IPR PHARMACEUTICALS, INC., Plai

Case 1:16-cv-01336-RDM Document 43 Filed 07/05/16 Page 1 of 56

IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF COLUMBIA

ASTRAZENECA PHARMACEUTICALS LP; IPR PHARMACEUTICALS, INC.,

Plaintiffs,

SYLVIA MATHEWS BURWELL, Secretary of Health & Human Services; ROBERT CALIFF, Commissioner of Food and Drugs; FOOD AND DRUG ADMINISTRATION,

Defendants, Civ. No. 16-cv-1336 (RDM)

and

PAR PHARMACEUTICAL, INC.; APOTEX CORP.; APOTEX INC.; SANDOZ INC.; SUN PHARMA GLOBAL FZE; SUN PHARMACEUTICALS INDUSTRIES INC.,

Intervenor-Defendants.

FEDERAL DEFENDANTS’ MOTION TO DISMISS AND OPPOSITION TO PLAINTIFFS’ MOTION FOR TEMPORARY RESTRAINING ORDER Case 1:16-cv-01336-RDM Document 43 Filed 07/05/16 Page 2 of 56

TABLE OF CONTENTS

I. INTRODUCTION ...... 2 II. STATUTORY AND REGULATORY BACKGROUND ...... 6 A. New Drug Applications and Supplemental New Drug Applications ...... 6 B. Abbreviated New Drug Applications ...... 6 C. Citizen Petitions Submitted to FDA Pursuant to 21 U.S.C. § 355(q)(2)(B) ...... 7 D. Marketing Exclusivity ...... 8 E. Labeling Carve Outs ...... 9 1. Generally ...... 9 2. Otsuka Pharmaceutical Co. Ltd. v. Burwell ...... 10 III. FACTUAL BACKGROUND ...... 12 A. AstraZeneca’s NDA for Crestor ...... 12 B. AstraZeneca’s sNDA for Crestor for a Pediatric HoFH Indication ...... 13 C. FDA’s Approval of Watson Laboratories Inc.’s ANDA for Generic Crestor ...... 14 D. AstraZeneca’s Pending Citizen Petition Under 21 U.S.C. § 355(q) ...... 15 E. FDA’s Ongoing Review of ANDAs for Generic Crestor ...... 17 IV. ARGUMENT ...... 17 A. Plaintiffs’ Case Must Be Dismissed for Lack of Jurisdiction ...... 17 1. 21 U.S.C. § 355(q)(2)(B) Is a Jurisdictional Bar Mandating Dismissal of Plaintiffs’ Action ...... 18 2. AstraZeneca Lacks Standing ...... 24 3. AstraZeneca’ Claims Are Not Ripe ...... 26 a. AstraZeneca’s Claims Are Not Fit for Judicial Review Because The Issues Here Are Not Purely Legal ...... 27 b. Plaintiffs Fail to Show Hardship ...... 29 B. Plaintiffs Fail to Establish Any of the Factors Necessary for a TRO ...... 30 1. Plaintiffs Fail to Establish that they Are Likely to Succeed on the Merits ...... 31 2. AstraZeneca Fails to Establish That It Will Suffer Irreparable Injury in the Absence of Preliminary Relief ...... 34 3. The Balance of the Hardships Weighs in Favor of the Federal Defendants ...... 42 4. The Public Interest Is Not Served By Entry of a TRO ...... 43 V. CONCLUSION ...... 45 i Case 1:16-cv-01336-RDM Document 43 Filed 07/05/16 Page 3 of 56

TABLE OF AUTHORITIES

FEDERAL CASES A.L. Pharm., Inc. v. Shalala, 62 F.3d 1484 (D.C. Cir. 1995) ...... 33 Abbott Labs. v. Gardner, 387 U.S. 136 (1967) ...... 26, 27 Achagzai v. Broad. Bd. of Governors, Civil No. 14-768, 2016 WL 471274 (D.D.C. Feb. 2, 2016) ...... 37 Aetna Life Ins. Co. v. Haworth, 300 U.S. 227 (1937) ...... 17 Aktieselskabet AF 21 November 2001 v. Fame Jeans Inc., 525 F.3d 8 (D.C. Cir. 2008) ...... 18 Almurbati v. Bush, 366 F. Supp. 2d 72 (D.D.C. 2005) ...... 35 Apotex Inc. v. U.S. FDA, 508 F. Supp. 2d 78 (D.D.C. 2007) ...... 45 *Apotex, Inc. v. FDA, No. 06-0627 (JDB), 2006 WL 1030151 (D.D.C. Apr. 19, 2006) ...... 36, 37-38 Apotex, Inc. v. Sebelius, 700 F. Supp. 2d 138 (D.D.C. 2010) ...... 36, 41 Ark. Dairy Coop. v. USDA, 576 F. Supp. 2d 147 (D.D.C. 2008) ...... 43 *Astellas Pharma US, Inc. v. FDA, 642 F. Supp. 2d 10 (D.D.C. 2009) ...... 1, 31, 35, 36 *Astrazeneca Pharms. LP v. FDA, 850 F. Supp. 2d 230 (D.D.C. 2012) ...... 1, 28, 29 Avocados Plus Inc. v. Veneman, 370 F.3d 1243 (D.C. Cir. 2004) ...... 18, 19 Babbitt v. UFW Nat’l Union, 442 U.S. 289 (1979) ...... 25 *Authorities upon which we chiefly rely are marked with asterisks

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Biovail Corp. v. U.S. FDA, 448 F. Supp. 2d 154 (D.D.C. 2006) ...... 30, 36, 39 Biovail Corp. v. U.S. FDA, 519 F. Supp. 2d 39 (D.D.C. 2007) ...... 1-2 Booth v. Churner, 532 U.S. 731 (2001) ...... 19 Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493 (D.C. Cir. 1996) ...... 1, 10, 34 *Bristol-Myers Squibb Co. v. Shalala, 923 F. Supp. 212 (D.D.C. 1996) ...... passim Chevron, U.S.A., Inc. v. NRDC, Inc., 467 U.S. 837 (1984) ...... 33 Citizens to Pres. Overton Park, Inc. v. Volpe, 401 U.S. 402 (1971) ...... 44 Coalition for Common Sense in Gov’t Procurement v. United States, 576 F. Supp. 2d 162 (D.D.C. 2008) ...... 36 EEOC v. FLRA, 476 U.S. 19 (1986) ...... 19 Experience Works, Inc. v. Chao, 267 F. Supp. 2d 93 (D.D.C. 2003) ...... 35, 36-37 Fisons Corp. v. Shalala, 860 F. Supp. 859 (D.D.C. 1994) ...... 2 Fla. Audubon Soc’y v. Bentsen, 94 F.3d 658 (D.C. Cir. 1996) (en banc) ...... 25 Fla. Power & Light Co. v. EPA, 145 F.3d 1414 (D.C. Cir. 1998) ...... 29-30 FTC v. Std. Oil Co., 449 U.S. 232 (1980) ...... 28 Graceway Pharms., LLC v. Sebelius, 783 F. Supp. 2d 104 (D.D.C. 2011) ...... 1 Gulf Oil Corp. v. Dep’t of Energy, 514 F. Supp. 1019 (D.D.C. 1981) ...... 36, 42 Hall v. Johnson, 599 F. Supp. 2d 1 (D.D.C. 2009) ...... 31 iii

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*Hi-Tech Pharmacal Co. v. U.S. FDA, 587 F. Supp. 2d 1 (D.D.C. 2008) ...... 1, 29, 36 Hospira, Inc. v. Burwell, No. GJH-14-02662, 2014 WL 4406901 (D. Md. Sept. 5, 2014)) ...... 10, 34 I.A.M. Nat’l Pension Fund Benefit Plan C v. Stockton Tri Indus., 727 F.2d 1204 (D.C. Cir. 1984) ...... 19 In re Barr Labs., 930 F.2d 72 (D.C. Cir. 1991) ...... 40, 45 Int’l Bhd. of Teamsters v. Transp. Sec. Admin., 429 F.3d 1130 (D.C. Cir. 2005) ...... 24 Int’l Internships Programs v. Napolitano, 798 F. Supp. 2d 92 (D.D.C. 2011) ...... 40 Lewis v. Cont’l Bank, 494 U.S. 472 (1990) ...... 24 Lujan v. Defenders of Wildlife, 504 U.S. 555 (1992) ...... 24 Milk Indus. v. Glickman, 949 F. Supp. 882 (D.D.C. 1996) ...... 35 Mpoy v. Fenty, 674 F. Supp. 2d 163 (D.D.C. 2009) ...... 31 Munaf v. Geren, 553 U.S. 674 (2008) ...... 31 *Mylan Labs. v. Leavitt, 484 F. Supp. 2d 109 (D.D.C. 2007) ...... 36, 38, 42, 43 Mylan Pharms. v. Henney, 94 F. Supp. 2d 36 (D.D.C. 2000) ...... 42 Mylan Pharms. v. Thompson, 139 F. Supp. 2d 1 (D.D.C. 2001) ...... 36, 41 Mylan Pharms. v. U.S. FDA, 789 F. Supp. 2d 1 (D.D.C. 2011) ...... 1, 29 Mylan Pharms., Inc. v. Shalala, 81 F. Supp. 2d 30 (D.D.C. 2000) ...... 35, 37 N. Air Cargo v. U.S. Postal Serv., 756 F. Supp. 2d 116 (D.D.C. 2010) ...... 41, 42 iv

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Nw. Airlines, Inc. v. FAA, 795 F.2d 195 (D.C. Cir. 1986) ...... 25 Ohio Forestry Ass’n v. Sierra Club, 523 U.S. 726 (1998) ...... 26, 27, 30, 32 Otsuka Pharm. Co. v. Burwell, No. GJH-15-852, 2015 WL 1962240 (D. Md. Apr. 29, 2015) ...... 12 *Otsuka Pharm. Co. v. Burwell, No. GJH-15-852, 2015 WL 3442013 (D. Md. May 27, 2015) ...... passim *Pfizer Inc. v. Shalala, 182 F.3d 975 (D.C. Cir. 1999) ...... 1, 28, 29 Qwest Corp. v. FCC, 482 F.3d 471 (D.C. Cir. 2007) ...... 23 Reno v. Catholic Soc. Servs., Inc., 509U.S. 43 (1993) ...... 26 Robertson v. Cartinhour, 429 F. App’x 1 (D.C. Cir. 2011) ...... 35 *Sandoz, Inc. v. F.D.A., 439 F. Supp. 2d 26 (D.D.C. 2006) ...... 36, 38, 39 Sanofi-Aventis U.S. L.L.C. v. FDA, 733 F. Supp. 2d 162 (D.D.C. 2010) ...... 1 Schering Corp. v. FDA, 51 F.3d 390 (3d Cir. 1995) ...... 1 Schering Corp. v. Shalala, 995 F.2d 1103 (D.C. Cir. 1993) ...... 2 Schering Corp. v. Sullivan, 782 F. Supp. 645 (D.D.C. 1992) ...... 2 *Serono Labs. v. Shalala, 158 F.3d 1313 (D.C. Cir. 1998) ...... 1, 33, 34, 43, 44 *Sigma-Tau Pharms. v. Schwetz, 288 F.3d 141 (4th Cir. 2002) ...... 1, 10, 34 Sociedad Anonima Vina Santa Rita v. U.S. Dep’t of the Treasury, 193 F. Supp. 2d 6 (D.D.C. 2001) ...... 36 Somerset Pharms. v. Shalala, 973 F. Supp. 443 (D. Del. 1997) ...... 1 v

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*Spectrum Pharms., Inc. v. Burwell, ___ F.3d ___, 2016 WL 3126834 (D.C. Cir. June 3, 2016) ...... 1, 10, 34 Summers v. Earth Island Inst., 555 U.S. 488 (2009) ...... 24 Teva Pharms. USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C. Cir. 2010) ...... 28 Teva Pharm. Indus., Ltd. v. Sebelius, Civ. A. No. 14-0786 (ESH) (D.D.C. May 14, 2014) ...... 1, 29 Texas v. United States, 523 U.S. 296 (1998) ...... 17, 27, 32 United States v. Commonwealth of Puerto Rico, 764 F.Supp. 220 (D.P.R. 1991) ...... 42 United States v. Students Challenging Regulatory Agency Procedures, 412 U.S. 669 (1973) ...... 25 US Ecology, Inc. v. U.S. DOI, 231 F.3d 20 (D.C. Cir. 2000) ...... 18 Valley Forge Christian Coll. v. Americans United for Separation of Church & State, 454 U.S. 464 (1982) ...... 17 Varicon Int’l v. Office of Pers. Mgmt., 934 F. Supp. 440 (D.D.C. 1996) ...... 35 ViroPharma Inc. v. Hamburg, 471 F. App’x 1, No. 11-5143 (D.C. Cir. Mar. 21, 2012) ...... 28 ViroPharma, Inc. v. Hamburg, 777 F. Supp. 2d 140 (D.D.C. 2011) ...... 41 ViroPharma, Inc. v. Hamburg, 898 F. Supp. 2d 1 (D.D.C. 2012) ...... 41-42 Wash. Asso. for Television & Children v. FCC, 712 F.2d 677 (D.C. Cir. 1983) ...... 20 Weinberger v. Salfi, 422 U.S. 749 (1975) ...... 19, 21 Whitmore v. Arkansas, 495 U.S. 149 (1990) ...... 24 *Winter v. NRDC, Inc., 555 U.S. 7 (2008) ...... passim vi

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*Wis. Gas Co. v. Fed. Energy Regulatory Comm’n, 758 F.2d 669 (D.C. Cir. 1985) ...... 35, 40, 42

FEDERAL STATUTES 5 U.S.C. § 701 ...... 21 5 U.S.C. § 7123(c) ...... 19 21 U.S.C. § 10.25(a) ...... 21 21 U.S.C. § 355 ...... 6 21 U.S.C. § 355(a) ...... 6 21 U.S.C. § 355(b)(2) ...... 15 21 U.S.C. § 355(d) ...... 6 21 U.S.C. § 355(d)(1) ...... 6 21 U.S.C. § 355(d)(2) ...... 6 21 U.S.C. § 355(d)(5) ...... 6 21 U.S.C. § 355(j) ...... 6, 7 21 U.S.C. § 355(j)(2)(A)(iv) ...... 7 21 U.S.C. § 355(j)(2)(A)(v) ...... 9 21 U.S.C. § 355(j)(4)(F) ...... 7 21 U.S.C. § 355(j)(5)(F)(iv) ...... 8 21 U.S.C. § 355(j)(8)(B) ...... 7 21 U.S.C. § 355(q) ...... passim 21 U.S.C. § 355(q)(1)(A) ...... 7, 22, 23 21 U.S.C. § 355(q)(1)(F) ...... 8, 20, 23 21 U.S.C. § 355(q)(1)(H) ...... 7, 22 21 U.S.C. § 355(q)(1)(H) ...... 22 21 U.S.C. § 355(q)(1)(I) ...... 22 21 U.S.C. § 355(q)(2)(A) ...... 8, 20 21 U.S.C. § 355(q)(2)(B) ...... passim 21 U.S.C. § 355a(o) ...... 11, 12 21 U.S.C. § 360aa ...... 8 21 U.S.C. § 360bb ...... 8, 9 21 U.S.C. § 360cc ...... 9, 12 21 U.S.C. § 360cc(a)(2) ...... 8, 9 28 U.S.C. § 2201 ...... 21

vii

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35 U.S.C. § 156 ...... 6 35 U.S.C. § 271 ...... 6 35 U.S.C. § 282 ...... 6 42 U.S.C. § 405(h) ...... 21 47 U.S.C. § 405 ...... 20

FEDERAL REGULATIONS 21 C.F.R. § 10.25(a) ...... 7 21 C.F.R. § 10.30 ...... 7 21 C.F.R. § 10.45(b) ...... 21 21 C.F.R. § 314.70(b) ...... 6 21 C.F.R. § 314.70(b)(3)(iv) ...... 6 21 C.F.R. § 314.70(b)(3)(v) ...... 6 21 C.F.R. § 314.92(a)(1) ...... 9 21 C.F.R. § 314.94(a)(7) ...... 7 21 C.F.R. § 314.94(a)(8)(iv) ...... 9, 16, 33, 34 21 C.F.R. § 314.108(a) ...... 8 21 C.F.R. § 314.127(a)(6)(i) ...... 7 21 C.F.R. § 314.127(a)(7) ...... 9, 16, 44

HISTORY 153 Cong. Rec. S11831-01 (2007) ...... 7, 22 153 Cong. Rec. S11937-01 (2007) ...... 7, 22 U.S. Const. art. III ...... 17

viii

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This case is a transparent and manifestly premature attempt by one of the world’s largest drug companies—AstraZeneca Pharmaceuticals LP—to block generic competition. This case is not about the medical needs of a small population of pediatric patients with a rare disease. It is about AstraZeneca’s profit-driven desire to substantially extend its virtual monopoly on one of the world’s most popular medicines (Crestor) based on utter speculation about what the United

States Food and Drug Administration (“FDA”) might–or might not–do and when it might–or might not–do it. But for the recent entry of a single generic competitor (from which AstraZeneca itself is profiting), AstraZeneca has already enjoyed the right to market Crestor free of generic competition for some thirteen years. It wants to perpetuate this state of affairs for no less than

seven additional years. Speculating that FDA will, at some point, approve a number of generic

competitors, and anticipating that the agency will do so based, in part, on a statutory analysis that

AstraZeneca disagrees with, AstraZeneca brings this lawsuit as the latest in a long line of cases

in which the manufacturer of a brand name blockbuster drug product has attempted to stave off

generic competition by whatever means it can dream up.1

1 See, e.g., Spectrum Pharm., Inc. v. Burwell, ___ F.3d ____, 2016 WL 3126834, at *7 (D.C. Cir. June 3, 2016); Sigma-Tau Pharm., Inc. v. Schwetz, 288 F.3d 141, 148 (4th Cir. 2002); Pfizer Inc. v. Shalala, 182 F.3d 975, 980 (D.C. Cir. 1999); Bristol-Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1500-01 (D.C. Cir. 1996); Otsuka Pharm. Co., Ltd. v. Burwell, No. GJH-15-852, 2015 WL 3442013, at *14 (D. Md. May 27, 2015) (“Otsuka II”); Teva Pharm. Indus., Ltd. v. Sebelius, Civ. A. No. 14-0786 (ESH) (D.D.C. May 14, 2014), Dkt. No. 36; AstraZeneca Pharm. LP v. FDA, 850 F. Supp. 2d 230, 250-51 (D.D.C. 2012); Mylan Pharm. Inc. v. FDA, 789 F. Supp. 2d 1, 14 (D.D.C. 2011); see also Serono Labs., Inc. v. Shalala, 158 F.3d 1313, 1326 (D.C. Cir. 1998); Schering Corp. v. FDA, 51 F.3d 390, 399-400 (3d Cir. 1995); Graceway Pharm., Inc. v. Sebelius, 783 F. Supp. 2d 104, 117 (D.D.C. 2011); Sanofi-Aventis U.S. LLC v. FDA, 733 F. Supp. 2d 162, 176 (D.D.C. 2010); Astellas Pharma U.S., Inc. v. FDA, 642 F. Supp. 2d 10, 24 (D.D.C. 2009); Hi-Tech Pharmacal Co. Inc. v. FDA, 587 F. Supp. 2d 1, 8 (D.D.C. 2008); Biovail Corp. v. FDA, 519 F. Supp. 2d 39, 44 (D.D.C. 2007); Somerset Pharm., Inc. v. Shalala, 973 F. Supp. 443, 455 (D. Del. 1997); Bristol-Myers Squibb Co. v. Shalala, 923 F. Supp. 212, 213-14 (D.D.C. 1996); 1

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Courts in this district and elsewhere have repeatedly rejected these challenges, however,

and have routinely rebuffed bids by brand name companies to obtain pre-approval review of

anticipated FDA action on generic applications before the applications are even approved.

District courts are justifiably loathe to interfere with the agency’s consideration of a pending

drug application–much less in the face of an explicit statutory bar that precludes judicial

challenge while a petition raising the self-same issue is pending before the agency. But that is

precisely what AstraZeneca asks this Court to do. This Court should decline AstraZeneca’s

unprecedented invitation and dismiss this ill-founded and unripe challenge.

I. INTRODUCTION

Plaintiffs AstraZeneca Pharmaceuticals LP and iPR Pharmaceuticals, Inc. (collectively

“AstraZeneca” or “Plaintiffs”) seek to enjoin FDA from approving generic versions of Crestor

(rosuvastatin calcium), Plaintiffs’ blockbuster cholesterol-lowering drug. However, FDA has yet

to make a final decision on whether or not to approve generic versions of Crestor, where the

generic manufacturer does not hold a license from AstraZeneca.2 Indeed, the agency is currently

considering a special type of citizen petition filed by AstraZeneca under 21 U.S.C. § 355(q), in

which AstraZeneca argues, first, that certain scientific and factual issues prevent FDA from approving generic versions of Crestor and, second, that FDA lacks the legal authority under its statute and regulations to approve such generics.

Fisons Corp. v. Shalala, 860 F. Supp. 859, 860 (D.D.C. 1994); Schering Corp. v. Sullivan, 782 F. Supp. 645, 647 (D.D.C. 1992), vacated as moot sub nom. Schering Corp. v. Shalala, 995 F.2d 1103 (D.C. Cir. 1993).

2 AstraZeneca does not object to FDA’s approval of generic versions of Crestor where AstraZeneca has granted a license to the generic manufacturer, see infra Section III.C.

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Although Congress granted FDA only 150 days to consider petitions under 21 U.S.C.

§ 355(q), it made clear that no judicial review could be had in the meantime – that is, until either

FDA acts on the petition or the 150-day period elapses.3 Thus, Congress categorically barred the judiciary from retaining jurisdiction over a civil action that raises issues contained in a pending

§ 355(q) petition. See 21 U.S.C. § 355(q)(2)(B). Specifically, the statute states that “[i]f a civil action is filed against the Secretary with respect to any issue raised in the [§ 355(q)] petition before the Secretary has taken final agency action on the petition . . . the court shall dismiss without prejudice the action for failure to exhaust administrative remedies.” Id. (emphasis added). Because AstraZeneca’s pending § 355(q) petition was filed barely a month ago, and because the second issue raised in the petition is identical to the issue AstraZeneca raises here, this action must be dismissed pursuant to the plain language of 21 U.S.C. § 355(q)(2)(B).

In addition, even in the absence of the bar in 21 U.S.C. § 355(q)(2)(B), AstraZeneca has no injury for standing purposes and this action is patently unripe for adjudication. AstraZeneca literally asks this Court to review future FDA decisions without knowing what those decisions will be (to approve or not approve generic drug applications, and on what grounds), and without the benefit of a record of any kind. Plaintiffs can only guess as to whether FDA will grant generic approvals and speculate as to the rationale that the agency may use in reaching its decisions. It should go without saying that AstraZeneca, like any other litigant, must await an

FDA decision before it can raise a judicially reviewable claim and this Court should resist

AstraZeneca’s ill-disguised effort to manufacture jurisdiction where none exists and thwart the agency’s decision-making process on pending generic drug applications.

3 AstraZeneca submitted its § 355(q) petition on May 31, 2016, accordingly, as of the date of this filing, 115 days remain in this period.

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In an effort to avoid dismissal based on the obvious lack of ripeness, Plaintiffs incorrectly

frame the issue as a purely legal one, i.e., a question of statutory interpretation, which Plaintiffs assert the agency has already decided and which will determine the outcome of future approval of generic versions of Crestor. Plaintiffs speculate that FDA will approve generic versions of

Crestor based, in part, on the same rationale the agency adopted in approving generic versions of another drug (i.e., Abilify), in a separate case, with different parties and different facts. But that is far from clear. Plaintiffs gloss over the fact that, unlike the Abilify case, here there are important scientific and factual issues, which AstraZeneca has raised before the agency, and which FDA is in the process of evaluating. These scientific and factual issues may ultimately

result in the agency denying approval for generic versions of Crestor, thus obviating the need for

this Court to rule on Plaintiffs’ claims and making any opinion at this juncture completely

advisory. Moreover, even if FDA does approve generic versions of Crestor, these scientific and factual issues may well have a significant bearing on FDA’s rationale and statutory analysis, again, making any decision now advisory.

Even if this Court does not dismiss this action, AstraZeneca falls well short of meeting the heavy burden required for entry of a temporary restraining order (“TRO”). Indeed,

AstraZeneca has satisfied none of the factors for emergency relief.

First, Plaintiffs cannot establish that they are likely to succeed on the merits because, as noted, dismissal of this case is mandated by 21 U.S.C. § 355(q)(2)(B). In addition, Plaintiffs cannot show that they are likely to succeed on the merits simply because they hypothesize that yet-to-be-taken agency action will be arbitrary and capricious. Because AstraZeneca can only speculate if, or on what basis, FDA may approve generic versions of Crestor, it cannot demonstrate that it is likely to succeed on the merits. Furthermore, even assuming arguendo that

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the agency uses the same rationale as it did in approving generic versions of Abilify, FDA’s

decision in that case was upheld. See Otsuka Pharm. Co., Ltd. v. Burwell, No. GJH-15-852,

2015 WL 3442013, at *14 (D. Md. May 27, 2015) (“Otsuka II”). And while the decision in

Otsuka II is not binding on this Court, Judge Hazel’s decision is well reasoned and, as the only relevant precedent on point, provides a strong indicator that Plaintiffs are not likely to succeed on the merits should FDA ultimately adopt the same, or a similar, statutory construction here.

Not only does AstraZeneca have no likelihood of success on the merits, it has not

established that it will suffer certain, great, and irreparable injury in the absence of a TRO.

Whatever economic losses AstraZeneca might incur during the brief period before the case is decided on the merits would comprise a miniscule percentage of its $24.7 billion annual

revenues, and would not threaten or even seriously injure its business. Even assuming arguendo

that FDA approves generic versions of Crestor, AstraZeneca has long planned for the inevitable

introduction of generic competition, and multi-billion dollar companies of its ilk, with diversified

portfolios and worldwide distribution are more than capable of weathering such foreseeable

economic events. Tellingly, AstraZeneca does not allege that any harm it might suffer in the

absence of a TRO would threaten its business. In such circumstances, courts have routinely

found such allegations insufficient to rise to the level of irreparable harm.

Finally, the balance of harms and the public interest weigh strongly against the entry of

temporary relief because AstraZeneca’s desire to further delay generic competition does not

outweigh FDA’s interest in the thoughtful and careful exercise of its discretion in making generic

approval decisions free of premature judicial interference, or the public’s interest in low-cost

alternatives to brand name Crestor. Indeed, assuming arguendo that FDA approves generic

versions of Crestor, such approvals would inure to the benefit of the American public who would

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gain quicker access to less expensive prescription drugs. And any financial loss AstraZeneca might suffer as a result would be equaled, if not exceeded, by the financial harm to its generic competitors if approval of their marketing applications is wrongfully delayed.

II. STATUTORY AND REGULATORY BACKGROUND

A. New Drug Applications and Supplemental New Drug Applications

Under the Federal Food, Drug, and Cosmetic Act (“FDCA”), pharmaceutical companies seeking to market the initial version of a drug (also known as the “innovator” or “pioneer” drug) must first obtain FDA approval by filing a new drug application (“NDA”) containing extensive scientific data demonstrating the safety and effectiveness of the drug. 21 U.S.C. § 355(a), (d). A sponsor may thereafter submit a supplemental new drug application (“sNDA”) seeking FDA’s approval of a new indication of an already approved drug. 21 C.F.R. § 314.70(b). Drug sponsors must justify the labeling change proposed in the supplement by submitting data supporting the safety and effectiveness of the drug for the new indication. 21 U.S.C. § 355(a) and (d); 21 C.F.R. § 314.70(b)(3)(iv)-(v). FDA will refuse to approve the supplement if, inter alia, the sponsor’s investigations do not show that the drug is safe or effective for “the conditions of use prescribed, recommended, or suggested in the proposed labeling.” 21 U.S.C. § 355(d)(1),

(2), (5).

B. Abbreviated New Drug Applications

The Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-

Waxman Amendments), codified at 21 U.S.C. § 355 and 35 U.S.C. §§ 156, 271, and 282, permits a manufacturer to submit an abbreviated new drug application (“ANDA”) requesting approval of a generic version of an approved drug product. 21 U.S.C. § 355(j). ANDA applicants need not submit clinical data to demonstrate the safety and efficacy of the generic

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product, see id, rather, an ANDA relies on FDA’s previous findings that the innovator product

approved under the NDA is safe and effective. Among other information, an ANDA must

include data showing that the generic drug product is bioequivalent4 to the innovator product. 21

U.S.C. § 355(j)(2)(A)(iv), (j)(4)(F); 21 C.F.R. §§ 314.127(a)(6)(i), 314.94(a)(7).

C. Citizen Petitions Submitted to FDA Pursuant to 21 U.S.C. § 355(q)

FDA regulations permit any “interested person” to “petition the Commissioner to issue,

amend, or revoke a regulation or order, or to take or refrain from taking any other form of administrative action.” 21 C.F.R. § 10.25(a); see 21 C.F.R. § 10.30. In 2007, Congress amended the FDCA to add 21 U.S.C. § 355(q) out of concern that citizen petitions were being abused by

NDA sponsors in order to improperly delay approval of generic drugs. See 153 Cong. Rec.

S11937-01 (2007); 153 Cong. Rec. S11831-01 (2007). Section 355(q) applies to citizen petitions that are submitted when an application under 21 U.S.C. § 355(j) (i.e., an ANDA) is pending, and the petitioner requests an action that could delay approval of that application. 21 U.S.C.

§ 355(q)(1)(A). Such a petition must include a certification that, among other things, the petition also includes known information that is unfavorable to the petitioner and the date on which the information on which the petition is based first became known to the petitioner. See 21 U.S.C.

§ 355(q)(1)(H).

If a civil action is filed against the Secretary with respect to any issue raised in the petition before the Secretary has taken final agency action on the petition, “the court shall dismiss without prejudice the action for failure to exhaust administrative remedies.” 21 U.S.C.

4 Two drugs are considered bioequivalent if, in general, the rate and extent of absorption of the generic drug do not show a significant difference from the rate and extent of absorption of the listed drug. 21 U.S.C. § 355(j)(8)(B).

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§ 355(q)(2)(B) (emphasis added). By statute, FDA is required to answer petitions submitted

under 21 U.S.C. § 355(q) within 150 days and is considered to have taken final agency action on a petition if 150 days have expired and FDA has failed to make a final decision. See 21 U.S.C.

§ 355(q)(1)(F); 21 U.S.C. § 355(q)(2)(A).

D. Marketing Exclusivity

The ANDA approval timing may depend, in part, on some form of marketing exclusivity afforded to the innovator drug. For instance, pioneer drugs may be eligible for three years of exclusivity under the Hatch-Waxman Amendments (“three-year Hatch-Waxman exclusivity”) for a change approved in a sNDA if it “contains reports of new clinical investigations (other than bioavailability studies)5 essential to the approval of the supplement and conducted or sponsored

by the person submitting the supplement.” 21 U.S.C. § 355(j)(5)(F)(iv).

In addition, pioneer drugs may be eligible for seven years of exclusivity under the

Orphan Drug Act for approval of an orphan-designated indication. Congress enacted the Orphan

Drug Act (Pub. L. No. 97-414) in 1983, to provide incentives to develop drugs to treat rare

diseases and conditions. See 21 U.S.C. § 360aa et seq.6 The statute generally grants seven-year

orphan exclusivity to designated drugs for the specified indication upon its approval. 21 U.S.C.

5 FDA’s implementing regulation (21 C.F.R. § 314.108(a)) defines “new clinical investigation” as “an investigation in humans the results of which have not been relied on by FDA to demonstrate substantial evidence of effectiveness of a previously approved drug product for any indication or of safety for a new patient population and do not duplicate the results of another investigation that was relied on by the agency to demonstrate the effectiveness or safety in a new patient population of a previously approved drug product.”

6 Under 21 U.S.C. § 360bb, a rare disease or condition is defined as one that affects fewer than 200,000 people in the United States. To obtain orphan exclusivity, a sponsor must first request and obtain from FDA orphan designation for the drug for the proposed orphan indication. 21 U.S.C. § 360bb.

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§ 360cc(a)(2). Orphan exclusivity does not attach to the product as a whole, only to the

indication for which orphan designation was obtained and for which the drug was subsequently

approved. 21 U.S.C. §§ 360bb and 360cc.

E. Labeling Carve Outs

1. Generally

Although the FDCA generally mandates that generic drug labeling be “the same” as the

reference listed drug’s labeling (e.g., the pioneer’s labeling), see 21 U.S.C. § 355(j)(2)(A)(v)7,

“the same” does not mean identical. Differences are allowed due to the fact that the new ANDA drug and the “listed drug are produced or distributed by different manufacturers.” See also 21

C.F.R. §§ 314.94(a)(8)(iv), 314.92(a)(1), 314.127(a)(7). Such differences include, for example,

“differences in expiration date, formulation, bioavailability of pharmacokinetics, labeling revisions to comply with current FDA labeling guidelines or other guidance, or omission of an indication or other aspect of labeling protected by patent or accorded exclusivity under section

505(j)(5)(F) of the act.” 21 C.F.R. §§ 314.94(a)(8)(iv). Thus, ANDA applicants may “carve out” indications protected by patent or exclusivity in certain circumstances. See also 21 C.F.R.

§ 314.127(a)(7).8 In order to approve an ANDA containing proposed labeling that omits such

protected information, FDA must find that the “differences do not render the proposed drug

7 Section § 355(j)(2)(A)(v) requires that an ANDA contain “information to show that the labeling proposed for the new [generic] drug is the same as the labeling approved for the listed drug.”

8 For example, if the pioneer drug is approved for four indications, one of which is protected by patent, a generic drug produced by a different manufacturer may still be approved for the three non-protected indications. The labeling, consequently, will not be identical to the pioneer’s because it cannot include the one patent protected indication.

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product less safe or effective than the listed drug for all remaining, non-protected conditions of

use.” Id.

Courts have confirmed an ANDA applicant’s ability to carve out labeling protected by

exclusivity. See, e.g., Spectrum Pharm., Inc. v. Burwell, --- F.3d ----, 2016 WL 3126834, at *3

(D.C. Cir. June 3, 2016) (explaining that D.C. Circuit has “approved FDA’s general approach to labeling carve-outs as an acceptable interpretation of the [FDCA]” and upholding FDA’s approval of generic drug with carved out indication protected by orphan exclusivity); Bristol-

Myers Squibb Co. v. Shalala, 91 F.3d 1493, 1500 (D.C. Cir. 1996) (the FDCA “expresses the legislature’s concern that the new generic be safe and effective for each indication that will appear on its label; whether the label for the new generic lists every indication approved for use

of the pioneer is a matter of indifference”); Sigma-Tau Pharms., Inc. v. Schwetz, 288 F.3d 141,

147-48 (4th Cir. 2002) (upholding ANDA applicant’s ability to carve out an indication protected

by orphan exclusivity and noting dangers of expanding exclusivity beyond Congressional intent);

Otsuka II, 2015 WL 3442013, at *13 (upholding FDA’s carve out of a pediatric indication

protected by orphan exclusivity); cf. Hospira, Inc. v. Burwell, 2014 WL 4406901, at *17 (D. Md.

Sept. 5, 2014) (upholding FDA’s carve out of information protected by patent).

2. Otsuka Pharmaceutical Co. Ltd. v. Burwell

What Plaintiffs refer to as the “2015 Interpretation,” in actuality, represents FDA’s

determination regarding one company’s exclusivity for its drug, Abilify (aripiprazole), and

ANDA approvals for that specific drug issued by FDA on April 28, 2015, in the midst of related

litigation.

As AstraZeneca has done here, the plaintiffs in Otsuka filed suit on March 24, 2015,

before FDA made any determination regarding the approval of generic Abilify, prematurely

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seeking to block any approval. See Otsuka Dkt. No. 1. The Otsuka plaintiffs sought to block approval using the same basic argument that AstraZeneca advances in this action (and as the second argument in its § 355(q) petition), namely, that FDA lacked the authority under

§ 505A(o) of the FDCA (21 U.S.C. § 355a(o)) to carve out pediatric indications protected by orphan exclusivity and, thus, could not approve ANDAs for Abilify without running afoul of the same labeling requirements. Notably, the Otsuka plaintiffs did not make any argument akin to the first argument AstraZeneca raises in its § 355(q) petition, specifically, that carving out the particular orphan-protected pediatric indication at issue would cause a safety risk.

The Otsuka plaintiffs filed a motion for summary judgment contemporaneously with their complaint, see Otsuka Dkt. No. 2, and the government moved to dismiss on ripeness and standing grounds. See Otsuka Dkt. No. 54. The court subsequently denied as moot both plaintiffs’ motion for summary judgment and defendants’ motion to dismiss in light of the

Otsuka plaintiffs’ intention to amend their complaint and file a motion for a TRO and/or preliminary injunction. See Otsuka Dkt. No. 64.

On April 15, 2015, still before FDA had made any determination regarding the approval of generic versions of Abilify, the Otsuka plaintiffs filed an amended complaint and motion for a

TRO and/or preliminary injunction. See Otsuka Dkt. Nos. 76 & 77. The government filed an opposition to this motion renewing its jurisdictional arguments and arguing that plaintiffs failed to establish any of the factors necessary for emergency relief. See Otsuka Dkt. No. 82. The government explained that FDA had not made any decision regarding approval of generic versions of Abilify and entry of a TRO and/or preliminary injunction before such a decision would be improper. The court agreed and requested that FDA notify chambers after a decision on ANDA approval was rendered so that the court could hold a prompt hearing on plaintiffs’

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motion. On April 28, 2015, FDA issued its exclusivity decision and approved several ANDAs.

See Otsuka Pharm. Co., Ltd. v. Burwell, No. GJH-15-852, 2015 WL 1962240, at *1 (D. Md.

April 29, 2015) (“Otsuka I”). The court held a hearing that day and denied plaintiffs’ motion for

a TRO and/or preliminary injunction the following day, April 29, 2015, finding that the Otsuka

plaintiffs had failed to show any of the four required factors. Id.

Thereafter, FDA filed the administrative record underlying its decisions and the parties

submitted merits briefs. See Otsuka Dkt. Nos. 106-109, 112-114. The court held a hearing on

May 20, 2015, see Otsuka Dkt. No. 116, and issued its merits opinion on May 27, 2015. The court held that:

[T]he FDCA, its legislative history, the case law, and FDA’s regulations all support the FDA’s construction of the statute that allows it to carve out an indication or other information from ANDA labeling when that indication or information is protected by orphan drug exclusivity as long as the ANDA with that carved out label remains safe and effective for the remaining non-protected conditions of use. To be sure, Otsuka’s reading of section 355a(o) would nullify the limitation expressly written into section 360cc—that the exclusivity is given to a drug “for [the orphan] disease or condition”—and instead treat the orphan drug exclusivity as extending to the drug for any and all diseases and conditions, directly contradicting that provision’s text and the Fourth Circuit’s holding in Sigma–Tau. If that was Congress’s intent, it is certainly left unclear by the statute and FDA’s interpretation is reasonable.

See Otsuka II, 2015 WL 3442013, at *14.

III. FACTUAL BACKGROUND

A. AstraZeneca’s NDA for Crestor

AstraZeneca holds an NDA (No. 21366) for various strengths (i.e., 5, 10, 20, and 40 milligrams (mg)) of rosuvastatin calcium tablets, which the company markets under the proprietary name Crestor.9 Crestor is a synthetic lipid and cholesterol lowering drug for oral

9 See drugs@fda, available at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm (search for “Crestor”) (last accessed July 3, 2016).

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administration first approved on August 12, 2003.10 Eight specific indications currently appear

in Crestor’s FDA-approved labeling.11

B. AstraZeneca’s sNDA for Crestor for a Pediatric HoFH Indication

On July 27, 2015, AstraZeneca filed a sNDA for Crestor for a new indication, treatment

of pediatric patients 7 to 17 years of age with homozygous familial hypercholesterolemia

(“HoFH”), an inherited condition in which the body is unable to remove LDL-C (“bad cholesterol”) from the blood. Although AstraZeneca requested priority review of its sNDA,

FDA placed the sNDA on the standard review track because it did not meet the requirements for

priority review.12 FDA approved AstraZeneca’s sNDA for the pediatric HoFH indication on

May 27, 2016. AstraZeneca received a seven year orphan drug exclusivity period with respect to

this pediatric HoFH indication, which will run until May 27, 2023.13

10 Id.

11 Id.

12 Priority review provides an expedited goal date for completion of FDA’s review of an application, but does not require completion by that date if additional time is needed for a thorough review. See Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (May 2014) (“Expedited Programs Guidance”) at 24, available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM358301.pdf (last visited July 3, 2016). AstraZeneca did not qualify for priority review that applies to pediatric studies submitted under section 505A because its pediatric HoFH studies were not submitted pursuant to a Written Request under section 505A. See 21 U.S.C. § 355a(i)(1).

13 The Orange Book also lists three-year Hatch Waxman exclusivity for AstraZeneca’s Crestor, 20 mg, expiring on May 27, 2019. See Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) (listing for “Crestor”) http://www.accessdata.fda.gov/scripts/ cder/ob/docs/patexclnew.cfm?Appl_No=021366&Product_No=004&table1=OB_Rx (last accessed July 3, 2016). AstraZeneca has challenged the attachment of that exclusivity to Crestor and the agency is currently reviewing the issue.

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C. FDA’s Approval of Watson Laboratories Inc.’s ANDA for Generic Crestor

Crestor was marketed without generic competition for over a decade, until April 29,

2016, when, with AstraZeneca’s permission, FDA granted final approval to Watson Laboratories

Inc.’s (“Watson’s”) ANDA No. 79167.14 Watson began marketing its version of generic Crestor on May 2, 2016, and continues to do so. Watson was able to receive final approval for its generic version of Crestor because, as part of a 2013 patent litigation settlement, AstraZeneca granted Watson a license to market its generic version of Crestor and receives 39 percent of its net sales until July 8, 2016. Accordingly, AstraZeneca does not object to generic competition from Watson. AstraZeneca also provided Watson with a selective waiver of all periods of exclusivity applicable to the pediatric HoFH indication; thus, the labeling for Watson’s generic

Crestor may include the pediatric HoFH information without objection from AstraZeneca.

Watson’s entry into the market on May 2, 2016, triggered the 180-day exclusivity period that may be awarded to ANDA applicants who are the first to submit a substantially complete

ANDA, provided that the applications meet certain other criteria.15 This 180-day exclusivity period allows eligible first applicants to market before other subsequent ANDA applicants. As noted in Watson’s approval letter, at least one other first applicant remains eligible for 180-day exclusivity, although such applicant or applicants will receive only the portion of the 180-day exclusivity period that remains at the time of their approval or approvals.

14 See Approval Letter for Watson’s ANDA 079167, available at http://www.accessdata.fda.gov/ drugsatfda_docs/appletter/2016/079167Orig1s000ltr.pdf (last accessed July 3, 2016).

15 Multiple applicants can qualify as first applicants and be eligible for 180-day exclusivity provided that each meets the necessary criteria.

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D. AstraZeneca’s Pending Citizen Petition Under 21 U.S.C. § 355(q)

On May 31, 2016, AstraZeneca submitted a citizen petition to FDA under 21 U.S.C.

§ 355(q), raising the argument that FDA cannot approve generic versions of Crestor for any

indication, including those without any remaining patent or exclusivity protection, until the

expiration of AstraZeneca’s seven-year orphan exclusivity period for its pediatric HoFH

indication.16 Pls.’ Appl. for TRO, Ex. E at 1. AstraZeneca’s seven-year orphan exclusivity

period runs from the date of approval for the pediatric HoFH indication, May 27, 2016, meaning

that, under AstraZeneca’s analysis, additional generic competitors would not be able to obtain approval for any indication until, at the earliest, May 27, 2023. Id.

AstraZeneca advances two principle arguments in its § 355(q) petition. Although only cursorily mentioned in AstraZeneca’s pleadings, the first argument in AstraZeneca’s § 355(q) petition is that carving out the pediatric HoFH indication from a generic’s labeling would present substantial safety and efficacy risks. Id. at 1, 11-17. AstraZeneca stated that “[a]lthough FDA may in some instances approve ANDAs that omit protected pediatric labeling, FDA has made clear that a carve out is inappropriate when, as here, the protected pediatric labeling is ‘necessary for the safe use of the drug.’” Id. at 1-2 (citation omitted). AstraZeneca contends that because

Crestor’s label contains both an indication for adult HoFH patients, as well as the pediatric

HoFH indication, id. at 2, and because Crestor also is labeled for treatment of heterozygous familial hypercholesterolemia (“HeFH”), a related but less severe condition, id., there are risks that doctors would over- or under-treat pediatric HoFH patients if generic versions of Crestor

16 AstraZeneca’s 21 U.S.C. § 355(q) petition also argued FDA could not approve any application submitted under 21 U.S.C. § 355(b)(2) (another type of abbreviated application referencing an innovator product). That argument is not at issue in this lawsuit.

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omitted AstraZeneca’s protected pediatric HoFH labeling. Id. AstraZeneca provides scientific

background on Crestor, HoFH, and the development of Crestor for the pediatric HoFH indication, id. at 3-9, as well as several examples of how it believes that carving out the pediatric

HoFH indication would potentially lead to over- or under-treatment and information on why any

such risk could not be cured by a general disclaimer. Id. at 13-15.

The agency is currently using its scientific and technical expertise to evaluate the merits

of the safety issues AstraZeneca has raised because those issues could be dispositive. Should

FDA agree with AstraZeneca’s safety argument, no further generic versions of Crestor would

receive approval and there would be no need for the agency and, correspondingly, this Court, see infra Section IV.A.2 & 3, to decide the statutory interpretation arguments.

AstraZeneca’s petition raises a second argument, however, which is the only argument

AstraZeneca brings before this Court, namely, that FDA cannot approve generics here because the agency lacks the legal authority to carve out pediatric labeling protected by orphan drug exclusivity. Id. at 2, 17-26. Specifically, AstraZeneca argues that the Hatch-Waxman Act’s same-labeling requirement and FDA’s pediatric-labeling regulations combine to bar the agency from carving out pediatric labeling information protected by orphan drug exclusivity from generic-drug labeling. Id. at 2, 17-19. AstraZeneca also argues that § 505A(o) cannot provide a basis for carving out labeling protected by orphan drug exclusivity because it only permits the carve out of labeling protected by patent and Hatch-Waxman exclusivity, see id. at 2, 19-20, and, although AstraZeneca acknowledges that FDA possesses general carve out authority at 21 C.F.R.

§§ 314.94(a)(8)(iv), 314.127(a)(7), it argues that those regulations cannot provide a basis for a carve out because of FDA’s subsequently adopted pediatric-labeling rules and § 505A(o). Id. at

2, 20-26. As it does in this lawsuit, AstraZeneca acknowledges in its petition that the United

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States District Court for the District of Maryland concluded in the Otsuka litigation that FDA has authority to carve out pediatric labeling protected by orphan drug exclusivity; however,

AstraZeneca contends that the court’s conclusion was incorrect. Id. at 2, 26.

E. FDA’s Ongoing Review of ANDAs for Generic Crestor

Aside from granting final approval for Watson’s ANDA, see supra Section III.C, FDA has not approved any other generic version of Crestor and, as of the date of this submission, has made no final determination with respect to whether or when it will, or will not, approve any further generic versions. Nor, as of this date, has FDA made any final determinations regarding whether or not exclusivities that AstraZeneca holds, including orphan drug exclusivity, preclude approval of generic versions of Crestor.

IV. ARGUMENT

A. Plaintiffs’ Case Must Be Dismissed for Lack of Jurisdiction

The federal judicial power is limited by Article III of the Constitution to the resolution of

“cases” and “controversies.” See, e.g., Valley Forge Christian Coll. v. Ams. United for

Separation of Church and State, Inc., 454 U.S. 464, 471 (1982). To invoke federal court jurisdiction, a party must establish the existence of a “justiciable controversy” with the adverse party – one that is “definite and concrete, touching the legal relations of parties having adverse legal interests.” Aetna Life Ins. Co. v. Haworth, 300 U.S. 227, 240-41 (1937).

A plaintiff must also establish that its claim is ripe. “A claim is not ripe for adjudication if it rests upon ‘contingent future events that may not occur as anticipated, or indeed may not occur at all.’” Texas v. United States, 523 U.S. 296, 300 (1998) (citations omitted). The party seeking to invoke the jurisdiction of a federal court bears the burden of establishing that the court has jurisdiction. U.S. Ecology, Inc. v. U.S. Dep’t of Interior, 231 F.3d 20, 24 (D.C. Cir. 2000).

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1. 21 U.S.C. § 355(q)(2)(B) Is a Jurisdictional Bar Mandating Dismissal of Plaintiffs’ Action

Plaintiffs’ action must be dismissed pursuant to the unambiguous language of 21 U.S.C.

§ 355(q)(2)(B), which mandates that:

If a civil action is filed against the Secretary with respect to any issue raised in the petition before the Secretary has taken final action on the petition within the meaning of subparagraph (A), the court shall dismiss without prejudice the action for failure to exhaust administrative remedies.

Id. (emphasis added). AstraZeneca’s § 355(q) petition squarely raises the statutory interpretation

at issue in this action, which the company does not deny. Compare Pls.’ Appl. for TRO, Ex. E at

2, 17-26, with Compl. generally & Pls.’ Mem. at 26-38. As noted, FDA has yet to take any

action with respect to AstraZeneca’s pending § 355(q) petition.17

21 U.S.C. § 355(q)(2)(B) is a jurisdictional exhaustion requirement, which courts do not

have the power to excuse. See Avocados Plus Inc. v. Veneman, 370 F.3d 1243, 1247 (D.C. Cir.

2004) (“If the statute does mandate exhaustion, a court cannot excuse it.”). As the D.C. Circuit

explained, there are two distinct legal concepts that go by the name “exhaustion.” Id. The first type of exhaustion “is a judicially created doctrine requiring parties who seek to challenge

agency action to exhaust available administrative remedies before bringing their case to court,”

referred to as “non-jurisdictional exhaustion,” which, courts may, in their discretion, excuse in

17 AstraZeneca blames FDA for the fact that its § 355(q) petition is still within the 150-day period that the agency has to answer such petitions, insinuating that it could have filed its petition earlier had FDA granted priority review to its sNDA for the pediatric HoFH indication. However, AstraZeneca’s sNDA did not meet the requirements for priority review and, tellingly, AstraZeneca does not challenge the denial of priority review as itself unlawful. In any event, it was AstraZeneca’s decision to wait until July 2015, to submit its sNDA in the first instance; it could have pursued new orphan indications at any time since initial approval of Crestor in 2003. AstraZeneca should not be rewarded for a crisis of its own making.

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certain exceptional circumstances. Id. The second form of exhaustion, termed “jurisdictional

exhaustion,” arises when a statute “requires resort to the administrative process as a predicate to judicial review.” Id. In those cases, exhaustion “is rooted, not in prudential principles, but in

Congress’ power to control the jurisdiction of the federal courts.” Id.

To mandate exhaustion, a statute must contain “‘[s]weeping and direct’ statutory

language indicating that there is no federal jurisdiction prior to exhaustion.” Id. at 1248 (quoting

Weinberger v. Salfi, 422 U.S. 749, 757 (1975)). Congress must “‘state[] in clear, unequivocal

terms that the judiciary is barred from hearing an action until the administrative agency has come

to a decision.’” Id. (quoting I.A.M. Nat’l Pension Fund Benefit Plan C v. Stockton Tri Indus.,

727 F.2d 1204, 1208 (D.C. Cir. 1984)). However, “[i]f the statute does mandate exhaustion, a

court cannot excuse it.” Id. at 1247-48; see also Booth v. Churner, 532 U.S. 731, 741 n. 6 (2001)

(“[W]e will not read futility or other exceptions into statutory exhaustion requirements where

Congress has provided otherwise.”).

Section 355(q)(2)(B) of the FDCA does far more than state that a party must first present

an issue to an agency before going to court; the statutory language is unequivocal, mandating in

no uncertain terms, that “the court shall dismiss without prejudice the action for failure to

exhaust administrative remedies.” 21 U.S.C. § 355(q)(2)(B) (emphasis added). This language is

“sweeping and direct.” See Avocados Plus, 370 F.3d at 1248. It specifically implicates the

power of the court, directing the court to take definitive action to divest itself of jurisdiction, i.e.,

dismiss. See EEOC v. FLRA, 476 U.S. 19, 23 (1986) (finding it significant that the statute

“speaks to courts, not parties” in deciding that 5 U.S.C. § 7123(c) creates a jurisdictional bar).

The statute employs mandatory language, using the term “shall” and leaving no room for judicial

discretion. Indeed, had Congress intended dismissal to be optional, it could have said the court

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“may dismiss,” thereby enabling the court to retain jurisdiction to ascertain whether traditional

exhaustion exceptions applied. Accordingly, 21 U.S.C. § 355(q)(2)(B) constitutes a jurisdictional bar on a court’s ability to hear a case.18

In light of this sweeping and direct language, 21 U.S.C. § 355(q)(2)(B) cannot, as

Plaintiffs suggest, be characterized as codifying the judicially created doctrine of exhaustion.

Indeed, 21 U.S.C. § 355(q)(2)(B) contrasts sharply with the language of the statute in the single

case Plaintiffs cite for their proposition, Washington Ass’n for Television and Children v. F.C.C.,

712 F.2d 677 (1983) (WATCH). Contrary to Plaintiffs’ suggestion, WATCH does not involve

21 U.S.C. § 355(q)(2)(B); rather, 47 U.S.C. § 405, a statute with very different wording: “The

filing of a petition for rehearing shall not be a condition precedent to judicial review of [an FCC

decision] except where the party seeking such review . . . relies on questions of law or fact upon

which the Commission . . . has been afforded no opportunity to pass.” Id. at 681. The D.C.

Circuit explained that it construed the language of § 405 (e.g., “afforded no opportunity to pass”) to only require the party to give the FCC a “fair opportunity” to pass on a legal or factual argument, id. No such discretionary language is included in 21 U.S.C. § 355(q)(2)(B). Instead,

21 U.S.C. § 355(q)(2)(B) directs the court to dismiss “with respect to any issue raised in the petition before the Secretary has taken final agency action on the petition” regardless of whether

FDA previously had an opportunity to pass on the issue. Id. (emphasis added); see also

18 Although companies are not required to submit § 355(q) petitions, once they do, 21 U.S.C. § 355(q)(2)(B) requires exhaustion of administrative remedies as a predicate to judicial review. Such a result is fair, as the statute also requires FDA to answer § 355(q) petitions within 150 days and is considered to have taken final agency action on a petition if 150 days have expired and the agency has failed to make a final decision. See 21 U.S.C. § 355(q)(1)(F); 21 U.S.C. § 355(q)(2)(A). Having chosen its path, AstraZeneca cannot now escape its consequences.

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Weinberger, 422 U.S. at 762 (jurisdictional bar in 42 U.S.C. § 405(h) extends to “any action seeking to recover on any Social Security claim”) (internal quotations omitted).

Further supporting the conclusion that 21 U.S.C. § 355(q)(2)(B) does more than codify

existing exhaustion principles is the fact that at the time it was enacted in 2007, the agency

already had a regulation at 21 C.F.R. § 10.45(b), setting forth general exhaustion principles for

citizen petitions.19 Accordingly, there was no need for Congress to codify traditional exhaustion

principles. Instead, the existence of 21 C.F.R. § 10.45(b) underscores that 21 U.S.C.

§ 355(q)(2)(B) represents a specific Congressional mandate for a particular kind of citizen petition, one filed under 21 U.S.C. § 355(q).

The conclusion that 21 U.S.C. § 355(q)(2)(B) is a jurisdictional exhaustion requirement also is buttressed by its legislative history. Congress enacted 21 U.S.C. § 355(q) to limit the ability of innovators to abuse the citizen petition process to delay generic approvals:

The bill also takes action on the abuse of citizens petitions. FDA has a commonsense policy to allow ordinary citizens or medical experts to submit petitions to the agency about drugs that it is considering approving. This procedure should be used to protect public health -- but too often, it is subverted by those who seek only to delay the entry onto the market of generic drugs.

19 21 C.F.R. § 10.45(b) provides that:

A request that the Commissioner take or refrain from taking any form of administrative action must first be the subject of a final administrative decision based on a petition submitted under § 10.25(a) or, where applicable, a hearing under § 16.1(b) before any legal action is filed in a court complaining of the action or failure to act. If a court action is filed complaining of the action or failure to act before the submission of the decision on a petition under § 10.25(a) or, where applicable, a hearing under § 16.1(b), the Commissioner shall request dismissal of the court action or referral to the agency for an initial administrative determination on the grounds of a failure to exhaust administrative remedies, the lack of final agency action as required by 5 U.S.C. 701 et seq., and the lack of an actual controversy as required by 28 U.S.C. 2201.

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Remarks by Senator Kennedy, 153 Cong. Rec. S11937-01, S11938, 2007 WL 2746562 (2007);

see also Remarks by Senator Kennedy, 153 Cong. Rec. S11831-01, S11831, 2007 WL 2736398

(2007) (“The bill . . . will end the abuse of citizens petitions that are too often used not for their intended purpose of brining [sic] important public health concerns to the attention of the FDA, but rather to delay the approval of generic drugs.”).20 It follows then that 21 U.S.C.

§ 355(q)(2)(B) was meant to prevent drug companies from using litigation to delay ANDA

approvals by placing a categorical bar on the ability of courts to hear civil actions that raise

issues pending before the agency in § 355(q) petitions. AstraZeneca’s interpretation not only is

contrary to the plain language of the statute, but also would subvert Congress’s stated goal of

shielding generic applicants from undue delay by allowing pioneer companies to file suits

regarding a pending petition before the agency answered, thereby sowing the very delay that

Congress sought to prevent.

Regardless, even if this Court were to apply general exhaustion principles, dismissal is

warranted here. Plaintiffs argue that it would be “plainly futile” to await FDA’s decision on their

§ 355(q) petition, Pls.’ Mem. at 24, because they speculate that FDA will apply the same statutory analysis to Crestor as the agency did in the Otsuka case to grant generic Abilify

approvals.21 But this is pure speculation. The D.C. Circuit has explained that “[a]s to futility,

20 This purpose is evident in the content and structure of the statutory provision itself. See 21 U.S.C. § 355(q)(1)(A) (FDA “shall not delay approval of a pending [ANDA] . . . because of any request to take any form of action relating to the application” unless FDA determines, “upon reviewing the petition, that a delay is necessary to protect the public health.”). The statute requires petitioners to submit statements certifying that they have presented any information that is unfavorable to their position, and verifying the truthfulness of the filing and the date that the information became known to the petitioner. 21 U.S.C. §§ 355(q)(1)(H), (I).

21 The Otsuka plaintiffs did not submit a § 355(q) petition to the agency. 22

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our decisions entertaining the exception have demanded a very convincing record.” Qwest Corp.

v. F.C.C., 482 F.3d 471, 476 (2007) (declining to reach the issue of whether an exhaustion

statute presented a jurisdictional bar to suit because, even assuming the statute did incorporate

exhaustion exceptions, the plaintiff failed to meet its burden to show futility). Indeed, the futility

exception is appropriate only where an agency’s position has “crystallized” or where the agency

is “firmly entrenched,” and requires a “showing that an adverse decision was a certainty.” Id. at

476-77 (citations omitted).22

Plaintiffs can make no such showing here. AstraZeneca’s § 355(q) petition raises a

factual and scientific argument not present in Otsuka, namely, that carving out the pediatric

HoFH indication from the labeling for generic versions of Crestor would present substantial safety and efficacy risks. Pls.’ Appl. for TRO, Ex. E at 1, 11-17. Plaintiffs attempt to sweep the import of their safety argument under the rug, but this Court should not allow itself to be misdirected. As noted, should FDA agree with AstraZeneca’s safety argument, no further generic versions of Crestor would receive approval until the relevant exclusivity period expires in seven years, resulting in no injury to AstraZeneca. Moreover, assuming arguendo that FDA does not agree with AstraZeneca’s safety argument, the agency’s resolution of the scientific issues may affect its statutory interpretation analysis, potentially resulting in a statutory interpretation that is not identical to the one in Otsuka. At a minimum, given the factual differences between Crestor’s labeling and Abilify’s labeling and AstraZeneca’s related safety

22 Plaintiffs’ futility claim is not well taken when they only raised their exclusivity argument to the agency on May 31, 2016. As noted, under 21 U.S.C. § 355(q)(1)(A), FDA is obliged to answer a petition under that section within 150 days, barely 30 of which have passed. See 21 U.S.C. § 355(q)(1)(F). Having given the agency little more than a month to consider its arguments, AstraZeneca cannot be heard to claim “futility” as an excuse for bypassing the statutorily-mandated procedure in favor of a hasty and ill-conceived rush to the courthouse.

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argument, the agency may need to evaluate additional statutory and regulatory provisions,

making any ruling by this Court on the interpretation used in the Otsuka case irrelevant and a

waste of the parties’ and Court’s resources. Indeed, despite their protests to the contrary,

Plaintiffs understand that their safety argument, which raises scientific and factual issues, and

their challenge to the statutory interpretation are inextricably linked; otherwise, AstraZeneca

would not have included them in the same petition.

Accordingly, Plaintiffs’ action should be dismissed for failure to exhaust administrative

remedies, no matter whether evaluated under the jurisdictional exhaustion requirement of 21

U.S.C. § 355(q)(2)(B), or traditional exhaustion principles.

2. AstraZeneca Lacks Standing

“Under Article III of the Constitution, federal courts may adjudicate only actual, ongoing

cases or controversies. To invoke jurisdiction of a federal court, a litigant must have suffered, or

be threatened with, an actual injury traceable to the defendant and likely to be redressed by a

favorable judicial decision.” Lewis v. Cont’l Bank Corp., 494 U.S. 472, 477 (1990) (citations

omitted); see also Summers v. Earth Island Inst., 555 U.S. 488, 493 (2009); Lujan v. Defenders

of Wildlife, 504 U.S. 555, 560 (1992); Int’l Bhd. of Teamsters v. Transp. Sec. Admin., 429 F.3d

1130, 1134 (D.C. Cir. 2005). “The party invoking federal jurisdiction bears the burden of

establishing these elements.” Defenders of Wildlife, 504 U.S. at 561.

The “actual injury” must be “concrete in both a qualitative and temporal sense.”

Whitmore v. Arkansas, 495 U.S. 149, 155 (1990). The injury must be “distinct and palpable” and

“actual or imminent,” not “conjectural” or “hypothetical.” Id. (citations omitted). To establish injury in fact, a “plaintiff must allege that he has been or will in fact be perceptibly harmed by the challenged agency action, not that he can imagine circumstances in which he could be

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affected by the agency’s action.” United States v. Students Challenging Regulatory Agency

Procedures (SCRAP), 412 U.S. 669, 688-89 (1973); see also Fla. Audubon Soc’y v. Bentsen, 94

F.3d 658, 663 (D.C. Cir. 1996) (en banc) (plaintiff must show that a particularized injury is at least imminent). The requirement of injury in fact is not satisfied “simply because a chain of events can be hypothesized in which the action challenged eventually leads to actual injury.”

Nw. Airlines, Inc. v. FAA, 795 F.2d 195, 201 (D.C. Cir. 1986).

Here, AstraZeneca has not identified an injury sufficiently imminent and concrete for purposes of Article III standing. There is no date certain as to when AstraZeneca will begin to lose revenue based on generic competition. AstraZeneca can only speculate if and when FDA may approve further ANDAs for Crestor. FDA’s evaluation of these ANDAs and AstraZeneca’s

§ 355(q) petition is ongoing, and it is possible that the agency could agree with AstraZeneca on one or more of the issues it has raised or find another basis for non-approval. As noted above, even if FDA construes the relevant statutory and regulatory provisions as AstraZeneca fears it will, that would still not be dispositive of the approvability of any generic applications. Only if

FDA resolves both issues raised in AstraZeneca’s § 355(q) petition adversely to it will

AstraZeneca face the prospect of imminent generic competition. Babbitt v. United Farm

Workers Nat’l Union, 442 U.S. 289, 298 (1979) (requiring a plaintiff to show that “the injury is certainly impending”) (citation and quotation marks omitted). Indeed, AstraZeneca is the epitome of a plaintiff who “can imagine circumstances” in which it could be affected by agency action, but literally does not know if it “will in fact be perceptibly harmed” by the action if and when it occurs. SCRAP, 412 U.S. at 688-89. But speculation and impatience do not confer standing. And a case or controversy cannot be predicated on a plaintiff’s predictions about what it thinks an agency may or may not decide to do. This Court should reject AstraZeneca’s

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entreaty to issue an advisory opinion on an issue that may or may not affect it at some point in

the future and instead dismiss Plaintiffs’ complaint for want of standing.

3. AstraZeneca’ Claims Are Not Ripe

As the Supreme Court explained in Abbott Laboratories v. Gardner, 387 U.S. 136, 148

(1967), “injunctive and declaratory judgment remedies are discretionary, and courts traditionally

have been reluctant to apply them to administrative determinations unless these arise in the

context of a controversy ‘ripe’ for judicial resolution.” The purpose of this doctrine is “to

prevent the courts, through avoidance of premature adjudication, from entangling themselves in

abstract disagreements over administrative policies, and also to protect the agencies from judicial

interference until an administrative decision has been formalized and its effects felt in a concrete

way by the challenging parties.” Id. at 148-49.

The ripeness doctrine is rooted in both Article III limitations on judicial power and

prudential reasons for declining to exercise jurisdiction. Reno v. Catholic Soc. Servs., Inc., 509

U.S. 43, 58 n.18 (1993). To determine whether an agency decision is ripe for review, courts

examine “both the fitness of the issues for judicial decision and the hardship to the parties of

withholding court consideration.” Abbott Labs., 387 U.S. at 149. In evaluating the fitness of an

issue for judicial review, courts should consider whether the issue is “purely legal” and whether

the agency action is final, id., or, on the other hand, whether “the courts would benefit from

further factual development of the issues presented.” Ohio Forestry Ass’n v. Sierra Club, 523

U.S. 726, 733 (1998). With respect to the hardship factor, there must be a “sufficiently direct and immediate” impact on the plaintiff’s “day-to-day business,” such that the plaintiff faces the dilemma of either complying with the challenged agency action or risking prosecution for failure to do so. Abbott Labs., 387 U.S. at 152. A court must also consider “whether judicial

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intervention would inappropriately interfere with further administrative action.” Ohio Forestry

Ass’n, 523 U.S. at 733. Finally, “[a] claim is not ripe for adjudication if it rests upon ‘contingent future events that may not occur as anticipated, or indeed may not occur at all.’” Texas, 523 U.S. at 300 (internal quotation marks omitted).

AstraZeneca’s complaint fails to satisfy any of these ripeness criteria.

a. AstraZeneca’s Claims Are Not Fit for Judicial Review Because the Issues Here Are Not Purely Legal

First, AstraZeneca’s claims are not fit for review because, contrary to AstraZeneca’s

claims, they are not purely legal, and will benefit from the agency’s careful consideration of the

complex facts and science surrounding the safety argument AstraZeneca raises in its § 355(q)

petition, an issue which Plaintiffs admit is not ripe for adjudication. See Pls.’ Mem. at 14.

Indeed, FDA’s resolution of AstraZeneca’s safety argument could lead the agency to decide not

to approve pending ANDAs and, thus, obviate the need for the agency to revisit the statutory

analysis it employed in the Otsuka case to determine that generic versions of Abilify could carve

out certain protected information from their labeling. And even if AstraZeneca’s safety

argument is not dispositive, its resolution may affect FDA’s analysis of its statutory and regulatory provisions making resolution of AstraZeneca’s claims at this juncture premature.

Plaintiffs attempt to excise a potential legal issue from their § 355(q) petition, but that is

not what the case law permits. Indeed, a contrary result would flood courts with piecemeal legal

challenges asking courts to make decisions on particular aspects of a § 355(q) petition or

particular aspects of a potential ANDA approval without the benefit of an administrative record

setting out the agency’s assessment of the petition or application as a whole. Pfizer Inc. v.

Shalala, 182 F.3d 975, 980 (D.C. Cir. 1999) (explaining that that “judicial intervention [pre-

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ANDA approval] could lead to ‘piecemeal review which at the least is inefficient and upon

completion of the agency process might prove to have been unnecessary.’”) (citing FTC v.

Standard Oil Co., 449 U.S. 232, 242 (1980)).

Nor are Plaintiffs aided by Teva Pharmas. USA, Inc. v. Sebelius, 595 F.3d 1303 (D.C.

Cir. 2010), in which the D.C. Circuit held that a plaintiff’s claims about an exclusivity issue were ripe, notwithstanding that the agency had not yet made an exclusivity decision. Teva is readily distinguishable from the instant case. As the D.C. Circuit made clear, that case was found to be ripe because “[i]n short, the question before us is one of pure statutory interpretation; we know precisely what the FDA thinks the answer is; and its resolution will almost certainly determine whether Teva is entitled to the exclusivity it claims.” Id. at 1310; see also id. at 1308-09 (“[The issues] turn on questions of statutory construction . . . and the interpretations chosen by the FDA and proposed by Teva both constitute bright-line rules, impervious, so far as appears, to factual variation.”) (internal citations omitted). By contrast, in this case, FDA’s ultimate decision on

AstraZeneca’s exclusivity and generic approvals involve questions of fact and science that are inextricably intertwined with issues of statutory construction. See AstraZeneca Pharm. v. FDA,

850 F. Supp. 2d 230, 247 (D.D.C. 2012) (dismissing case as unripe and refusing to apply Teva because “[a]lthough AstraZeneca tenders a number of legal arguments in support of its interpretation, the FDA could decide to approve or not approve pending applications for any number of reasons independent of AstraZeneca’s interpretation”); see also Viropharma Inc. v.

Hamburg, No. 11-5143, 471 F. App’x 1, 2 (D.C. Cir. March 21, 2012) (explaining that Teva is inapplicable when FDA’s ultimate decision, or the basis for that decision, is unclear).

Teva notwithstanding, this Court should follow the long line of cases in this circuit holding that challenges to exclusivity determinations and ANDA approvals are not ripe until the

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agency makes a decision on whether or not to approve an application. See, e.g., Teva Pharm.

Indus., Ltd. v. Sebelius, Civ. A. No. 14-0786 (ESH) (D.D.C. May 14, 2014) (Dkt. No. 36) (order

denying plaintiffs’ preliminary injunction motion and dismissing as unripe plaintiffs’ pre-

approval challenge to FDA’s ANDA decisions); AstraZeneca Pharm. v. FDA, 850 F. Supp. 2d

230 (D.D.C. 2012) (dismissing as unripe case in which AstraZeneca sought to obtain a decision

on its pediatric exclusivity period and block future generic approvals); Mylan Pharm. v. FDA,

789 F. Supp. 2d 1 (D.D.C. 2011) (finding claims unripe because uncertainties about the

approvability of the ANDA presented “open factual questions that the FDA needs to determine.

This Court should not prematurely intrude in that process, but rather afford ‘the agency . . . the

opportunity to apply its expertise.’”); Pfizer Inc., 182 F.3d at 980 (dismissing as unripe a

challenge by Pfizer to potential approval of a competitor’s ANDA, even though FDA had

already answered a citizen petition on the disputed issue); see also Hi-Tech Pharmacal Co. v.

FDA, 587 F. Supp. 2d 1, 8 (D.D.C. 2008) (rejecting plaintiff’s attempt to get an early 180-day

exclusivity decision on its theory of unreasonable delay because there has been no final agency action).

b. Plaintiffs Fail to Show Hardship

AstraZeneca has also failed to demonstrate that withholding judicial review now will

cause a direct and immediate impact on its day-to-day operations. Nothing prevents AstraZeneca

from seeking judicial recourse if and when FDA renders a final approvability decision that is not

to AstraZeneca’s liking. The burden of participating in such a proceeding later than today

“[does] not constitute sufficient hardship for the purposes of ripeness.” See Fla. Power & Light

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v. EPA, 145 F.3d 1414, 1421 (D.C. Cir. 1998); see also Ohio Forestry Ass’n, 523 U.S. at 735;

Biovail Corp. v. FDA, 448 F. Supp. 2d 154, 165 (D.D.C. 2006).23

Further, contrary to Plaintiffs’ contention, the hardship facing the plaintiff in Teva was

much different than the potential hardship to AstraZeneca here. The potential harm at issue in

Teva was Teva’s “first-mover advantage,” an exclusivity period of 180 days before additional

generics could lawfully enter the market, which the court found was an injury that would not be

remedied by Teva’s securing 180 days of exclusivity later on. Id. at 1311. Here, assuming

arguendo that FDA makes a decision to approve one or more ANDAs with protected labeling

carved out and AstraZeneca later prevails on the merits, it will have almost seven years with no

competition (but for its licensee Watson) to recoup market share and profits.24

B. Plaintiffs Fail to Establish Any of the Factors Necessary for a TRO

Preliminary injunctive relief is an “extraordinary and drastic” remedy that “may only be

awarded upon a clear showing that the plaintiff is entitled to such relief.” Winter v. NRDC, Inc.,

23 AstraZeneca incorrectly states that it need not address the hardship prong because FDA has no “institutional interests favoring postponement of review.” Pls.’ Mem. at 23. On the contrary, FDA has a significant interest in the appropriate interpretation and application of its statutory scheme, see infra Section IV.B.3.

24 As expressed to AstraZeneca before it filed its hasty motion for a TRO, the Federal Defendants are willing to agree to expedited merits briefing once FDA has made a decision on AstraZeneca’s § 355(q) petition and any pending generic Crestor applications. Thus, even if FDA ultimately approves any generic versions of Crestor, AstraZeneca would likely face no more than a month or two of generic competition before the case is decided on the merits, at which point, if Plaintiffs were to prevail, competition would cease and AstraZeneca’s generic competitors would remain off the market for some seven years thereafter. Such an eventuality hardly qualifies as “hardship” to a multi-billion dollar company that has long anticipated and prepared for the loss of Crestor’s exclusivity, see infra Section IV.B.2.

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555 U.S. 7, 22 (2008); Munaf v. Geren, 553 U.S. 674 (2008); see also Mpoy v. Fenty, 674 F.

Supp. 2d 163, 165 (D.D.C. 2009) (“Injunctive relief is an extraordinary remedy, and plaintiff

bears a substantial burden to obtain it.”). To obtain a TRO, a party must demonstrate that: (1) it is likely to succeed on the merits; (2) it will suffer irreparable injury in the absence of preliminary relief; (3) other interested parties will not be substantially injured if the requested relief is granted; and (4) granting such relief would serve the public interest. Winter, 555 U.S. at 20; see also Hall v.

Johnson, 599 F. Supp. 2d 1, 3 n.2 (D.D.C. 2009) (the same standard applies to both TROs and

preliminary injunctions).

Because AstraZeneca has failed to make any of the showings necessary to justify such

extraordinary relief, its motion for a TRO should be denied.

1. Plaintiffs Fail to Establish that they Are Likely to Succeed on the Merits

It is “particularly important” for a movant to demonstrate likely success on the merits.

Astellas Pharma US, Inc. v. FDA, 642 F. Supp. 2d 10, 16 (D.D.C. 2009) (absent “substantial indication” of likely success, there would be no justification for court’s intrusion into ordinary processes of administration and judicial review). Moreover, a party seeking preliminary injunctive relief must demonstrate an actual “likelihood” of success on the merits, not merely the existence of “questions so serious, substantial, difficult and doubtful, as to make them fair ground for litigation . . . .” Munaf, 553 U.S. at 690 (citations omitted).

Plaintiffs cannot demonstrate that they are likely to succeed on the merits because their arguments are not ripe; rather, their arguments are built on layers of speculation and assumptions, see supra Section IV.A.3. Specifically, Plaintiffs assume (1) that FDA will approve generics, and (2) that AstraZeneca can correctly foresee and predict the reasoning that

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FDA will use in so doing.25 The reality is that FDA may ultimately agree with AstraZeneca and

not approve any generics at this time, or it may do so on the basis of a different rationale than

Plaintiffs have anticipated. In either event, Plaintiffs’ claims (and perhaps the anticipated dispute

itself) would be negated.

Plaintiffs cannot show a likelihood of success on the merits of a claim that FDA acted

arbitrarily and capriciously when FDA has not acted in the first instance. Plaintiffs’ proffered

reasons for why they are likely to succeed on the merits are pure speculation and assumptions.

For example, Plaintiffs assert that FDA will grant final approval for generic versions of Crestor

based on the same statutory interpretation analysis the agency used in the Otsuka case, but there

is no FDA decision at this time on AstraZeneca’s case.26 It should go without saying that

plaintiffs cannot show a likelihood of success on the merits when their claims rest upon utter

conjecture. See Texas, 523 U.S. at 300 (explaining that “[a] claim is not ripe for adjudication if it

rests upon contingent future events that may not occur as anticipated, or indeed may not occur at

all”) (citation omitted); see also Ohio Forestry Ass’n, 523 U.S. at 733 (issue not fit for judicial review where “the courts would benefit from further factual development of the issues presented”).

25 The Federal Defendants reserve their right to further respond to AstraZeneca’s arguments, if and when, the agency makes a determination regarding AstraZeneca’s § 355(q) petition and, if and when, it issues any further approvals for generic versions of Crestor.

26 Plaintiffs spill much ink about Glucophage, a drug at issue more than a decade ago, and prior to various changes to the FDCA. See, e.g., Pls. Mem at 8-9, 26-30. Regardless, Plaintiffs’ arguments only serve to underscore the complexity of the issues at play in this case and how FDA approval decisions can vary with different facts. FDA’s decision-making process, and ultimate decision in Glucophage to approve ANDAs with protected labeling carved out, was irrelevant to its decision regarding Abilify—the decision Plaintiffs fear will be applied to Crestor. Accordingly, the only relevance of FDA’s decision in Glucophage here is to underscore why this case is unripe and why judicial review at this juncture is inappropriate.

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This case raises complex scientific questions related to drug safety and generic approval

issues, which fall squarely within FDA’s expertise. As the agency with the relevant scientific

and technical expertise, and the agency most familiar with the regulatory scheme, FDA must be

given the opportunity to review these issues, compile a record upon which to base its decision, and then make the decision in the first instance before judicial review may be had. FDA’s determination may turn on both its interpretation of the applicability and scope of the statutory and regulatory provisions that FDA is charged with implementing, which interpretations would be entitled to deference under Chevron, U.S.A., Inc. v. NRDC, 467 U.S. 837 (1984), and its progeny, and the agency’s evaluation of scientific information within its area of technical expertise, which are traditionally accorded great deference. See, e.g., Serono Labs., Inc. v.

Shalala, 158 F.3d 1313, 1320 (D.C. Cir. 1998) (FDA’s evaluations of scientific data within its area of expertise are “entitled to a ‘high level of deference’ from this court.”) (quoting A.L.

Pharma, Inc. v. Shalala, 62 F.3d 1484, 1490 (D.C. Cir. 1995)).

Further, even assuming arguendo, that FDA adopts the same statutory interpretation that

it did with respect to Abilify and decides against AstraZeneca on its safety argument (two

speculative and contingent assumptions), AstraZeneca still fails to establish that it is likely to

succeed on the merits of its statutory claim. Indeed, the only time similar issues were litigated,

the arguments on which Plaintiffs rely lost the day. See Otsuka II, 2015 WL 3442013, at *14.

While that decision is not binding on this Court, it is the only relevant precedent on the issue at

hand and, thus, a strong indicator that Plaintiffs are not likely to succeed on the merits.27 This is

27 A careful reading of Otsuka II reveals that it is a thorough and well-reasoned opinion and that Plaintiffs’ criticisms are unwarranted or factually inaccurate. For instance, Plaintiffs claim that Otsuka II is based on a “faulty understanding of a key regulation,” and contend that the court incorrectly quoted 21 C.F.R. § 314.94(a)(8)(iv) to read “omission of an indication or other aspect 33

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particularly true in light of the substantial judicial authority, including D.C. Circuit cases,

upholding FDA’s general carve out authority. See, e.g., Spectrum Pharms., Inc., --- F.3d ----,

2016 WL 3126834, at *3 (explaining that the D.C. Circuit has “approved FDA’s general

approach to labeling carve-outs as an acceptable interpretation of the [FDCA]” and upholding

FDA’s approval of a generic drug with a carved out indication protected by orphan exclusivity);

Bristol-Myers Squibb, 91 F.3d at 1500 (noting that the FDCA “expresses the legislature’s

concern that the new generic be safe and effective for each indication that will appear on its

label; whether the label for the new generic lists every indication approved for use of the pioneer

is a matter of indifference”); Sigma-Tau Pharms., Inc., 288 F.3d at 147-48 (upholding ANDA

applicant’s ability to carve out an indication protected by orphan exclusivity and noting dangers

of expanding exclusivity beyond Congressional intent); Otsuka II, 2015 WL 3442013, at *13

(upholding FDA’s carve out of a pediatric indication protected by orphan exclusivity); cf.

Hospira, Inc., 2014 WL 4406901, at *17 (upholding FDA’s carve out of information protected

by patent).

AstraZeneca can only speculate if, or on what basis, FDA may approve generic versions

of Crestor, much less demonstrate a likelihood of success on the merits of its premature claims.

2. AstraZeneca Fails to Establish That It Will Suffer Irreparable Injury in the Absence of Preliminary Relief

Not only does AstraZeneca have no likelihood of success on the merits, it also cannot

demonstrate that it will suffer irreparable harm absent preliminary relief. Winter v. NRDC, 555

of labeling protected by patent or accorded exclusivity under [the FDCA].” Pls.’ Mem. 36-37 & n.16 (quoting Otsuka II, 2015 WL 3442013 at *14). Although Plaintiffs suggest that the court’s truncation was improper and that the omitted text was important, they overlook that, at the end of the same paragraph from which they quote, the court again quotes 21 C.F.R. § 314.94(a)(8)(iv), this time including the very text Plaintiffs complain was initially omitted.

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U.S. 7, 20 (2008). “The sine qua non of granting any preliminary injunctive relief is a clear and

convincing showing of irreparable injury to the plaintiff.” Experience Works, Inc. v. Chao, 267

F. Supp. 2d 93, 96 (D.D.C. 2003). Further, “[t]o obtain injunctive relief, the petitioners must

show that the threatened injury is not merely ‘remote and speculative.’” Almurbati v. Bush, 366

F. Supp. 2d 72, 78 (D.D.C. 2005) (quoting Milk Indus. Found. v. Glickman, 949 F. Supp. 882,

897 (D.D.C. 1996)). Thus, proving “irreparable” injury is a considerable burden, requiring proof that the movant’s injury is certain, great and actual—not theoretical—and imminent, creating a clear and present need for extraordinary equitable relief to prevent harm. Wis. Gas Co. v. FERC,

758 F.2d 669, 674 (D.C. Cir. 1985); Bristol-Myers Squibb Co. v. Shalala, 923 F. Supp. 212, 220

(D.D.C. 1996) (“Irreparability of injury is a very high standard.”); Varicon Int’l v. OPM, 934 F.

Supp. 440, 447 (D.D.C. 1996).

In this circuit, “it is well-settled that economic loss alone will rarely constitute irreparable harm.” Astellas Pharma US, Inc. v. FDA, 642 F. Supp. 2d 10, 22 (D.D.C. 2009); see, e.g., Wis.

Gas, 758 F.2d at 674; Mylan Pharm., Inc. v. Shalala, 81 F. Supp. 2d 30, 42-43 (“Courts within the Circuit have generally been hesitant to award injunctive relief based on assertions about lost opportunities and market share”); Bristol-Myers Squibb, 923 F. Supp. at 220. Rather, economic loss may constitute irreparable harm “only where the loss threatens the very existence of the movant’s business.” Wis. Gas., 758 F.2d at 674 (emphasis added). Contrary to Plaintiffs’ claim this is far from a “misstatement of the law.” Pls.’ Mem. at 39.28 Although Wisconsin Gas

28 The case Plaintiffs rely on to support this argument involves a distinct situation not present here—where fraudulently obtained assets could have disappeared completely. See Robertson v. Cartinhour, 429 Fed. App’x 1, 3 (D.C. Cir. 2011). The language omitted by AstraZeneca (appearing in italics), highlights the distinction: “That presumption does not hold and the general rule does not apply where, as here, the plaintiff has shown the defendant is likely, in 35

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involved recoverable economic damages, cases in this circuit have made clear that even

irrecoverable financial loss does not rise to the level of irreparable harm unless the financial

injury is “serious in terms of its effect on the plaintiff.” Gulf Oil Corp. v. Dep’t of Energy, 514

F. Supp. 1019, 1026 (D.D.C. 1981). See also Apotex, Inc. v. Sebelius, 700 F. Supp. 2d 138, 141

(D.D.C. 2010) (finding an irrecoverable multi-million dollar loss did not rise to the level of

irreparable harm); Hi-Tech Pharmacal Co. v. FDA, 587 F. Supp. 2d 1, 11 (D.D.C. 2008)

(“Irretrievable” monetary loss, may constitute irreparable harm only if it is “so severe as to cause

extreme hardship to the business or threaten its very existence.”) (internal quotation marks

omitted); Mylan Labs., Inc. v. Thompson, 139 F. Supp. 2d 1, 27 (D.D.C. 2001) (To satisfy the

standard of irreparable injury to justify a preliminary injunction, the movants’ loss must be

“more than simply irretrievable”).29

This Court has recognized the high standard Plaintiffs must meet: “To demonstrate

irreparable harm, ‘the injury must be both certain and great; it must be actual and not

theoretical,’ and the movant carries the burden of showing that ‘the injury complained of is of

such imminence that there is a clear and present need for equitable relief to prevent irreparable

furtherance of the fraud in suit, to dissipate the only assets available for relief.” (emphasis added).

29 See also, e.g., Astellas Pharma US, Inc. v. FDA, 642 F. Supp. 2d 10, 22 (D.D.C. 2009); Coal. for Common Sense in Gov’t Procurement v. United States, 576 F. Supp. 2d 162, 168- 69 (D.D.C. 2008); Mylan Labs., Inc. v. Leavitt, 484 F. Supp. 2d 109, 123 (D.D.C. 2007); Apotex, Inc. v. FDA, No. 06-0627 (JDB), 2006 WL 1030151 at * 17 (D.D.C. Apr. 19, 2006); Biovail Corp. v. FDA, 448 F. Supp. 2d 154, 164 (D.D.C. 2006); Sandoz, Inc. v. FDA, 439 F. Supp. 2d 26, 32 (D.D.C. 2006); Sociedad Anonima Viña Santa Rita v. Dep’t of Treasury, 193 F. Supp. 2d 6, 14 (D.D.C. 2001); Bristol-Myers, 923 F. Supp. at 221; Experience Works, Inc., 267 F. Supp. 2d at 96.

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harm.’” Achagzai v. Broadcasting Board of Governors, Civ. No. 14-768, 2016 WL 471274, at

*4 (D.D.C. Feb. 8, 2016) (citations omitted).

Plaintiffs have failed to meet this high burden for a number of reasons. First, they use the

wrong time period to calculate injuries. Second, Plaintiffs’ estimates are not put in the context of

the company’s overall revenues. Third, Plaintiffs’ loss estimates are highly speculative. Finally,

Plaintiffs’ reliance on the government’s sovereign immunity is wholly misplaced.

First, Plaintiffs guess at their economic harm by layering a series of assumptions: they claim that “generic manufacturers are likely to flood the market immediately with at least six

months’ worth of generic product,” which they theorize will result in “loss of approximately

$400 million by December 31, 2016.” Pls.’ Mem. at 41 (emphasis added). This is misleading

because AstraZeneca fails to limit its financial loss projections to the finite period of time that is

legally at issue. The appropriate time period for measuring economic harm is the pendency of

the litigation, that is, the time between when generics enter the market and when Plaintiffs’

claims are decided. Mylan, 81 F. Supp. 2d at 43; see also Apotex, Inc. v. FDA, No. 06-0627,

2006 WL 1030151, at *17 (D.D.C. Apr. 19, 2006) (“[T]he actual relevant period for assessing

harms is probably only a few months”30 – from the time of generic launch to the time the case is

resolved on the merits.); Bristol-Myers Squibb, 923 F. Supp. at 221 (“If it ultimately prevails on

the merits, Bristol’s total sales will be insignificantly affected over the duration of the

litigation.”) (emphasis added).

30 As mentioned above, the Federal Defendants are willing to agree to expedited merits briefing once FDA has made a decision on AstraZeneca’s § 355(q) petition and any pending generic Crestor applications.

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Second, Plaintiffs fail to put its projected losses for the drug at issue in the context of its overall operations. In evaluating financial information, “[m]onetary figures are relative, and depend for their ultimate quantum, on a comparison with the overall financial wherewithal of the corporation involved.” Mylan Labs., Inc. v. Leavitt, 484 F. Supp. 2d 109, 123 (D.D.C. 2007)

(citation omitted); see also Sandoz, Inc. v. FDA, 439 F. Supp. 2d 26, 32 (D.D.C. 2006) aff'd, No.

06-5204, 2006 WL 2591087 (D.C. Cir. Aug. 30, 2006).

When viewed in context of the entire company, even accepting the $400 million number,

AstraZeneca will suffer no significant loss. AstraZeneca has a broad and diverse product

portfolio. In 2015, the company reported $24.7 billion in total revenue and over $20 billion in

gross profit.31 The estimated loss of $400 million would represent 1.6% of 2015 revenue. And

when using the appropriate time frame (approximately two months), their speculated losses are

decreased to approximately $200 million, or .8% of 2015 revenues. Critically, should

AstraZeneca succeed in litigation, the company would enjoy seven additional years of exclusivity

– the financial rewards of which would dwarf any minor losses it may incur during the litigation

of this action.

In any event, AstraZeneca’s projected losses appear to be vastly overstated based on its

own Annual Reports and statements to investors. AstraZeneca has long been preparing for

generic competition. In its 2015 Annual Report, Chairman Leif Johanasson, quotes Chief

Financial Officer, Marc Dunoyer, in saying that losses related to the end of exclusivity of Crestor

are “a normal part of an innovative medicine’s life-cycle. It is expected and we plan for it.”

31 See https://www.google.com/finance?q=NYSE%3AAZN&fstype=ii&ei= pDd0V4H5K8vBepCHgcgH (last accessed July 5, 2016).

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(2015 Annual Report, at 83.32) Also in this Annual Report, AstraZeneca CEO, Pascal Soriot,

stated, “As we face the transitional period of patent expiry for Crestor in the US, we’re confident

that our strong execution on strategy, combined with the benefits of focused investments and new

launches, keeps us on track to return to sustainable growth in line with our targets.” (Id. at 7.)

In 2016, CEO Soriot, told its investors that AstraZeneca was aware of the ending of the

Crestor patent, and, in response, the company was broadening its portfolios and planning to

“reduce costs at the global, regional, and country level, and make far greater use of shared

services.” (Q1 2016 Earnings Conference Call transcript, attached as Ex A.) In 2015, Mr. Soriot

also stated, “[o]ver the medium term the performance of our Growth Platforms and upcoming

launches should, together with the increasing cost reduction should help us offset the short-term

headwinds that come from those patent [including Crestor’s] expiries.” (Q4 2015 Earnings

Conference Call transcript, attached as Ex. B.) In sum, while AstraZeneca has painted a dire

picture for this Court, Pls.’ Mem. at 41-42, the message it has given its investors is that the loss of

exclusivity over Crestor has been “expected” and “offset.”

Even if AstraZeneca were to lose some portion of its sales to generic manufacturers, it has

not shown that the resulting financial harm would be so significant as to cause “extreme

hardship,” much less threaten its existence. As the company has acknowledged, all brand name

manufacturers know from the outset that the eventual approval of lower cost generics generally

leads to loss of sales for the brand-name and lower prices for consumers; this economic fact of

life does not justify entry of extraordinary injunctive relief. See Biovail, 448 F. Supp. 2d at 164-

65 (“[T]he fact that the plaintiff will face competition in the market and may lose profits . . . is

32 Available at http://www.astrazeneca- annualreports.com/2015/assets/pdf/AZ_Annual_Report_2015.pdf (last accessed July 5, 2016).

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insufficient to establish irreparable harm”). Indeed, the Hatch-Waxman Amendments were

intended to introduce such competition. In re Barr Labs., Inc., 930 F.2d 72, 76 (D.C. Cir. 2006)

(explaining that in enacting the Hatch-Waxman Amendments, “Congress sought to get generic

drugs into the hands of patients at reasonable prices – fast”).

Third, AstraZeneca has made little effort to specifically quantify the alleged harm it

would purportedly suffer without a TRO. In support of its alleged harm, AstraZeneca offers a

single declaration with scant, vague, unquantified allegations of harm with no supporting

documentation. See Declaration of Rod Wooten, attached as Ex. A to Pls.’ Mem. (“Wooten

Decl.”) (Dkt. No. 22-2). Such vague assertions of damages for such a large and lucrative

business are simply insufficient to satisfy the irreparable injury prong. See, e.g., Int’l Internships

Programs v. Napolitano, 798 F. Supp. 2d 92, 100 (D.D.C. 2011), vacated on other grounds, 463

F. App’x 2 (D.C. Cir. Feb. 21, 2012) (declining to find irreparable harm where the “plaintiff

[did] not offer a single piece of evidence—not a bill, financial statement, past budget, current budget, or financial projection—to support the [economic] harm it alleges” and, accordingly, did

“not meet the burden of showing that ‘the injury [is] both certain and great . . . actual and not theoretical’”) (quoting Wis. Gas Co., 758 F.2d at 674).

Plaintiffs’ allegations regarding their sales force are similarly uncertain. See Pls.’ Mem.

at 41; Wooten Decl. at ¶ 24 (loss of Crestor revenue “would likely require AstraZeneca to

eliminate a significant number of these positions to reduce expenses and bridge this financial

gap.”) (emphasis added). Similarly, Plaintiffs contend that certain research and development

efforts would be undercut by generic competition. See Pls.’ Mem. at 41-42, Wooten Decl. at

¶¶ 26-28 (generic competition “would lead to a material reduction in the R&D budget, which

could in turn have devastating consequences for AstraZeneca’s drug development.”) (emphasis

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added). Again, any such (speculative) loss is not cognizable as irreparable harm unless it threatens the survival of a business and plaintiffs make no such claims here. Cf. ViroPharma,

Inc. v. Hamburg, 777 F. Supp. 2d 140, 147 (D.D.C. 2011) (finding no causation between

FDA’s actions and “harms” that plaintiff “elected to take in response” to potential future actions).

Finally, AstraZeneca states that its harm is irreparable because it “has no right against of action FDA to recover damages.” Pls.’ Mem. at 39. But this is always the case in suits against government agencies and of no moment for purposes of determining irreparability of injury. Indeed, AstraZeneca’s construction of the irreparable harm standard would effectively eviscerate any requirement that Plaintiffs demonstrate anything other than a nominal degree of loss, and would fly in the face of the requirement to demonstrate harm that is truly

“irreparable.” N. Air Cargo v. USPS, 756 F. Supp. 2d 116, 125 n.6 (D.D.C. 2010)

(“[P]rospective injunctive relief would often cease to be an ‘extraordinary remedy’ in cases involving government defendants” if it were available whenever the plaintiff cannot recover damages from the defendant due to the defendant’s sovereign immunity.); see also Mylan

Labs., Inc. v. Thompson, 139 F. Supp. 2d 1, 27 (D.D.C. 2001) (to satisfy the standard of irreparable injury to justify a preliminary injunction, the movants’ loss must be “more than simply irretrievable”), rev’d on other grounds, 268 F.3d 1323 (D.C. Cir. 2001); Apotex, Inc. v. Sebelius, 700 F. Supp. 2d 138, 141 (D.D.C. 2010) (finding an irrecoverable multi-million dollar loss did not rise to the level of irreparable harm).

Instead, courts have concluded that even if the harm is irrecoverable because the government is immune from suits seeking monetary damages, “it remains incumbent on plaintiffs to demonstrate . . . that they are threatened with serious injury.” ViroPharma, Inc.

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v. Hamburg, 898 F. Supp. 2d 1, 25-26 (D.D.C. 2012); see also Gulf Oil Corp. v. DOE, 514

F. Supp. 1019, 1026 (D.D.C. 1981) (“[I]njury must be more than simply irretrievable; it must also be serious in terms of its effect on the plaintiff.”); N. Air Cargo, 756 F. Supp. 2d at 125 n.6 (“While the Court agrees that irrecoverable financial loss may constitute irreparable injury in some cases, this Court is of the opinion that a party asserting such a loss is not relieved of its obligation to demonstrate that its harm is ‘great.’”) (quoting Wis. Gas

Co., 758 F.2d at 674). As discussed above, AstraZeneca has not shown that its harm will be great – particularly in relation to its vast size and financial wherewithal. In these circumstances, Plaintiffs to do not come close to establishing they will suffer irreparable harm absent exigent injunctive relief.

3. The Balance of the Hardships Weighs in Favor of the Federal Defendants

The balance of harms also weighs against the entry of emergency relief. Plaintiffs desire to delay generic competition does not outweigh FDA’s interest in the thoughtful and careful exercise of its generic approval decisions. First, AstraZeneca wrongly asserts that “FDA would not be harmed if this Court bars further generic approval.” Pls.’ Mem. at 42. Although FDA has no commercial stake in the outcome of this litigation, assuming it determines that generic approval is not blocked in this case (as AstraZeneca presumes it will), FDA has an interest in seeing that decision effectuated. See Mylan Pharms., Inc. v. Henney, 94 F. Supp. 2d 36, 59

(D.D.C. 2000) (the government has an “interest in giving immediate force to an agency’s orders and an interest in the authority and finality of agency decisions in general.”) (citing United States v. Commonwealth of Puerto Rico, 764 F.Supp. 220, 224 (D.P.R. 1991)). FDA must implement the statutory scheme governing the approval of generic drugs in the manner outlined by Congress

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in the FDCA and FDA, as the expert agency entrusted by Congress with the authority to interpret and apply the FDCA, has a significant interest in the appropriate interpretation and application of its statutory scheme, as well as in making correct scientific decisions. See Mylan, 484 F. Supp.

2d at 124 (“A faithful and coherent interpretation of the FDCA and Hatch-Waxman outweighs the purely financial harm to these drug companies.”).

Finally, assuming FDA does approve one or more ANDAs referencing Crestor at some future date, any financial harm that AstraZeneca would incur in the absence of a TRO will be matched, if not exceeded, by the financial harm that a lawfully-approved ANDA holder would suffer while deprived of its right to market during the period that a TRO is in effect. This is especially true here, as AstraZeneca has already enjoyed a marketing monopoly for Crestor for over twelve years. The D.C. Circuit has found in similar circumstances that the balance of harms

“results roughly in a draw.” Serono Labs. Inc., 158 F.3d at 1326; see also Bristol-Myers Squibb,

923 F. Supp. at 221 (noting that generic company had “endured a seven year process to obtain

FDA approval” and that “the effect of an injunction on [the generic company] would be dramatically greater than the harm to [plaintiff]”); cf. Ark. Dairy Coop., Inc. v. USDA, 576 F.

Supp. 2d 147, 161 (D.D.C. 2008) (noting that any harm plaintiffs would suffer absent preliminary injunctive relief would be offset by substantial harm to defendant-intervenors if injunction were granted).

Therefore, the balance of harms weighs against the entry of a TRO here.

4. The Public Interest Is Not Served By Entry of a TRO

Finally, AstraZeneca has also failed to show that the entry of temporary injunctive relief would be in the public interest. See Winter, 555 U.S. at 24 (“In exercising their sound discretion, courts of equity should pay particular regard for the public consequences in employing the

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extraordinary remedy of injunction.”). Although AstraZeneca posits that the public interest would “be served by requiring FDA to comply with the law,” Pls.’ Mem. at 43, here, FDA has not acted at all, much less in contravention of the FDCA. Thus, AstraZeneca’s public interest argument is as specious and speculative as its argument on the merits.

As the D.C. Circuit has recognized, FDA’s interest and the public’s interest in generic drug approvals are the same. See Serono Labs. Inc., 158 F.3d at 1326 (determining that the public interest is “inextricably linked” to Congress’s purpose in passing the Hatch-Waxman

Amendments). AstraZeneca contends that the public interest is furthered by interpreting the

FDCA to allow its seven year orphan drug exclusivity for its recently obtained pediatric HoFH indication to blanket all of its previous indications, including those for which exclusivity was granted and has since expired, because such a result incentivizes research into pediatric orphan diseases. Pls.’ Mem. at 43. But here, AstraZeneca currently enjoys orphan drug exclusivity for its pediatric HoFH indication and will continue to enjoy orphan exclusivity for that indication for another seven years regardless of whether FDA grants approval of generic versions of Crestor for other indications.

Moreover, the public interest ultimately depends on the faithful application of the statute, not a particular result to a particular company, i.e., maintaining exclusivity for AstraZeneca if the statute or the science does not support that result. FDA is charged with administering the statute and does so in accordance with its mission. Cf. Citizens to Preserve Overton Park, Inc. v. Volpe,

401 U.S. 402, 415 (1971) (courts afford administrative agencies a “presumption of regularity”).

Assuming arguendo that FDA decides to carve out information related to the indication at issue here, the agency must, to protect the public health, ensure that any generic approval will not

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result in a drug that is less safe or effective than the brand-name drug for the remaining non-

protected conditions of use. See 21 C.F.R. § 314.127(a)(7).

Finally, should FDA ultimately approve one or more generic versions of Crestor, any

such approval would inure to the benefit of the American consumer who would gain quicker

access to less expensive prescription drugs. In enacting the Hatch-Waxman Amendments,

“Congress sought to get generic drugs into the hands of patients at reasonable prices – fast.” In re Barr Labs., Inc., 930 F.2d at 76. AstraZeneca argues that entry of a TRO would not preclude access to generic Crestor because Watson currently markets its version of generic Crestor. Pls.’

Mem. at 44. However, the public benefits from having multi-source generics available; accordingly, the availability of Watson’s generic does not counsel in favor of a TRO. “[T]he public has a well-recognized interest in receiving generic competition to brand-name drugs as soon as possible, and a delay in the marketing of [the generic] drug could easily be against the public interest in reduced prices.” Apotex Inc. v. FDA, 508 F. Supp. 2d 78, 88 (D.D.C. 2007)

(internal citations and quotations omitted).

V. CONCLUSION

For the foregoing reasons, AstraZeneca’s motion for a temporary restraining order should

be denied and the Federal Defendants motion to dismiss should be granted.

Dated: July 5, 2016 Respectfully submitted,

BENJAMIN C. MIZER Principal Deputy Assistant Attorney General

JONATHAN F. OLIN Deputy Assistant Attorney General

MICHAEL S. BLUME 45

Case 1:16-cv-01336-RDM Document 43 Filed 07/05/16 Page 55 of 56

Director

ANDREW CLARK Assistant Director

/s/ Charles J. Biro Of Counsel: Charles J. Biro MARGARET M. DOTZEL Illinois Bar No. 6277139 Acting General Trial Attorney Counsel Consumer Protection Branch U.S. Dept. of Health & Human Services Civil Division United States Department of Justice ELIZABETH H. DICKINSON P.O. Box 386 Chief Counsel Washington, DC 20044 Food and Drug Administration 202-307-0089 [email protected] ANNAMARIE KEMPIC Deputy Chief Counsel, Litigation

ANN M. OXENHAM Associate Chief Counsel for Enforcement U.S. Dept. of Health & Human Services Office of the General Counsel Food and Drug Division 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 Tel: (301) 796-8710 [email protected]

Case 1:16-cv-01336-RDM Document 43 Filed 07/05/16 Page 56 of 56

CERTIFICATE OF SERVICE

I certify that a copy of this pleading was filed via the Court’s CM/ECF system and served on the attorneys of record for all parties via the Court’s CM/ECF system.

/s/ Charles J. Biro Charles J. Biro United States Department of Justice