditioning, post-transplant reinfusion and at any other time during bone marrow or stem cell transplant for the purpose of improving the survival rate of transplant recipients,” as set forth in the Specification. Ex. 1001, 6:13–17. The Specification describes each of those “various stages of transplantation.” Id. at 6:17–63. In particular, the Specification explains that “‘[i]nduction’ is meant to refer to the initial therapies aimed at achieving induction of remission. Typically, induction involves the administration of some type of chemotherapy, i.e., CHOP.” Ex. 1001, 6:17–20. Thus, we agree with Petitioner that “the administration of the anti-CD20 antibody (e.g., rituximab) at the induction of CHOP chemotherapy but before the actual collecting or transplanting of stem cells” is encompassed in the claim phrase directed to administering rituximab “in combination with stem cell transplantation.” Indeed, Patent Owner acknowledges that “[e]ven administration of an anti-CD20 antibody at an induction stage of a stem cell transplantation regimen can fall within the scope of the claims.” PO Resp. 19. We determine that construction of additional claim terms is not necessary for purpose of this Decision. See Vivid Techs., Inc. v. Am. Sci. &
7 Independent claim 1 recites “in combination with stem cell transplantation regimen,” and independent claim 5 recites “in combination with stem cell transplantation.” The parties’ proposed constructions treat those phrases the same. We do too, as the Specification uses “stem cell transplantation” and “stem cell transplantation regimen” interchangeably, wherein both phrases refer to the “various stages of transplantation.” See, e.g., Ex. 1001, 6:13–63. 8
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Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (only terms which are in controversy need to be construed). B. Level of Ordinary Skill in the Art The level of skill in the art is a factual determination that provides a primary guarantee of objectivity in an obviousness analysis. Al-Site Corp. v. VSI Int’l Inc., 174 F.3d 1308, 1324 (Fed. Cir. 1999) (citing Graham v. John Deere Co., 383 U.S. 1, 17–18 (1966); Ryko Mfg. Co. v. Nu-Star, Inc., 950 F.2d 714, 718 (Fed. Cir. 1991)). According to Petitioner, a person of ordinary skill in the art at the time of the invention would have “include[d] a practicing oncologist with at least an M.D. degree and several years of experience treating patients with NHL and/or researching treatments for NHL, including with chemotherapeutic drugs.” Pet. 9 (citing Ex. 1002 ¶ 15). Patent Owner disagrees with Petitioner’s description of the level of ordinary skill in the art, asserting that oncologists having ordinary skill in the field of treating intermediate- and high-grade NHL “would have had experience treating patients, but would not have had experience researching new treatments for patients.” PO Resp. 16 (citing Ex. 2011 ¶ 25). According to Patent Owner and its declarant, Dr. Kahl, only a person whose skill in the art was “extraordinary” would have had “‘experience researching treatments for NHL, and those oncologists were innovators,’ not people having only ordinary skill in the art.” Id. at 15–16 (citing Ex. 2011 ¶ 24). Therefore, Patent Owner asserts that a person of ordinary skill in the art “would have on average been a practicing oncologist with at least an M.D. degree and about one to three years of experience treating patients with NHL.” Id. at 15.
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In the Reply, Petitioner explains that because the Specification describes clinical trial testing, a person of ordinary skill in the art would have had clinical research expertise. Reply 4–5. Petitioner asserts also that Dr. Ozer is qualified under either Petitioner’s or Patent Owner’s description of the level of ordinary skill in the art. Further, Petitioner asserts that Dr. Kahl does not satisfy either description, as he is a hematologist and not an oncologist. Id. at 5 (citing Ex. 1034, 27:3–5). Based upon our consideration of the arguments and evidence, we determine that the record, as a whole, supports finding that a person having ordinary skill in the art of treating NHL, including DLCL, in elderly patients, would have at least an M.D. degree, with more than one year of experience treating patients with NHL as a practicing oncologist or hematologist, and would have had familiarity with published research and clinical trials directed toward treating NHL patients. In particular, Petitioner’s declarant, Dr. Ozer, confirmed that “one to three years” of experience satisfies Petitioner’s and his description of “several years of experience.” Ex. 2008, 15:11–15. Regarding the relevant medical field, Patent Owner asserts that the person of ordinary skill in the art is a “practicing oncologist,” but offers a hematologist as its declarant. PO Resp. 15–16 (citing Ex. 2011 ¶¶ 23–24). Despite that apparent contradiction, we determine that the record as a whole supports finding that a hematologist with the requisite experience treating NHL, including DLCL, also exemplifies a person having ordinary skill in the art. Indeed, Petitioner’s description of the person having ordinary skill in the art is not limited to a practicing oncologist, as Petitioner states the person “include[s] a practicing oncologist.” Pet. 9. Further, Petitioner’s declarant, Dr. Ozer, confirmed
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Appx10 Case: 19-1364 Document: 32 Page: 89 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 that a practicing hematologist with an M.D. degree and the required experience meets his definition of a person having ordinary skill in the art. Tr. 26:3–7. Additionally, we note that the applied prior art reflects the appropriate level of skill at the time of the claimed invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001). Based upon our review of the credentials of Drs. Ozer, Soiffer, and Kahl, we consider each of them to be qualified to provide an opinion on the knowledge of a person of ordinary skill in the art at the time of the invention.8 The relative weight that we assign such testimony, however, is subject to additional factors. See, e.g., Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,763 (Aug. 14, 2012) (“Opinions expressed without disclosing the underlying facts or data may be given little or no weight.”). C. Obviousness over Moreau, Link, McNeil, Maloney, and Coiffier Petitioner asserts that claims 1–5 of the ’873 patent are unpatentable as obvious over a combination of Moreau, Link, McNeil, Maloney, and Coiffier. Pet. 42–54. Patent Owner disagrees. PO Resp. 21–61. “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.” Id. at 417.
8 Petitioner does not rely on Dr. Bennett’s testimony (Ex. 1016) to support its contentions regarding the level of ordinary skill in the art. See, e.g., Pet. 31 (referring to Ex. 1016 as support for the public accessibility of cited references). 11
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1. Moreau Moreau describes a drug trial designed to investigate the feasibility of high-dose therapy followed by autologous peripheral blood stem cell transplantation (PBSCT) as a component of front-line therapy for patients with disseminated intermediate- and high-grade NHL, aged 61–65 years. Ex. 1007, 1.9 Eight of the original fourteen patients in the study had B cell lymphoma, Working Formulation (IWF) subtype “G.” Id. at 2, Table 1. Patients with mantle-cell, lymphoblastic or diffuse small non-cleaved cell lymphomas were excluded from the analysis. Id. at 1. Initially, all fourteen patients were administered three courses of CHOP therapy. Id. The eleven patients who achieved a partial or complete response to CHOP, including seven IWF-G patients, were eligible for PBSCT after granulocyte colony- stimulating factor (G-CSF) priming. Id. After stem cell collection, and before intensive therapy, a fourth course of CHOP was administered. Id. at 2. Moreau reports that seven of the eleven transplanted patients “are alive and free from disease.” Id. at 3. “No severe cardiac, renal, hepatic or pulmonary toxicity was documented” for any of the fourteen patients. Id. Although seven of the initial fourteen patients died either before or after stem cell transplant, those deaths were due to progressive disease and not toxicity. Id. Moreau explains that its “pilot study demonstrates that PBSCT can probably be performed in patients between 61 and 65 years of age.” Id.
9 We reference exhibit page numbers added by the filing party, rather than the original page numbering therein, except for the ’873 patent (Ex. 1001). 12
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2. Link Link describes a phase II pilot study of the safety and efficacy of administering Rituxan in combination with CHOP chemotherapy to thirty- one patients with previously untreated intermediate- or high-grade NHL. Ex. 1005, 5 (Abstract 7). Patients had a median age of 49 and included those with a pathology of IWF-G (DLCL). Id. Link describes Rituxan as “rituximab, IDEC-C2B8,” a chimeric monoclonal antibody that targets the CD20 antigen expressed on normal and malignant B-cells. Id. Link reports that the study resulted in nineteen patients having a complete response, ten patients having a partial response, and one patient with progression. Id. According to Link, the study regimen “represents a tolerable therapy . . . and may offer higher response rates” than seen with conventional CHOP therapy alone. Id. 3. McNeil McNeil describes a randomized trial for elderly patients with intermediate-grade NHL involving a combination treatment of CHOP and Rituxan (IDEC-C2B8). Ex. 1003, 1. McNeil explains that the trial, organized by the Eastern Cooperative Oncology Group (“ECOG”), “will recruit 630 patients age 60 and over” to receive either CHOP alone or CHOP with Rituxan. Id. McNeil explains that researchers are focusing more on NHL in older patients because the incidence of NHL in those patients is rising and CHOP, the standard chemotherapy for intermediate-grade NHL, cures only about half as many elderly patients as younger patients. Id. McNeil describes “[o]ne more approach to NHL in the elderly involves peripheral stem cell transplants[,] an approach that is combined with low- dose chemotherapy regimens.” Id. at 2.
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4. Maloney Maloney describes a phase I multiple-dose trial using “the chimeric anti-CD20 monoclonal antibody (mAb) IDEC-C2B8,” i.e., rituximab, to treat 20 patients with relapsed low-grade or intermediate/high- grade NHL. Ex. 1008, 3, 4. Two patients had intermediate-grade NHL, with a histologic grade “G,” i.e., IWF-G. Id. at 5, Table 1. All twenty patients were scheduled to receive four weekly IV infusions of rituximab, three patients (median age 48 years) received a dose of 125 mg/m2, seven patients (median age 59 years), including one IWF-G patient, received a dose of 250 mg/m2, and ten patients (median age 59.5 years), including one IWF-G patient, received 375 mg/m2. Id. at 5. All patients required therapy due to disease progression after failing to respond to prior chemotherapy. Id. Marrow involvement was present in 50% of patients. Id. Tumor responses occurred in peripheral blood, bone marrow, spleen, bulky lymph nodes, and extranodal sites. Id. at 3. Eighteen patients were assessable for efficacy. Id. at 7. The overall clinical response rate was 33%. Id. Two of the four patients with intermediate-grade lymphoma bulky disease died two and four months following treatment due to progressive lymphoma. Id. at 8. Maloney concludes that rituximab is a “practical outpatient treatment given over a brief, 3-week course.” Id. at 8. Maloney reasons that “[s]ince this antibody does not appear to impair marrow reserves, it could possibly be used in patients who are myelosuppressed due to recent chemotherapy or following high-dose chemotherapy with ABMT [autologous bone marrow transplantation] or peripheral stem-cell rescue.” Id. at 10.
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5. Coiffier Coiffier describes a phase II study to evaluate the efficacy and tolerability of rituximab in patients with more aggressive types of lymphoma. Ex. 1006, 1. Of the 52 patients in the study, 30 had DLCL. Id. at 2 and 3, Table 3. Patients received eight weekly infusions of either a standard or higher dose of rituximab. Id. at 1, 6. Coiffier describes a dominant feature of the population of patients was “relatively old age.” Id. at 5. Specifically, 50% of the patients receiving the standard dose and 62% of patients receiving the higher dose were older than 60 years of age. Id. at 6. Coiffier explains that there were no responses observed in patients whose largest tumor was greater than 10 cm in diameter. Id. at 4. As for the results in the remaining patients, Coiffier concludes that the results of the study “indicate that rituximab therapy has significant anti-lymphoma activity in DLCL and [mantle cell lymphoma] patients without the toxicity commonly observed with combination chemotherapy regimens.” Id. at 6. 6. Analysis Independent claims 1 and 5 are directed to a method of treating a patient who has DLCL and is >60 years old by administering rituximab and CHOP, wherein rituximab is administered to the patient in combination with stem cell transplantation.10 Petitioner asserts that Moreau taught all of the
10 As discussed in the claim construction analysis above in section II. A., consistent with the parties’ proposed constructions, we treat the phrases “in combination with stem cell transplantation” and “in combination with stem cell transplantation regimen” the same, based upon their usage in the Specification as both referring to the “various stages of transplantation.” Ex. 1001, 6:13–63. 15
Appx15 Case: 19-1364 Document: 32 Page: 94 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 elements of claims 1 and 5, except for the addition of rituximab. Pet. 44. In particular, Petitioner asserts that Moreau disclosed treating patients over the age of 60 having DLCL with a reduced CHOP regimen in combination with PBSCT. Id. at 43. Petitioner asserts that seven of the eight patients over 60 with DLCL responded to the initial CHOP therapy, and that four of those eight had a complete response following PBSCT. Id. (citing Ex. 1007, 2–3, Tables 1 and 3). According to Petitioner, based on the study results, Moreau concluded that CHOP and PBSCT “can probably be performed in patients between 61 and 65 years of age.” Id. (quoting Ex. 1007, 3). Patent Owner does not dispute that Moreau taught all of the elements of claims 1 and 5, except for the addition of rituximab. See, e.g., PO Resp. 26 (acknowledging Petitioner’s assertion that Moreau taught all elements of claim 1, except administering rituximab); see also Ex. 1034, 71:19–73:10 (deposition testimony of Dr. Kahl, comparing claim 1 with Moreau). Rather, the points of contention involving Petitioner’s challenge to those claims are whether Petitioner has established by a preponderance of the evidence that a person of ordinary skill in the art would have been motivated to combine rituximab with the CHOP in Moreau’s treatment method, and whether the person of ordinary skill in the art would have had a reasonable expectation of success in treating Moreau’s patient, i.e., a DLCL patient greater than 60 years old, by doing so. Thus, we next consider the arguments and evidence relating to those issues. According to Petitioner, a person of ordinary skill in the art would have been motivated to find and combine with Moreau’s method a treatment that could have “increased efficacy, reduced toxicity, or d[one] both” because only half of Moreau’s DLCL patients achieved complete responses
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Appx16 Case: 19-1364 Document: 32 Page: 95 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 with regimen combining CHOP and PBSCT. Pet. 44. Specifically, Petitioner asserts that Link and McNeil would have provided a skilled artisan a reason to combine rituximab with Moreau’s method. Id. at 44–47; Ex. 1002 ¶¶ 88–90. Petitioner explains that Link teaches that a regimen combining CHOP and rituximab to treat intermediate- and high-grade NHL, including DLCL, provides a “tolerable therapy with serious adverse events occurring with a frequency similar to that seen with conventional CHOP therapy alone and may offer higher response rates.” Id. at 45 (quoting Ex. 1005, 5). Based upon those teachings, Petitioner asserts that an ordinarily skilled artisan would have been motivated to combine rituximab with a reduced CHOP regimen because doing so could achieve the same efficacy as CHOP monotherapy, with less toxicity, or more efficacy without adding toxicity. Id. at 45–46. Petitioner asserts that McNeil bolsters the motivation to combine the teachings of Moreau and Link to provide a therapy comprising CHOP plus rituximab, with a reasonable expectation of success. Pet. 46. Petitioner asserts that McNeil (a) explains that elderly patients have poorer outcomes with CHOP due to it being more toxic in that age group, id. (citing Ex. 1003, 1; Ex. 1002 ¶¶ 90–93), and (b) suggests that an alternative to standard CHOP therapy may be CHOP plus rituximab, id. at 46–47 (citing Ex. 1003, 1). According to Petitioner, an ordinarily skilled artisan would have reasonably expected from the combined teachings of Link and McNeil, that modifying Moreau’s CHOP regimen to include rituximab could successfully provide Moreau’s elderly patients with a more effective therapy without increasing toxicity. Id. at 47.
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Additionally, Petitioner asserts that Maloney provides a person of ordinary skill in the art with a reason to combine the teachings of Moreau and Link. Pet. 47. According to Petitioner, Maloney studied the use of rituximab in twenty patients with all grades of NHL who had relapsed after previous treatments. Id. at 22 (citing Ex. 1008, 3). Petitioner asserts that Maloney reasoned that “[s]ince [rituximab] does not appear to impair marrow reserves, it could possibly be used in patients who are myelosuppressed due to recent chemotherapy or following high-dose chemotherapy with AMBT [autologous bone marrow transplantation] or peripheral stem-cell rescue.” Id. at 47 (quoting Ex. 1008, 10). According to Petitioner, an ordinarily skilled artisan would have been motivated to add rituximab to Moreau’s method, which included patients receiving transplantation, because Maloney taught that rituximab does not negatively affect the cells needed for transplantation. Id. at 47–48. Patent Owner asserts that Petitioner failed to identify any prior art disclosure of administering rituximab to a patient during a stem cell transplantation regimen. PO Resp. 23–24. However, such an express disclosure is not required to demonstrate obviousness. Rather, “a patent claiming the combination of elements of prior art” may be shown to be obvious if “the improvement is [no] more than the predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417; see also In re Rosselet, 347 F.2d 847, 851 (CCPA 1965) (“test of obviousness is not express suggestion of the claimed invention in any or all the references but rather what the references taken collectively would suggest to those of ordinary skill in the art”). Petitioner has shown persuasively how the combined teachings of the prior art would have
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Appx18 Case: 19-1364 Document: 32 Page: 97 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 motivated a person of ordinary skill in the art to administer rituximab with CHOP in Moreau’s stem cell transplantation patients for the reasons just discussed. Petitioner has particularly shown how the teachings of Link and McNeil would have provided a person of ordinary skill in the art a reason to add rituximab to CHOP in Moreau’s method, Pet. 44–47, and has further explained how Moreau would have suggested to the artisan that rituximab would be suitable for use in a stem cell transplantation, Pet. 47 (citing Ex. 1008, 10). Patent Owner urges us to view Maloney narrowly as suggesting administration of rituximab only after stem cell transplantation or recent chemotherapy. PO Resp. 42 (citing Ex. 2011 ¶¶ 99, 144). We instead credit Drs. Ozer’s and Soiffer’s testimony that a person of ordinary skill in the art “would have understood Maloney to be suggesting the combination of rituximab with CHOP and stem cell transplantation.” Ex. 1002 ¶ 71; Ex. 1035 ¶ 28. The obviousness analysis “can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR, 550 U.S. at 418. “A person of ordinary skill is also a person of ordinary creativity, not an automaton.” Id. at 421. In particular, Dr. Soiffer explained that in Maloney, “the key teaching is that rituximab ‘does not appear to impair marrow reserves,’ further suggesting that rituximab would have been an obvious agent to test with a stem cell transplantation regimen.” Ex. 1035 ¶ 28 (citing Ex. 1008, 10). As Dr. Soiffer explained, a person of ordinary skill in the art would have realized that “Maloney’s suggestion of using rituximab following high-dose therapy was but one example of a possible application.” Id.
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Patent Owner also takes issue with Maloney because there were only two DLCL patients in the study and they did not respond to the administered rituximab dose. PO Resp. 40–42. However, Dr. Soiffer explains persuasively that a person of ordinary skill in the art would have understood that “Maloney’s teaching applies to all grades of NHL.” Ex. 1035 ¶ 28. Specifically, Dr. Soiffer states that “[a]lthough there were only two DLCL patients in that study who happened not to improve, a POSA would not have understood [Maloney’s] teaching about rituximab’s impact on marrow reserves to have been limited by this fact.” Id. Further, Dr. Soiffer explains that “DLCL patients have a significant mortality rate even with treatment, and poor results in a few patients would not have deterred a POSA from using or studying a drug in a broader patient population.” Id. Patent Owner asserts also that a person of ordinary skill in the art would not have been motivated to add rituximab to CHOP and a stem cell transplantation regimen because “no two of those therapies had been shown to be better than the individual therapies alone—even in lymphoma patients generally, let alone the claimed DLCL patients >60 years old.” PO Resp. 27. Patent Owner, however, has not provided any authority for applying such a standard for establishing a motivation to combine known elements according to their established functions, nor do we recognize such a standard. There need only be “some articulated reasoning with rational underpinnings to support the legal conclusion of obviousness.” KSR, 550 U.S. at 418 (quoting In re Kahn, 441 F.3d 977, 989 (Fed. Cir. 2006). Here, Petitioner has articulated persuasively that, as part of the combination of references, Link would have provided a reason for a person of ordinary skill in the art to administer rituximab with CHOP when treating
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DLCL in patients over 60 years of age. Pet. 44–49. Specifically, Link discloses treating thirty-one patients with previously untreated intermediate- or high-grade NHL, including twenty-one patients with IWF-G pathology, i.e., DLCL, with a combination of rituximab and CHOP. Ex. 1005, 5. Link reports that there were no deaths in the study, and that the thirty patients evaluable for response include nineteen demonstrating a complete response, ten with a partial response, and one progression. Id. According to Link, its combination of rituximab and CHOP “represents a tolerable therapy with serious adverse events occurring with a frequency similar to that seen with conventional CHOP therapy alone and may offer higher response rates.” Id. Patent Owner takes issue with Link because it did not study patients over 60. PO Resp. 32. According to Patent Owner, “a POSA would have known that age was a critical prognostic factor for NHL.” Id. In support of that contention, Patent Owner quotes McNeil’s teaching that “age—being over age 60—was the most important factor independently associated with poorer survival in patients with intermediate- and high-grade lymphoma.” Id. (quoting Ex. 1003, 1). Although treating elderly DLCL patients was not a focus of Link, as it only discloses that the median age of the patients enrolled in the study was forty-nine, Petitioner and Dr. Ozer explain credibly that a person of ordinary skill in the art would have been motivated to use Link’s combination in elderly patients because those patients were known to have a greater risk of toxicity and Link taught that the combination of rituximab and CHOP may offer higher response rates than CHOP alone with no greater frequency of serious adverse effects than encountered with CHOP alone. Pet. 45–46;
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Ex. 1002 ¶¶ 88–90. Indeed, Petitioner and Dr. Ozer rely on the teaching of McNeil cited by Patent Owner describing the criticality of age to survival in intermediate- and high-grade lymphoma. As noted by Petitioner and Dr. Ozer, McNeil also explains that “[o]ne alternative could be CHOP plus the monoclonal antibody [rituximab],” and describes a clinical trial of the combination therapy in patients age 60 and over. Ex. 1003, 1. According to Dr. Ozer, those teachings and suggestions in McNeil “would have motivated a POSA to do what McNeil suggested—namely, combine CHOP and rituximab in patients over 60 years old with intermediate grades of lymphoma.” Ex. 1002 ¶ 91. We agree. Further, Dr. Soiffer explains that “although Link did not specifically study rituximab and CHOP in patients over 60, Coiffier would have disclosed to a POSA that rituximab was safe for use with DLCL patients over 60.” Ex. 1035 ¶ 26. Of the fifty-two patients in Coiffier’s study, thirty had DLCL. Ex. 1006, 3, Table 3. Coiffier describes a dominant feature of the population of patients was “relatively old age.” Id. at 5. Coiffier concludes generally that the results of the study “indicate that rituximab therapy has significant anti-lymphoma activity in DLCL and [mantle cell lymphoma] patients without the toxicity commonly observed with combination chemotherapy regimens.” Id. at 6. Dr. Soiffer explains that “[a]lthough Coiffier did not break down the study’s results by age, a POSA would have concluded that its general findings applied to patients over 60.” Ex. 1035 ¶ 26. Indeed, Patent Owner’s declarant, Dr. Kahl, similarly concluded that “you can look at [Coiffier] and look at the toxicity profile and determine that this [rituximab] is a tolerable treatment for older patients, that’s . . . just fairly clear from the paper.” Ex. 1034, 114:21–24.
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Still further, Petitioner supports its contentions relating to a motivation to combine rituximab with CHOP in Moreau’s method by referring to the teachings of Maloney, Pet. 47–48, for the reasons discussed above, i.e., Maloney explains that rituximab “does not appear to impair marrow reserves,” Ex. 1008, 10. According to Drs. Ozer and Soiffer, “a POSA reading Maloney would have understood that rituximab could be added to CHOP in combination with PBSCT as disclosed in Moreau for treating elderly patients with DLCL.” Ex. 1002 ¶ 92; Ex. 1035 ¶ 28. Based upon our review of the record as a whole, the foregoing provides sound reasoning, supported by a preponderance of the evidence, for combining rituximab with CHOP in Moreau’s method of treating DLCL in elderly patients. Indeed, based upon the combined teachings of Moreau, Link, McNeil and Maloney, as discussed above, Petitioner has demonstrated persuasively that the modification of Moreau amounts to no more than “the predictable use of prior art elements according to their established functions.” KSR, 550 U.S. at 417. Patent Owner asserts also that a person of ordinary skill in the art would not have been motivated to add rituximab to CHOP in Moreau’s method because doing so “would have confounded the analysis of patient chemosensitivity.” PO Resp. 29. For this contention, Patent Owner asserts that “a person having ordinary skill in the art would have known that stem cell transplantation was not indicated for patients who did not have chemosensitive disease.” Id. (citing Ex. 1010, 12). Patent Owner refers also to Dr. Ozer’s deposition testimony that “it was known that a patient whose disease is refractory to chemotherapy is not a good candidate to begin a stem cell transplantation regimen.” Id. (quoting Ex. 2008, 39:7–11). Patent
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Owner and Dr. Kahl assert that physicians would administer chemotherapy to a patient shortly before starting the patient on a stem cell transplantation regimen, as Moreau did, to determine whether such chemosensitivity exists, i.e., to determine if a patient’s disease is responsive or resistant to chemotherapy. Id. at 30 (citing Ex. 2011 ¶¶ 48, 73, 123–124; Ex. 1007, 1). According to Patent Owner, “[a] POSA would have known that adding rituximab to those three doses of CHOP would have confounded that assessment,” as a response seen in a patient may be a result of rituximab and not CHOP. Id. (citing Ex. 2011 ¶ 124). Based on the record as a whole, we find that Petitioner’s declarant, Dr. Soiffer, more precisely describes the determination of a patient’s disease sensitivity during the induction stage of stem cell transplantation as concerning “treatment sensitivity” rather than specifically “chemosensitivity.” Reply 21 (citing Ex. 1035 ¶¶ 32–35). Dr. Soiffer explains persuasively that at the time of the invention there was no evidence “that a lymphoma had to previously respond to chemotherapy per se to improve the likelihood of a successful outcome with transplantation.” Ex. 1035 ¶ 35. Rather, Dr. Soiffer clarifies that “[a]ny modality that substantially decreased tumor burden could render a patient an appropriate transplant candidate.” Id. In particular, Dr. Soiffer explains that adding “rituximab to a regimen like CHOP had and still has the potential to kill more lymphoma cells, allowing patients to enter transplant with a lower burden of disease.” Id. According to Dr. Soiffer, “[t]he reduction in the burden of disease, not the specific modality to achieve that reduction, determines a patient’s prognosis with respect to transplant outcome.” Id. As Dr. Soiffer has provided a more comprehensive discussion regarding the
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Appx24 Case: 19-1364 Document: 32 Page: 103 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 determination of disease sensitivity during the induction stage of a stem cell transplant regimen, we find his testimony relating to treatment sensitivity more credible and reliable than the limited discussion provided by Dr. Kahl. See, e.g., Ex. 2011 ¶¶ 45–48, 121–123. Patent Owner raises additional arguments asserting that “Petitioner fails to establish that any of Link, McNeil, or Maloney would have motivated a POSA to add rituximab to the three doses of CHOP in Moreau.” PO Resp. 31. Patent Owner supports those contentions by identifying how each of those references, separately, differs from Moreau. See id. at 31–44. For example, Patent Owner asserts that Link would not have motivated a person having ordinary skill in the art to add rituximab to the CHOP in Moreau because Link does not disclose (a) treating patients older than 60 years of age, (b) the same number of CHOP cycles as Moreau, or (c) stem cell transplantation. Id. at 31–32. Patent Owner asserts that McNeil would not have motivated a person having ordinary skill in the art to add rituximab to CHOP in Moreau because McNeil does not suggest administering rituximab in combination with stem cell transplantation and does not report any results from the phase III trial of rituximab and CHOP that is discusses. Id. at 37. Patent Owner asserts that Maloney would not have motivated a person having ordinary skill in the art to add rituximab to CHOP in Moreau because Maloney is a study of rituximab monotherapy that does not disclose responses in DLCL patients, and “describes administration of rituximab only after the stem cell transplantation or recent chemotherapy pretreatment.” Id. at 41–42. As for Coiffier, Patent Owner asserts that the reference studied rituximab monotherapy using eight doses of rituximab on a weekly basis, did not report any responders as older than 60 years of age, and did not
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Appx25 Case: 19-1364 Document: 32 Page: 104 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 suggest any combination of rituximab with CHOP or stem cell transplantation. Id. at 44–45. Each of those arguments, however, is misdirected as they consider only Moreau and each cited reference, separately, rather than considering the combined teachings of each of the cited references together. In an obviousness analysis, the references “must be read, not in isolation, but for what [they] fairly teach[] in combination with the prior art as a whole.” In re Merck & Co, Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986); see also Intellectual Ventures I LLC v. Motorola Mobility LLC, 870 F.3d 1320, 1335 (Fed. Cir. 2017) (“Obviousness is determined based on the teachings in the prior art, and whether it would have been obvious to select and combine these teachings.”). Moreover, we have addressed above how Petitioner has shown by a preponderance of the evidence that those combined teachings would have motivated a person of ordinary skill in the art to add rituximab to Moreau’s method of treating DLCL patients over 60. Patent Owner asserts also that Link, Maloney, and Coiffier each teaches administering rituximab on a different dosing schedule than would likely be used for the CHOP in Moreau. See PO Resp. 34, 42, and 45. In particular, Patent Owner asserts that Link administers six doses of rituximab, whereas Moreau administers three doses of CHOP, id. at 34; Maloney administers four doses of rituximab weekly, and although Moreau does not disclose the cycle days for CHOP, CHOP is usually administered every 21 days, id. at 42; and Coiffier administers eight doses of rituximab on a weekly basis, id. at 45. Insofar as Patent Owner asserts that there would have been no motivation to add rituximab to Moreau’s CHOP therapy based upon the dosing used for rituximab in Link, Maloney or Coiffier, see PO Resp. 34, 42,
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Appx26 Case: 19-1364 Document: 32 Page: 105 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 and 45, we disagree. To begin, adding rituximab to Moreau’s CHOP therapy does not require administering the medications simultaneously, for the same number of doses, and/or at the same interval. Indeed, the challenged claims do not recite any requirement to do so. Rather, regarding the administration of rituximab, the claims are directed to administering rituximab “in combination with stem cell transplantation” or “in combination with stem cell transplantation regimen.” As discussed, Petitioner has shown persuasively that the preponderance of the evidence supports finding motivation to administer rituximab at the same stage of the stem cell transplantation as CHOP, without requiring the dosing schedule within that stage to be precisely the same as that of CHOP. It is the time frame, i.e., stage, during which rituximab is administered, not the dosing schedule therein, that is relevant and sufficient to meet the claim recitation of administering rituximab “in combination with” stem cell transplantation. Patent Owner asserts that “Petitioner never contended that adding rituximab to the three doses of CHOP in Moreau would have resulted in administering rituximab during a stem cell transplantation regimen.” PO Resp. 46 (emphasis added). However, as discussed above in Section II. A., we have determined that the broadest reasonable construction of the claim phrase directed to administering rituximab “in combination with stem cell transplantation,” means that the rituximab may be administered “at induction, in vivo purging, mobilization, conditioning, post-transplant reinfusion and at any other time during bone marrow or stem cell transplant for the purpose of improving the survival rate of transplant recipients,” as described in the Specification. Ex. 1001, 6:13–17. Further, we explained that the Specification describes “induction” as referring to the initial
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Appx27 Case: 19-1364 Document: 32 Page: 106 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 therapies aimed at achieving induction of remission, typically involving the administration of chemotherapy, i.e., CHOP. Id. at 6:17–20. Thus, as Petitioner asserts, “the administration of the anti-CD20 antibody (e.g., rituximab) at the ‘induction’ of CHOP chemotherapy but before the actual collecting or transplanting of stem cells” is encompassed in the claim phrase directed to administering rituximab “‘in combination with’ stem cell transplantation.” See Pet. 30. That is the precise stage at which Moreau discloses administering CHOP. See Ex. 1003, 1. Thus, combining rituximab with Moreau’s administration of CHOP at that stage meets the claim limitation requiring administration of rituximab in combination with stem cell transplantation. Patent Owner asserts that “Petitioner fails to show that a POSA would have had a reasonable expectation of success in combining Moreau, Link, McNeil, Maloney, and Coiffier to arrive at the claimed invention.” PO Resp. 47. In particular, Patent Owner asserts that “Petitioner could not reasonably contend that so long as the toxicities of the multiple therapies did not overlap, a multiple therapy regimen with no efficacy would have been considered by a POSA to be successful.” Id. at 49. Further, Patent Owner asserts that Petitioner fails to adduce evidence that a POSA would have had “a reasonable expectation of any [] improved prognosis” for patients over 60 years of age. Id. at 50. According to Patent Owner, none of the asserted prior art “reports successful treatment of DLCL patients > 60 years old with rituximab alone, much less rituximab plus CHOP.” Id. at 50. The proper inquiry regarding a reasonable expectation of success involves considering whether a person of ordinary skill in the art would have had a reasonable expectation of successfully making the claimed invention
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Appx28 Case: 19-1364 Document: 32 Page: 107 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 in light of the prior art. See Amgen, Inc. v. F. Hoffman–La Roche Ltd., 580 F.3d 1340, 1362 (Fed. Cir. 2009) (“An obviousness determination requires that a skilled artisan would have perceived a reasonable expectation of success in making the invention in light of the prior art.”); see also Intelligent Bio-Sys, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367 (Fed. Cir. 2016) (referring to the “likelihood of success in combining references to meet the limitations of the claimed invention”). “[O]bviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007). Under the proper standard, “the expectation of success need only be reasonable, not absolute.” Id. Based upon our review of the record as a whole, we find that Petitioner has established by a preponderance of the evidence that a person having ordinary skill in the art would have had a reasonable expectation of success in treating a DLCL patient over the age of 60 with a modified version of Moreau’s method that includes administering rituximab with CHOP. As previously discussed, Petitioner has established by a preponderance of the evidence that Moreau taught a method of treating patients over the age of 60 with DLCL by administering CHOP at the induction stage of the stem cell transplant, and again after stem cell collection. Ex. 1007, 1–2. Based on its pilot study, Moreau concluded that its stem cell transplantation “can probably be performed in patients between 61 and 65 years of age,” as no severe cardiac, renal, hepatic, or pulmonary toxicity was documented, and that seven of the eleven patients who underwent the transplantation stage were found to be free from disease. Id.
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Appx29 Case: 19-1364 Document: 32 Page: 108 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 at 3. In other words, Moreau disclosed a successful method of treating DLCL patients over 60 years of age that was tolerable with “no toxic deaths,” and effective because it led to complete responses in half of the DLCL patients over 60. Ex. 1007, 3 and Table 3; see Ex. 1035 ¶ 25 (explaining that Moreau’s study was successful). Petitioner demonstrated also that a person having ordinary skill in the art would have understood from the combined teachings of Link, McNeil, Maloney, and Coiffier that an alternative to CHOP in elderly patients may be CHOP plus rituximab (McNeil), that the CHOP plus rituximab combination may provide an increased response in DLCL patients (Link), that rituximab therapy has significant anti-lymphoma activity in DLCL (Coiffier), and that rituximab does not impair bone marrow reserves (Maloney). Those combined teachings serve not only as motivation for combining rituximab with Moreau’s method, as discussed above, but also serve to demonstrate why a person of ordinary skill would have had a reasonable expectation of successfully treating a 60 year old DLCL patient by doing so. Rituximab was shown to be a well-tolerated drug alone and in combination with CHOP, making it attractive for use in the elderly “who were known to have larger risk of toxicity.” Ex. 1002 ¶ 89. Further, Dr. Ozer explained that a person having ordinary skill in the art would have understood from the combined prior art, particularly Maloney, that rituximab may be used with stem cell transplantation because it was shown not to impair bone marrow reserves. Id. at ¶¶ 70–71. Thus, we agree with Petitioner that a person of skill in the art would have reasonably expected Moreau’s well-tolerated and effective method would remain so upon adding rituximab. In other words, the preponderance of the evidence suggests encouraging results from such a
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Appx30 Case: 19-1364 Document: 32 Page: 109 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 combination that would provide a person of ordinary skill in the art a reasonable expectation of success in treating elderly DLCL patients.11 Accordingly, based on the foregoing, we find that Petitioner has established by a preponderance of the evidence that a person having ordinary skill in the art (a) would have been motivated to add rituximab to the CHOP administered in Moreau’s method of treating DLCL patients over 60 years of age with CHOP and PBSCT, in a manner that yields the inventions of claims 1 and 5, and (b) would have had a reasonable expectation of successfully treating those patients with that modified method. Patent Owner does not submit or rely upon any objective evidence of nonobviousness for us to consider regarding claims 1 and 5. See Graham, 383 U.S. at 1. Therefore, we conclude that Petitioner has established by a preponderance of the evidence that claims 1 and 5 are unpatentable over the combined teachings of Moreau, Link, McNeil, Maloney, and Coiffier. Claim 2 recites “[t]he method of claim 1, wherein the antibody comprises a chimeric anti-CD20 antibody,” and claim 3 recites “[t]he method of claim 2, wherein the antibody comprises rituximab.” Petitioner asserts that those claims would have been obvious over the combined teachings of the cited art for the same reasons as discussed regarding claim 1, particularly because the antibody that Maloney suggests adding to the combination therapy is described as “rituximab,” a “chimeric anti-CD20 monoclonal antibody.” Pet. 50. We agree. Patent Owner does not
11 We note that the claims are directed to a method of “treating” DLCL patients over the age of 60, without requiring such treatment to achieve a particular result or to provide any improved result over a treatment with CHOP and/or PBSCT either alone or combined. 31
Appx31 Case: 19-1364 Document: 32 Page: 110 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 separately argue claims 2 and 3. Nor does Patent Owner submit or rely upon any objective evidence of nonobviousness for us to consider regarding claims 2 and 3. Thus, for the same reasons discussed regarding claim 1, we conclude that Petitioner has established by a preponderance of the evidence that claims 2 and 3 are unpatentable over the combined teachings of Moreau, Link, McNeil, Maloney, and Coiffier. Claim 4 recites “[t]he method of claim 1, wherein the lymphoma is accompanied by bone marrow involvement.” Petitioner asserts that claim 4 is obvious over the same combination of references as claim 1, particularly because Maloney disclosed that marrow involvement was present in 50% of the patients in its study, and reported tumor responses in bone marrow. Pet. 50 (citing Ex. 1008, 3, 5). According to Petitioner, a person of ordinary skill in the art would have understood from Maloney that “adding rituximab to CHOP therapy could successfully treat patients with cancerous cells in the bone marrow.” Id. at 51. Additionally, Petitioner relies on Dr. Ozer’s testimony that “[t]here is nothing atypical about lymphoma accompanied by bone marrow involvement, and certainly nothing that requires unique treatment.” Id. (quoting Ex. 1002 ¶ 97). Further, Petitioner asserts that “Coiffier disclosed that rituximab successfully treated 43% – nearly half – of intermediate-grade patients with bone marrow involvement.” Id. at 53 (citing Ex. 1006, 3, Table 3; Ex. 1002 ¶¶ 100–101). Patent Owner asserts that claim 4 “would not have been obvious over the Maloney reference” because “Maloney did not even report success in any DLCL patients without bone marrow involvement, let alone DLCL patients >60 years old with bone marrow involvement, as claimed.” PO Resp. 59. However, that argument misses the point as we have determined
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Appx32 Case: 19-1364 Document: 32 Page: 111 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 that the preponderance of the evidence supports Petitioner’s contention that a person having ordinary skill in the art would have considered Maloney’s teaching that rituximab does not impact marrow reserves, in combination with the teachings and suggestions of Moreau, Link, McNeil and Coiffier as providing motivation to add rituximab to Moreau’s method with a reasonable expectation of successfully treating Moreau’s DLCL patients over 60 years of age, as discussed regarding claim 1, including those having bone marrow involvement. Indeed, as Drs. Ozer, Soiffer, and Kahl acknowledge, a person of ordinary skill in the art would have not treated lymphoma patients with bone marrow involvement any differently than those without such involvement. Ex. 1002 ¶¶ 97–98; Ex. 1034, 85:9–16; Ex. 1035 ¶ 29. Patent Owner does not submit or rely upon any objective evidence of nonobviousness for us to consider regarding claim 4. Therefore, for the foregoing reasons, we conclude that Petitioner has established by a preponderance of the evidence that claim 4 is also unpatentable over the combined teachings of Moreau, Link, McNeil, Maloney, and Coiffier. III. MOTIONS TO EXCLUDE Petitioner and Patent Owner each filed a motion to exclude evidence. Papers 38 and 42.
A. Petitioner’s Motion
Petitioner moves to exclude Patent Owner’s Exhibits 2013–2015 and 2017–2019. Paper 38, 1. Patent Owner opposes the motion. Paper 47. As the moving party, Petitioner has the burden of proof to establish that it is entitled to the requested relief.
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Petitioner asserts that Patent Owner introduced Exhibits 2013–2015 and 2017–2019 for the first time during the deposition of Petitioner’s Reply declarant, Dr. Soiffer. Paper 38, 3. According to Petitioner, those exhibits were untimely submitted during Dr. Soiffer’s deposition as they were not within the scope of his direct testimony. Id.; Paper 48, 4. Patent Owner urges that Petitioner failed to adequately object to the introduction of those exhibits during Dr. Soiffer’s deposition, and that it was not improper to introduce those new exhibits at that time. Paper 47, 1. We have not relied upon those exhibits in this Final Written Decision, nor has Patent Owner referred to them or the portion of Dr. Soiffer’s deposition testimony relating to them in any subsequent filings other than its opposition to Petitioner’s motion to exclude them. Accordingly, we dismiss Petitioner’s Motion to Exclude those exhibits as moot. B. Patent Owner’s Motion Patent Owner moves to exclude Petitioner’s Exhibits 1004, 1023, 1033, 1036, 1037, 1039, and parts of Exhibit 2020. Paper 42. Petitioner opposes the motion. Paper 45. As the moving party, Patent Owner has the burden of proof to establish that it is entitled to the requested relief. Exhibit 1004 is described by Petitioner as the “RituxanTM (rituximab) labeling (Nov. 1997), i.e., the Rituxan label. Pet. vi. Patent Owner asserts that the exhibit should be excluded because it allegedly lacks authentication under Federal Rules of Evidence “FRE” 901 and represents hearsay under FRE 802. Paper 42, 8. Patent Owner asserts that Petitioner’s declarant for this matter, Dr. Bennett, at most provides testimony that Exhibit 1004 is currently available from the FDA’s website. Id. at 9. According to Patent Owner, Petitioner has not established that the exhibit existed and was
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Appx34 Case: 19-1364 Document: 32 Page: 113 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 available in 1997. Id. That issue, however, relates to the status of the exhibit as prior art and should have been raised in the briefing and not a motion to exclude. See generally Groupon Inc. v. Blue Calypso, LLC, Case CBM2013-00033, slip op. at 25 (PTAB May 12, 2013) (Paper 29) (distinguishing admissibility of evidence from sufficiency of evidence). Regarding authentication, Patent Owner asserts that Dr. Bennett testified that “Attachment 6a is a true and accurate copy of the original 1997 drug label for Rituxan available from Drugs@FDA: FDA Approved Drug Products,” but does not state the same for Exhibit 1004. Id. at 8 quoting Ex. 1016, 27–28. A side-by-side comparison of Attachment 6a and Exhibit 1004 reveals that the documents are identical copies. Compare Ex. 1016, Attachment 6a with Exhibit 1004. Thus, Patent Owner has not demonstrated that Dr. Bennett has not sufficiently authenticated Exhibit 1004. Nor are we persuaded that Exhibit 1004 constitutes hearsay as Patent Owner has not demonstrated that Petitioner offers the exhibit to prove the truth of the matter asserted in any “statement” contained therein. See FRE 801 and 802. Accordingly, we deny Patent Owner’s motion to exclude with respect to Exhibit 1004. Patent Owner also moves to exclude Exhibits 1023 (an excerpt from the Physician’s Desk Reference, 53rd ed. 1999), 1033 (a journal article discussing “A Novel Preparing Regiment for Autologous Transplant in Non- Hodgkin’s Lymphomas: Long-Term Experience with Etoposide and Thiotepa”), 1036 (a journal article discussing “CHOP Chemotherapy Plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large B Cell Lymphoma”), and 1037 (a journal article discussing a “Phase II Study of Rituximab in Combination with CHOP Chemotherapy in Patients
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Appx35 Case: 19-1364 Document: 32 Page: 114 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 with Previously Untreated, Aggressive Non-Hodgkin’s Lymphoma”) as hearsay. Paper 42, 11–12. We are unpersuaded that any of those exhibits consists of inadmissible hearsay as Patent Owner has not explained its contention adequately by merely asserting that their contents are “being offered for the purpose of attempting to prove the truth of the matter asserted in the statements.” See id. Accordingly, we deny Patent Owner’s motion to exclude with respect to Exhibits 1023, 1033, 1036, and 1037. Patent Owner asserts that its request to exclude Exhibit 1039 is contingent on the Board granting Petitioner’s motion to exclude Patent Owner’s Exhibits 2013–2015 and 2017–2019, as all of those exhibits were similarly introduced as a new exhibits during the deposition of a reply declarant. Paper 42, 7. We have dismissed Petitioner’s motion regarding Exhibits 2013–2015 and 2017–2019, and, therefore, we dismiss Patent Owner’s contingent motion to exclude with respect to Exhibit 1039 also. Exhibit 2020 is the transcript of the deposition of Petitioner’s Reply declarant, Dr. Soiffer. Patent Owner requests that we exclude the entirety of the redirect testimony contained therein. Paper 42, 1 (citing Ex. 2020, 171:7–189:11). To begin, Patent Owner asserts that the testimony is unreliable because Petitioner’s counsel allegedly coached Dr. Soiffer during the break prior to the redirect examination. Id. However, Patent Owner supports that contention only with testimony from Dr. Soiffer that he discussed the redirect with Petitioner’s counsel during the break. Id. at 2 (citing Ex. 2020, 192:6–10). According to Patent Owner, “[i]t appears, therefore, that during the break, Petitioner’s counsel identified for Dr. Soiffer what testimony he gave during cross-examination that counsel wanted to change, and then discussed how to change that testimony through
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Appx36 Case: 19-1364 Document: 32 Page: 115 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 redirect questions.” Id. We are unpersuaded, as that argument is based merely upon speculation. Next, Patent Owner asserts that the redirect testimony should be excluded because the majority of the questions asked by Petitioner’s counsel were leading. Id. at 1. For example, Patent Owner asserts that Petitioner’s counsel directed Dr. Soiffer to read the relevant portion of his declaration or an article before asking leading questions about the contents therein. Id. at 3 (citing Ex. 2020, 174:21–175:12). Patent Owner, however, has not demonstrated that Petitioner’s questions were leading. Without a better explanation from Patent Owner, our review of the cited testimony appears to involve Dr. Soiffer attempting to answer a question relating to whether an exhibit was cited in his declaration after Petitioner provided him with a copy of the declaration for his reference. See Ex. 2020, 174:21–175:12. Finally, Patent Owner asserts that the redirect testimony should be excluded because the majority of the redirect testimony was outside the scope of the cross-examination. Paper 42, 1. We disagree. Patent Owner acknowledges that during cross-examination, Patent Owner asked Dr. Soiffer, “were there any other documents you reviewed that are not cited in your declaration?” Id. at 5 (citing Ex. 2020, 17:11–14). Dr. Soiffer’s answer referenced a “Freedman manuscript from 1997.” Id. (citing Ex. 2020, 17:19–21). Patent Owner asserts that Dr. Soiffer’s redirect testimony exceeded the scope of the cross-examination because Petitioner provided Dr. Soiffer with copies of two Freedman articles, Exs. 1038 and 1039, and asked if he had cited or intended to cite those references in his declaration. Paper 42, 5–7 (citing Ex. 2020, 175:9–178:7, 185:22–188:22). Based upon our review, however, we find that Patent Owner characterizes
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Appx37 Case: 19-1364 Document: 32 Page: 116 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2 the scope of the cross-examination too narrowly. We agree with Petitioner that Patent Owner “opened the door” to testimony concerning Exhibits 1038, 1039 by asking about documents that Dr. Soiffer had reviewed in preparation of his declaration. See Paper 45, 6. Accordingly, based on the foregoing, we deny Patent Owner’s Motion to Exclude the redirect testimony contained in Exhibit 2020. IV. CONCLUSION For the foregoing reasons, we conclude that Petitioner has shown by a preponderance of the evidence that claims 1–5 of the ’873 patent are unpatentable.
ORDER Accordingly, it is hereby: ORDERED that claims 1–5 of the ’873 patent are unpatentable under 35 U.S.C. § 103(a) as obvious over Moreau, Link, McNeil, Maloney, and Coiffier; FURTHER ORDERED that Petitioner’s Motion to Exclude is dismissed as moot; FURTHER ORDERED that Patent Owner’s Motion to Exclude is denied as to Exhibits 1004, 1023, 1033, 1036, 1037, and parts of Exhibit 2020, and dismissed as moot as to Exhibit 1039; and FURTHER ORDERED that because this is a Final Written Decision, parties to the proceeding seeking judicial review of the decision must comply with the notice and service requirements of 37 C.F.R. § 90.2.
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Appx38 Case: 19-1364 Document: 32 Page: 117 Filed: 04/15/2019 IPR2017-01168 Patent 8,821,873 B2
PETITIONER:
John Scheibeler Dimitrios T. Drivas WHITE & CASE LLP [email protected] [email protected]
Jovial Wong WINSTON & STRAWN LLP [email protected]
PATENT OWNER:
Michael R. Fleming Gary N. Frischling Keith A. Orso Yite John Lu David Gindler IRELL & MANELLA LLP [email protected] [email protected] [email protected] [email protected] [email protected] Genentech/[email protected]
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Appx39 Case: 19-1364 Document: 32 Page: 118 Filed: 04/15/2019 I 1111111111111111 11111 111111111111111 11111 11111 11111 11111 111111111111111111 US008821873B2 c12) United States Patent (IO) Patent No.: US 8,821,873 B2 White et al. (45) Date of Patent: Sep.2,2014
(54) TREATMENT OF DIFFUSE LARGE-CELL 5,099,069 A 3/1992 Gansowet al. LYMPHOMA WITH ANTI-CD20 ANTIBODY 5,124,471 A 6/1992 Gansowet al. 5,145,677 A 9/1992 Von Eichhorn et al. 5,165,922 A 11/1992 Hellstrom et al. (71) Applicant: Biogen Idec Inc., Weston, MA (US) 5,225,535 A 7/1993 Defreitas et al. 5,225,539 A 7/1993 Winter (72) Inventors: Christine A. White, Rancho Santa Fe, 5,246,692 A 9/1993 Gansowet al. CA (US); Antonio J. Grillo-Lopez, 5,250,732 A 10/1993 Kogan et al. Rancho Santa Fe, CA (US) 5,286,850 A 2/1994 Gansowet al. 5,439,665 A 8/1995 Hansen et al. 5,460,785 A 10/1995 Rhodes et al. (73) Assignee: Biogen Idec Inc., Weston, MA (US) 5,500,362 A 3/1996 Robinson et al. 5,530,101 A 6/1996 Queen et al. ( *) Notice: Subject to any disclaimer, the term ofthis 5,595,721 A 1/1997 Kaminski et al. patent is extended or adjusted under 35 5,633,425 A 5/1997 Lonberg et al. U.S.C. 154(b) by O days. 5,648,267 A 7/1997 Reff 5,677,171 A 10/1997 Hudziak et al. 5,677,180 A 10/1997 Robinson et al. (21) Appl. No.: 14/045,375 5,686,072 A 11/1997 Uhr et al. 5,691,135 A 11/1997 Braun et al. (22) Filed: Oct. 3, 2013 5,691,320 A 11/1997 von Borstel et al. 5,693,780 A 12/1997 Newman et al. (65) Prior Publication Data 5,721,108 A 2/1998 Robinson et al. 5,726,023 A 3/1998 Cheever et al. US 2014/0030263 Al Jan.3O,2O14 5,736,137 A 4/1998 Anderson et al. 5,776,456 A 7/1998 Anderson et al. 5,843,398 A 12/1998 Kaminski et al. Related U.S. Application Data 5,843,439 A 12/1998 Anderson et al. 6,015,542 A 1/2000 Kaminski et al. (62) Division of application No. 09/628,187, filed on Jul. 6,090,365 A 7/2000 Kaminski et al. 28, 2000, now Pat. No. 8,557,244. (Continued) (60) Provisional application No. 60/148,286, filed on Aug. 11, 1999. FOREIGN PATENT DOCUMENTS AU 56032/94 6/1994 (51) Int. Cl. EP 0 125 023 Al 11/1984 A61K 39/395 (2006.01) EP 0 173 494 A2 5/1986 A61K 311475 (2006.01) EP 0 274 394 A2 7/1988 A61K 311675 (2006.01) EP 0 274 394 A3 1/1990 EP 0 125 023 Bl 6/1991 A61K 35/28 (2006.01) EP 0 510 949 A2 10/1992 C07K 16128 (2006.01) EP 0 682 040 Al 11/1995 A61K 311704 (2006.01) EP 0451216 Bl 1/1996 A61K 311573 (2006.01) EP 0 669 836 Bl 3/1996 C07K 14/725 (2006.01) (Continued) A61K 39/00 (2006.01) (52) U.S.Cl. OTHER PUBLICATIONS CPC ..... A61K 39/39558 (2013.01); A61K 2039/505 Arber, D.A., et al. Am. J. Surg. Pathol. 29: 1549-1557, 2005.* (2013.01); A61K 311475 (2013.01); A61K Cancer Network, "Rituximab Effective in Patients with Bulky NHL", 311675 (2013.01); C07K 2317/24 (2013.01); Feb. 1, 1999, www.cancernetwork.com/display/article/ 10165/ YJ0S 424/801 (2013.01); A61K 35/28 86193, retrieved Feb. 23, 2011. (2013.01); C07K 1612887 (2013.01); A61K 311704 (2013.01); A61K 311573 (2013.01) (Continued) USPC ...... 424/144.1; 424/130.1; 424/133.1; Primary Examiner - Ram R Shukla 424/138.1; 424/141.1; 424/143.1; 424/152.1; 424/155.1; 424/156.1; 424/172.1; 424/174.1; Assistant Examiner - Anne Holleran 424/801 (74) Attorney, Agent, or Firm - Wendy Lee; Ginger R. (58) Field of Classification Search Dreger; Arnold & Porter LLP USPC ...... 424/130.1, 133.1, 138.1, 141.1, 143.1, (57) ABSTRACT 424/144.1, 152.1, 155.1, 156.1, 172.1, 424/174.1 The present invention concerns methods for the treatment of See application file for complete search history. diffuse large cell lymphoma by administration of an anti CD20 antibody and chemotherapy. Particular embodiments (56) References Cited include the administration of anti-CD20 antibody in combi nation with chemotherapy comprising CHOP (cyclophospha U.S. PATENT DOCUMENTS mide, hydroxydaunorubicin/doxorubicin, vincristine, and 4,816,397 A 3/1989 Boss prednisone/prednisolone) and/or in combination with a trans 4,816,567 A 3/ 1989 Cabilly plantation regimen. 4,831,175 A 5/ 1989 Gansow et al. 4,975,278 A 12/1990 Senter et al. 5 Claims, No Drawings
Appx40 Case: 19-1364 Document: 32 Page: 119 Filed: 04/15/2019
US 8,821,873 B2 Page 2
(56) References Cited OTHER PUBLICATIONS
U.S. PATENT DOCUMENTS Cancer.Net,"Lymphoma-Non-Hodgkin", copyright 2005-2012, pp. 1-6; www.cancer.net/cancer-types/lymphoma-non-hodgkin/sub 6,111,166 A 8/2000 Van de Winkel types. 6,120,767 A 912000 Robinson et al. 6,183,744 Bl 2/2001 Goldenberg Clinica!Trials.gov, "Combination Chemotherapy With or Without 6,287,537 Bl 9/2001 Kaminski et al. Monoclonal Antibody Therapy in Treating Patients With Stage III or 6,306,393 Bl 10/2001 Goldenberg Stage IV Low-Grade Non-Hodgkin's Lymphoma", First Received: 6,399,061 Bl 6/2002 Anderson et al. May 2, 2000; Last updated: Feb. 26, 2013; Last verified: Feb. 26, 6,399,649 Bl 6/2002 Lerner 2013 pp. 1-4; http://clinicaltrials.gov/show/NCT00003204. 9/2002 6,455,043 Bl Grillo-Lopez Clinical Trials (PDQ®); "Phase III Randomized Study of CHOP RE38,008 E 2/2003 Abrams et al. 6,565,827 Bl 5/2003 Kaminski et al. (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) 6,652,852 Bl 11/2003 Robinson et al. With or Without Rituximab in Older Patients With Diffuse Mixed, 6,682,734 Bl 1/2004 Anderson et al. Diffuse Large, or Immunoblastic Large Cell Non-Hodgkin's 6,893,625 Bl 5/2005 Robinson et al. Lymphoma" http://www.cancer.gov/clinicaltrials/search/ 7,381,560 B2 6/2008 Anderson et al. view?cdrid~65935&version~HealthProfessional; First Published: 7,422,739 B2 9/2008 Anderson et al. Jan. 1, 1998; Last Modified: Aug. 27, 2010; Retrieved: Jan.14, 2012; 7,682,612 Bl 3/2010 White et al. pp. 1-6. 7,744,877 B2 6/2010 Anderson et al. 8,206,711 B2 6/2012 White et al. Current Therapies and Future Directions in the Treatment of Non 8,329,172 B2 12/2012 Grillo-Lopez et al. Hodgkin's Lymphoma, Classification of Lymphoma, [Retrieved on 8,557,244 Bl 10/2013 White et al. 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No. 400, 1999, "Reduced-dose ZEVALIN™ radioimmunotherapy for relapsed or * cited by examiner Appx52 Case: 19-1364 Document: 32 Page: 131 Filed: 04/15/2019 US 8,821,873 B2 1 2 TREATMENT OF DIFFUSE LARGE-CELL However, a potential disadvantage in using ONCOLYM® LYMPHOMA WITHANTI-CD20ANTIBODY IgG2a monoclonal antibody in advanced forms of non Hodgkin's lymphoma is that such lymphomas are often char CROSS REFERENCE TO RELATED acterized by bone marrow involvement. Thus, administration APPLICATIONS 5 of a radiolabeled antibody to such patients often results in unwanted myelosuppression and damage to healthy progeni This application is a divisional application of U.S. appli tor cells. cation Ser. No. 09/628,187 filed Jul. 28, 2000 now U.S. Pat. It would be advantageous if alternative therapies and other No. 8,857,244, whichclaimspriorityunder35U.S.C. Section monoclonal antibodies could be administered to patients with 119(e) and the benefit of U.S. Provisional Application Ser. 10 intermediate- and high-grade lymphomas which circumvent No. 60/148,286 filed Aug. 11, 1999, the entire disclosures of some of the deficiencies associated with current treatments which are incorporated herein by reference in their entireties. and decrease the frequency of relapse. FIELD OF THE INVENTION SUMMARY OF THE INVENTION 15 The present invention concerns the use of anti-CD20 anti The present invention concerns methods of treating inter bodies for the treatment ofintermediate- and high-grade lym mediate- and high-grade non-Hodgkin's lymphomas, and phomas, particularly those which are characterized by bone lymphomas associated with a high level of bone marrow marrow involvement and bulky disease. In particular, the involvement with anti-CD20 monoclonal antibodies and 20 present inventors have surprisingly found that rituximab, a fragments thereof. chimeric anti-CD20 antibody already approved for the treat ment oflow-grade follicular non-Hodgkin's lymphoma, may BACKGROUND OF THE INVENTION be effective to treat more aggressive lymphomas as well. Non-Hodgkin's lymphoma is characterized by the malig- 25 DETAILED DESCRIPTION OF THE INVENTION nant growth of B lymphocytes. According to the American Cancer Society, an estimated 54,000 new cases will be diag The present invention relates to methods for treating or nosed, 65% of which will be classified as intermediate- or alleviating the symptoms of intermediate- or high-grade non high-grade lymphoma. Patients diagnosed with intermediate Hodgkin's lymphoma, or other lymphomas associated with a grade lymphoma have an average survival rate of 2-5 years, 30 high degree of bone marrow involvement, comprising admin and patients diagnosed with high-grade lymphoma survive an istering to a patient a therapeutically effective amount of an average of 6 months to 2 years after diagnosis. anti-CD20 antibody or other lymphoma cell depleting anti Intermediate- and high-grade lymphomas are much more body, e.g. anti-CD19 and anti-CD22 antibodies, or a thera aggressive at the time of diagnosis than are low-grade lym peutically effective fragment thereof. The present invention phomas, where patients may survive an average of 5-7 years 35 also includes administering anti-CD20 antibodies, or other with conventional therapies. Intermediate-and high-grade lymphoma cell depleting antibodies, as part of a transplant lymphomas are often characterized by large extranodal bulky regimen (autologous bone marrow transplant or allogeneic tumors and a large number of circulating cancer cells, which bone marrow transplant or peripheral blood stem cell trans often infiltrate the bone marrow of the patient. plant) to improve the survival of transplant recipients. Conventional therapies have included chemotherapy and 40 Therapeutically effective antibody "fragments" refers to radiation, possibly accompanied by either autologous or allo any portion of or derivative of an antibody that is capable of geneic bone marrow or stem cell transplantation if a suitable delivering substantially the same therapeutic effect as the Appx53 Case: 19-1364 Document: 32 Page: 132 Filed: 04/15/2019 US 8,821,873 B2 3 4 defined in the REAL classification system may appear as both induces apoptosis in the DHL-4 human B-cell lymphoma line indolent and more aggressive forms, and depending on the in a dose-dependent manner. In humans, the half-life of the severity may be classified as an intermediate- or high-grade antibody is approximately 60 hours after the first infusion and lymphoma. increases with each dose to 174 hours after the fourth infu For instance, the U.S. National Cancer Institute (NCI) has 5 sion. The immunogenicity of the antibody is low; of 355 in tum divided some of the REAL classes into more clinically patients in seven clinical studies, only three (<1%) had a useful "indolent" or "aggressive" lymphoma designations. detectable anti-chimeric antibody (HACA) response. "Aggressive" lymphomas include diffuse mixed and large The methods of the present invention may comprise cell lymphoma, Burkitt's lymphoma/diffuse small non administration of a radiolabeled antibody which binds to a cleaved cell lymphoma, Lymphoblastic lymphoma, Mantle 10 protein on the surface of cancerous B cells. Such radio labeled cell lymphoma and AIDS-related lymphoma. These lympho antibodies are preferably administered following administra mas would therefor be considered at least "intermediate" or tion of the human, chimeric or humanized antibody, which "high-grade," and would therefor benefit from the therapeutic will decrease the amount of cancerous B cells in the bone methods of the present invention. marrow and lessen the likelihood of unwanted myeloablative While strict classifications of some lymphomas may be 15 suppression due to antibody binding to tumor cells in the difficult, the lymphomas treatable by the present invention are marrow. Moreover, while CD20 is an ideal target for the generally characterized by a high number of circulating B immunotherapy of the present invention, it is possible that cells, possible bone marrow involvement, bulky disease, or radiolabeled antibodies directed to other B cell surface anti the involvement of extralymphatic organ or sites. gens may also be used in the methods of the present invention. Often, the patients which will most benefit from the dis- 20 In particularly preferred embodiments, the radiolabeled anti closed therapeutic methods are those patients who are refrac bodies are used in conjunction with unlabeled antibodies. tory to other types of treatments, or who have relapsed fol Approximately 80% of non-Hodgkin's lymphomas are lowing other types of treatments, such as chemotherapy or B-cell-malignancies and >95% of these express the CD20 radiotherapy. However, the monoclonal antibody treatments antigen on the cell surface. This antigen is an attractive target disclosed in the present invention will be beneficial also to 25 for immunotherapy because it is found exclusively on B cells, newly diagnosed patients, and may have a synergistic effect in and not on hematopoietic stem cells, pro-B cells, normal decreasing the chance of relapse if administered in conjunc plasma cells, or other normal tissues. It is not shed from the tion with other conventional therapies. cell surface and does not modulate upon antibody binding. For instance, the methods of the present invention include The radio labeled antibodies of the present invention may methods comprising the administration of both monoclonal 30 be labeled with any alpha or beta emitting radioisotope. How antibodies ( or fragments thereof) to CD20 along with a che ever, a preferred isotope is 90Y, and a preferred antibody is motherapeutic regimen. Depending on the particular patient, Y2B8. Y2B8 was engineered from the same murine antibody, said chemotherapy may be administered simultaneously or 2B8, as was rituximab. The 2B8 antibody has also been con sequentially in either order. "Simultaneously" means either jugated to different radio labels for diagnostic and therapeutic concurrently or during the same time period such that the 35 purposes. To this end, copending application Ser. Nos. circulating half-lives of the therapeutic agents overlaps. 08/475,813, 08/475,815 and 08/478,967, herein incorporated Chemotherapeutic regimens which may be combined with by reference in their entirety, disclose radio labeled anti-CD20 the antibody treatments of the present invention include conjugates for diagnostic "imaging" of B cell lymphoma CHOP, ICE, Mitozantrone, Cytarabine, DVP, ATRA, Idaru tumors before administration of therapeutic antibody. For bicin, hoelzer chemotherapy regime, La La chemotherapy 40 instance, the "In2B8" conjugate comprises the murine mono regime,ABVD, CEOP, 2-CdA, FLAG& IDA with or without clonal antibody, 2B8, attached to Indium[ 111] (1 11 In) via a subsequent G-CSF treatment), VAD, M & P, C-Weekly, bifunctional chelator, i.e., MX-DTPA (diethylenetriamine ABCM, MOPP and DHAP. The most preferred chemothera pentaacetic acid), which comprises a 1: 1 mixture of l-isothio peutic regimen is CHOP. cyanatobenzyl-3-methyl-DTPA and l-methyl-3-isothiocy The primary anti-CD20 antibodies of the present invention 45 anatobenzyl-DTPA. Indium-[111] is selected as a diagnostic are preferably human antibodies, or chimeric or humanized radionuclide because it emits gamma radiation and finds prior antibodies which are engineered with human constant region usage as an imaging agent. domains, such that the antibodies are able to stimulate human Patents relating to chelators and chelator conjugates are effector functions. A preferred antibody to be used in the known in the art. For instance, U.S. Pat. No. 4,831,175 of methods of the present invention is RITUXAN® rituximab 50 Gansow is directed to polysubstituted diethylenetriamine (IDEC Pharmaceuticals, Inc.). pentaacetic acid chelates and protein conjugates containing Rituximab is one of a new generation of monoclonal anti the same, and methods for their preparation. U.S. Pat. Nos. bodies developed to overcome limitations encountered with 5,099,069, 5,246,692, 5,286,850, and 5,124,471 of Gansow murine antibodies, including short half-life, limited ability to also relate to polysubstituted DTPA chelates. These patents stimulate human effector functions, and immunogenicity. 55 are incorporated herein in their entirety. Rituximab is a genetically engineered monoclonal antibody The specific bifunctional chelator used to facilitate chela with murine light-and heavy-chain variable regions and tion in application Ser. Nos. 08/475,813, 08/475,815 and human gamma I heavy-chain and kappa light-chain constant 08/ 478,967 was selected as it possesses high affinity for triva regions. The chimeric antibody is composed of two heavy lent metals, and provides for increased tumor-to-non-tumor chains of 451 amino acids and two light chains of 213 amino 60 ratios, decreased bone uptake, and greater in vivo retention of acids and has an approximate molecular weight of 145 kD. radionuclide at target sites, i.e., B-cell lymphoma tumor sites. Rituximab is more effective than its murine parent in fixing However, other bifunctional chelators are known in the art complement and mediating ADCC, and it mediates CDC in and may also be beneficial in tumor therapy. the presence of human complement. The antibody inhibits Also disclosed in application Ser. Nos. 08/475,813, cell growth in the B-cell lines FL-18, Ramos, and Raji, sen- 65 08/475,815 and 08/478,967 areradiolabeled therapeutic anti sitizes chemoresistant human lymphoma cell lines to diph bodies for the targeting and destruction ofB cell lymphomas theria toxin, ricin, CDDP, doxorubicin, and etoposide, and and tumor cells. In particular, the Y2B8 conjugate comprises Appx54 Case: 19-1364 Document: 32 Page: 133 Filed: 04/15/2019 US 8,821,873 B2 5 6 the same anti-human CD20 murine monoclonal antibody, to restore the immune system to patients who have undergone 2B8, attached to yttrium-[90] (90Y) via the same bifunctional radiotherapy or chemotherapy. However, as discussed above, chelator. This radionuclide was selected for therapy for sev the patients who will benefit by the methods disclosed herein eral reasons. The 64 hour half-life of 90Y is long enough to will often have lymphoma accompanied by bone marrow allow antibody accumulation by the tumor and, unlike e.g. 5 involvement. For such patients, there are often too many 131 I, it is a pure beta emitter of high energy with no accom cancerous cells in the marrow to perform autologous trans panying gamma irradiation in its decay, with a range of 100 to plantation. 1000 cell diameters. The minimal amount of penetrating When there is bone marrow involvement accompanying radiation allows for outpatient administration of 90Y-labeled the intermediate- or high-grade lymphoma, such patients may antibodies. Furthermore, internalization oflabeled antibodies 10 benefit by prior treatment with human, chimeric or human is not required for cell killing, and the local emission of ized anti-CD20 antibody before bone marrow harvesting in ionizing radiation should be lethal for adjacent tumor cells order to decrease the quantity of tumor cells in the bone lacking the target antigen. marrow or stem cell preparation. In fact, rituximab can be Because the 90Y radionuclide was attached to the 2B8 administered at induction, in vivo purging, mobilization, con- antibody using the same bifunctional chelator molecule MX 15 ditioning, post-transplant reinfusion and at any other time DTPA, the Y288 conjugate possesses the same advantages during bone marrow or stem cell transplant for the purpose of discussed above, e.g., increased retention of radionuclide at a improving the survival rate of transplant recipients. "Induc target site (tumor). However, unlike 111In, it cannot be used tion" is meant to refer to the initial therapies aimed at achiev for imaging purposes due to the lack of gamma radiation ing induction of remission. Typically, induction involves the associated therewith. Thus, a diagnostic "imaging" radionu 20 administration of some type of chemotherapy, i.e., CHOP. clide, such as 111 In, can be used for determining the location The phrase "in vivo purging" is meant to refer to treatment and relative size of a tumor prior to and/or following admin particularly geared toward purging tumor cells from the bone istration of therapeutic chimeric or 90Y-labeled antibodies in marrow within the patient, although certainly such treatment the combined regimens of the invention. Additionally, might be beneficial for tumor cells in the peripheral blood and indium-labeled antibody enables dosimetric assessment to be 25 at other sites as well. Such a step may precede the harvest of made. bone marrow as a means of decreasing the number of tumor Depending on the intended use of the antibody, i.e., as a cells therein. Rituximab and other chimeric lymphoma cell diagnostic or therapeutic reagent, other radio labels are known depleting antibodies provide an advantage in this regard over in the art and have been used for similar purposes . For radio labeled antibodies in that they may be used to purge the instance, radionuclides which have been used in clinical diag 30 bone marrow of cancerous cells without damaging healthy nosis include 1311, 1251, 1231, 99Tc, 67Ga, as well as 111In. progenitors. Antibodies have also been labeled with a variety ofradionu "Mobilization" refers to the process by which stem cells clides for potential use in targeted immunotherapy (Peirersz are mobilized to leave the bone marrow and enter the circu et al., 1987). The use of monoclonal antibody conjugates for latory system, and provides an alternative to bone marrow the diagnosis and treatment of cancer. Immunol. Cell Biol. 35 harvest per se as a source of stem cells for transplantation. 65: 111-125). Theseradionuclides include 188Re and 186Re as Mobilization is typically achieved by administering a short well as 90Y, and to a lesser extent 199Au and 67Cu. U.S. Pat. burst of chemotherapy and/or growth factors. The growth No. 5,460,785 provides a listing of such radioisotopes and is factor G-CSF is commonly used, but others may be used herein incorporated by reference. according to the knowledge of the skilled artisan. As reported in copending application Ser. Nos. 08/475, 40 Typically, during mobilization, stem cells are separated 813, 08/475,815 and 08/478,967 administration of the radio from blood (which is then put back into the patient), and the labeled Y2B8 conjugate, as well as unlabeled chimeric anti stem cells are frozen until the patient is ready to be reinfused. CD20 antibody (rituximab ), resulted in significant tumor Ex vivo purging with rituximab, or other antibodies known in reduction in mice harboring a B cell lymphoblastic tumor. the art to be useful for this purpose, may then be used to Moreover, human clinical trials reported therein showed sig- 45 deplete tumor cells in the stem cell preparation. nificant B cell depletion in low-grade NHL lymphoma "Conditioning" refers to a process by which the patient is patients infused with rituximab. In fact, rituximab has prepared to receive the autologous bone marrow reinfusion or recently been heralded the nation's first FDA-approved anti allogeneic transplant. This is typically accomplished with a cancer monoclonal antibody. In addition, U.S. application very high dose of chemotherapy in order to deplete all bone Ser. No. 08/475,813, herein incorporated by reference, dis- 50 marrow cells, i.e., both healthy cells and tumor cells, from the closes sequential administration ofRITUXAN® (rituximab ), bone marrow. Chemotherapeutic drugs that may be given at a chimeric anti-CD20, with both or either indium-labeled or sufficiently high doses without risking the patient's life, e.g. yttrium-labeled murine monoclonal antibody for the treat cyclophosphamide, are known in the art. ment oflow-grade NHL. Although the radiolabeled antibod- Thus, with rituximab treatment at the various stages of ies used in these combined therapies are murine antibodies, 55 transplantation, marrow may be harvested prior to myeloab initial treatment with chimeric anti-CD20 sufficiently lative radiotherapy, and reintroduced subsequent to such depletes the B cell population such that the HAMA response therapy with less concern about reintroducing tumor cells is decreased, thereby facilitating a combined therapeutic and originally harvested with the marrow back into the patient. Of diagnostic regimen. Moreover, it was shown in U.S. applica course, the patient may then benefit by additional or subse tion Ser. No. 08/475,813 that a therapeutically effective dos- 60 quent treatment with chimeric anti-CD20 antibody as part of age of the yttrium-labeled anti-CD20 antibody following a maintenance regimen, or by administration of a radiola administration of rituximab is sufficient to (a) clear any beled antibody such as Y2B8 to further decrease the chance of remaining peripheral blood B cells not cleared by the chi relapse. meric anti-CD20 antibody; (b) begin B cell depletion from The methods ofthe present invention also encompass com lymph nodes; or ( c) begin B cell depletion from other tissues. 65 bined therapy comprising administration of at least one Autologous bone marrow transplantation is often a suc cytokine along with an anti-CD20 antibody or fragment cessful accompaniment to myeloablative therapy in helping thereof. Such a cytokine may be administered simultaneously Appx55 Case: 19-1364 Document: 32 Page: 134 Filed: 04/15/2019 US 8,821,873 B2 7 8 or sequentially in any order. In particular, cytokines may be 17:3a). Of30 evaluable patients, there were 19 CR (63%) and useful in upregulating the expression of CD20 on the surface 10 PR (33%), for an ORR of96%. This regimen was consid of cancerous B cells prior to administration of the anti-CD20 ered well tolerated and may result in higher response rates antibody. Cytokines useful for this purpose include IL-4, than with rituximab or CHOP alone. The NCI Division of GM-CSF and TNF-alpha, and possibly others. 5 Cancer Treatment and Diagnosis is collaborating with IDEC Cytokines may also be administered simultaneously or Pharmaceuticals Corporation to explore rituximab treat within the same time frame in order to increase or control ment in other indications. A Phase II trial of CHOP versus certain effector functions mediated by the therapeutic anti CHOP andrituximab is being conducted by ECOG, CALGB, body. Cytokines useful for this purpose include interferon and SWOG in older patients (>60 years) with mixed, diffuse alpha, G-CSF and GM-CSF, and possibly others. 10 large cell, and immunoblastic large cell histology NHL Preferred dosage regimens and exemplary embodiments (N=630 planned). This study includes a secondary random will now be illustrated by way of the following data. ization to maintenance with rituximab versus nonmainte Single-Agent Studies nance. In a study conducted in Europe and Australia, alternative A Phase III trial of rituximab and CHOP in 40 patients with dosing schedules were evaluated in 54 relapsed or refractory 15 previously untreated mantle-cell lymphoma is also ongoing intermediate- or high-grade NHL patients (Coiffier B, Haioun at the Dana Farber Institute. Rituximab is administered on C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Day 1 and CHOP is given on Days 1-3 every 21 days for 6 Feuring-Buske M, Radford J A, Capdeville R, Diehl V, Reyes cycles. Accrual for this study has been completed. A Phase II F. Rituximab (anti-CD20 monoclonal antibody) for the treat trial of CHOP followed by rituximab in newly diagnosed follicular lymphoma conducted by SWOG has also been ment of patients with relapsing or refractory aggressive lym- 20 phoma: a multicenter phase H study. Blood 1998; 92:1927- completed. Results of these two trials are being analyzed. 1932). A Phase II trial of CHOP and rituximab versus CHOP Rituximab was infused at 3 75 mg/m2 weekly for 8 doses or alone in HIV-related NHL conducted by the AIDS Malig at 375 mg/m2 once followed by 500 mg/m2 weekly for 7 nancy Consortium is ongoing; 120 patients are planned. Rituximab after Myeloablative Therapy Relapse d?ses. The ORR was 31 %; (CR 9%, PR 22%) no significant 25 difference between the dosing regimens was observed. Rituximab has shown promising early results in patients Patients with diffuse large-cell lymphoma (N=30) had an with relapsed intermediate-grade NHL after high-dose ORR of 37% and those with mantle-cell lymphoma (N=12) therapy with autologous PBSC support. Six of seven patients had an ORR of33%. responded (1 CR and 5 PR) and one patient had stable disease; Treatment of Bulky Disease 30 therapy was well tolerated (Tsai D Moore H Porter D ~ontrary to early assumptions about antibody therapy Vaughn D, Luger S, Loh R, Schu;ter' S, Stadtm;uer E. Pro~ bemg useful only in micrometastatic disease, rituximab is gressive intermediate grade non-Hodgkin's lymphoma after quite active in high bulk disease. In a separate study, 31 high dose therapy and autologous peripheral stem cell trans patients with relapsed or refractory, bulky low-grade NHL plantation (PSCT) has a high response rate to rituximab. 2 Blood 1998; 92:415a, #1713). (~ing_le lesion of>l0 cm in diameter) received 375 mg/m 35 ntux1mab as four weekly infusions. Twelve of 28 evaluable The invention claimed is: patients (43%) demonstrated a CR (1, 4%) or PR (11, 39%) 1. A method of treating a patient with diffuse large cell (Davis T, White C, Grillo-Lopez A, Velasquez W, Link B, lymphoma comprising administering anti-CD20 antibody Maloney D, Dillman R, Williams M, Mohrbacher A, Weaver and chemotherapy to the patient, wherein the patient is >60 years old, wherein the chemotherapy comprises CHOP (cy R, Dowden S, Levy R. Rituximab: First report of a Phase II 40 (PII) trial in NHL patients (pts) with bulky disease. Blood clophosphamide, hydroxydaunorubicin/doxorubicin, vinc 1998; 92 (10 Suppl 1):414a). ristine, and prednisone/prednisolone), and wherein the anti- This suggests that with the appropriate dosages depending CD20 antibody is administered to the patient in combination on the extent of disease and the number of circulating tumor with stem cell transplantation regimen. 2. The method of claim 1, wherein the antibody comprises c_ells. (i.e., such as th~ increased dosages described above), 45 ntux1mab therapy will also be useful for more aggressive a chimeric anti-CD20 antibody. i~termediate- or high-grade NHLs accompanied by bulky 3. The method of claim 2, wherein the antibody comprises disease. rituximab. Combination ofRituximab and CHOP Chemotherapy 4. The method of claim 1, wherein the lymphoma is accom- In another study, 31 patients with intermediate- or high 50 parried by bone marrow involvement. grade NHL (19 females, 12 males, median age 49) received 5. A method of treating a patient with diffuse large cell rituximab on Day 1 of each of six 21-day cycles of CHOP: lymphoma comprising administering rituximab and CHOP Link B, Grossbard M, Fisher R, Czuczman M, Gilman P, (cyclophosphamide, hydroxydaunorubicin/doxorubicin, vin Lowe A, Vose J. Phase II pilot study of the safety and efficacy cristine, and prednisone/prednisolone) to the patient, in com- of rituximab in combination with CHOP chemotherapy in 55 bination with stem cell transplantation, wherein the patient is patients with previously untreated- or high-grade NHL. Pro >60 years old. ceedings ofthe American Society ofClinical Oncology 1998; * * * * * Appx56