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Takeda Pharms., U.S.A., Inc. v. Burwell

United States District Court, D. Columbia.

January 13, 2015

SYLVIA MATHEWS BURWELL, in her official capacity as SECRETARY, UNITED STATES DEPARTMENT OF HEALTH AND HUMAN SERVICES, et al., Defendants, and HIKMA PHARMACEUTICALS PLC, et al., Intervenor-Defendants. ELLIOTT ASSOCIATES, L.P., et al., Plaintiffs,

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For TAKEDA PHARMACEUTICALS U.S.A., INC. (TPUSA), Plaintiff (1:14-cv-01668-KBJ): Jessica L. Ellsworth, Susan Margaret Cook, LEAD ATTORNEYS, Catherine E. Stetson, HOGAN LOVELLS, U.S. LLP, Washington, DC.

For ELLIOTT ASSOCIATES, L.P., 14cv1850, ELLIOTT INTERNATIONAL, L.P., 14cv1850, Plaintiffs (1:14-cv-01668-KBJ): Matthew D McGill, LEAD ATTORNEY, Lucas C. Townsend, Mithun Mansinghani, GIBSON, DUNN & CRUTCHER, LLP, Washington, DC; Michael Sitzman, PRO HAC VICE, GIBSON, DUNN & CRUTCHER LLP, San Francisco, CA.

For KNOLLWOOD INVESTMENTS, L.P., 14cv1850, Plaintiff (1:14-cv-01668-KBJ): Matthew D McGill, LEAD ATTORNEY, Lucas C. Townsend, GIBSON, DUNN & CRUTCHER, LLP, Washington, DC; Michael Sitzman, LEAD ATTORNEY, GIBSON, DUNN & CRUTCHER LLP, San Francisco, CA.

For SYLVIA MATHEWS BURWELL, In her official capacity as Secretary, U.S. Department of Health and Human Services, MARGARET A. HAMBURG, In her official capacity as Commissioner of Food and Drugs, Food and Drug Administration, Defendants (1:14-cv-01668-KBJ): Jessica R. Gunder, LEAD ATTORNEY, U.S. DEPARTMENT OF JUSTICE, Washington, DC.


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Table Of Contents


A Colchicine: A Drug For The Treatment Of Gout

B FDA's Drug Approval Framework: The Hatch-Waxman Amendments

1 NDAs, ANDAs, and 505(b)(2) NDAs

2 The Patent Certification Requirement

3 The Labeling Requirements

C FDA's Approval Of Colcrys (A Colchicine Tablet)

1 Mutual Relies On ColBenemid, Published Literature, And Its Own

Clinical Studies To Support The Colcrys Application

For Acute Flares Of Gout

2 Mutual Relies on ColBenemid and Published Literature To Support The

Colcrys Application For Prophylactic Treatment of Gout

3 FDA Takes Enforcement Action Against Unapproved Oral Colchicine

Products Because Their Labels Do Not Reflect The Most Current Data

D FDA's Approval Of Mitigare (A Colchicine Capsule)

1 Mutual Files A Citizen Petition Protesting West-Ward's Application

And FDA Responds

2 FDA Approves Mitigare Capsule For Prophylaxis Of Gout Flares Based On

Col-Probenecid, Published Literature, and West-Ward's Own Studies

3 West-Ward Launches Mitigare, Alerting Takeda To

The Existence Of Mitigare

E Procedural History



A FDA's Approval Of Mitigare Without A Colcrys Reference And Related

Certifications To The Colcrys Patents Did Not Violate The

Agency's Rules Or. The FDCA

1 FDA's Procedural Rules Did Not Require West-Ward To Reference Colcrys

Because West-Ward Did Not Rely On Colcrys Data To Support West-Ward's

Application For FDA Approval Of Mitigare

a No FDA Policy Establishes That FDA's Reliance--As Opposed To

That Of The Section 505(b)(2) Applicant--Gives Rise To

Patent Certification Obligations

b. Even If Agency Reliance On Third-Party Data Is Relevant, FDA Did Not

Approve Mitigare In Reliance On Mutual's Information

2. Under FDA's Procedural Rules, An Applicant--Not FDA--Has The Right To

Choose The " Most Appropriate" Or. " Most Similar" Reference Drug For

Its 505(b)(2) Application

3. The FDCA Unambiguously Requires A Section 505(b)(2) Applicant To

Certify Only To Patents Associated With The Reference Listed Drug

B. FDA's Approval Of Mitigare Was Not An Unreasoned Change Of The

Agency's Prior Position Regarding Single-Ingredient

Oral Colchicine Products

C. FDA's Decision To Approve Mitigare With A Label That Contains

Safety Information That Differs From Colcrys Was

Not Arbitrary And Capricious


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KETANJI BROWN JACKSON, United States District Judge.

The Hatch-Waxman Amendments to the Food, Drug, and Cosmetic Act (" FDCA" ), Pub. L. No. 98-417, 98 Stat. 1585 (1984), " balance two competing interests in the pharmaceutical industry: (1) inducing pioneering research and development of new drugs and (2) enabling competitors to bring low-cost, generic copies of those drugs to market." Janssen Pharmaceutica, N.V. v. Apotex, Inc., 540 F.3d 1353, 1355 (Fed. Cir. 2008) (internal quotation marks and citation omitted). Hatch-Waxman achieves this balance, in part, by allowing new applicants for drug approval to rely on research and data that an innovator company generates so long as the new applicant " references" the innovator's drug and " certifies" to the innovator's patents. See infra Part I.B.2; see also 21 U.S.C. § 355(b)(2)(A). Plaintiffs Takeda Pharmaceuticals U.S.A., Inc. (" Takeda" ) and Elliott Associates, L.P., Elliott International, L.P., and Knollwood Investments, L.P. (collectively, " Elliott" ) allege that the Food and Drug Administration (" FDA" ) upset Hatch-Waxman's careful balance when the agency approved an application that Hikma Pharmaceuticals PLC (" Hikma" ) submitted through its U.S. agent West-Ward Pharmaceuticals Corp. (" West-Ward" ) for a gout medication named Mitigare. Mitigare is a single-ingredient 0.6 milligram (" mg" ) oral colchicine drug product that is substantially similar to Plaintiffs' colchicine drug, Colcrys, which FDA approved five years prior to Mitigare based in part on research studies that Takeda's predecessor Mutual Pharmaceutical Company, Inc. (" Mutual" ) conducted. In seeking approval for Mitigare, West-Ward neither referenced Colcrys nor certified to the Colcrys patents, and Hikma has now authorized West-Ward to market a generic version of Mitigare that will compete with--and cost less than--Plaintiffs' Colcrys.

In the separate but consolidated complaints that Takeda and Elliott have filed in this Court against Defendants Sylvia Mathews Burwell (in her official capacity as Secretary of the Department of Health and Human Services) and Margaret Hamburg (in her official capacity as head of the FDA), Plaintiffs maintain that FDA's approval of Mitigare without a Colcrys reference or the related patent certifications violates the Administrative Procedure Act (" APA" ) because that approval was inconsistent with the agency's procedural rules and the certification provisions of the FDCA. Plaintiffs also claim that FDA's approval of Mitigare was arbitrary and capricious because Mitigare's label lacks certain safety information that is on the Colcrys label--information that is related to Mutual's research and that FDA previously suggested should be on the label of future colchicine drug products. The lawsuits

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that Takeda and Elliott have filed (and in which Hikma and West-Ward have now intervened) request a stay or rescission of FDA's approval of Mitigare as a remedy for these alleged violations.

Before this Court at present are four cross-motions for summary judgment that the Plaintiffs, the Defendants, and the Defendant-Intervenors have submitted in the context of the two pending actions.[1] This Court has considered these dispositive motions, the oppositions thereto, the supplemental briefing, and the arguments made orally at the two hearings that this Court has held in relation to this matter. Because this Court agrees with Defendants and Defendant-Intervenors that (1) no statute, regulation, or policy required FDA to reject West-Ward's application for Mitigare because the application did not reference Colcrys or certify to the Colcrys patents; (2) FDA's scientific judgment that Mitigare is safe as labeled is well-reasoned and entitled to deference; and (3) FDA did not make an unreasoned change in policy when it approved Mitigare, Takeda's Motion for Summary Judgment in Takeda Pharmaceuticals U.S.A., Inc. v. Burwell, No. 14-1668-KBJ (D.D.C.), is DENIED; Elliott's Motion for Summary Judgment in Elliott Associates, L.P. v. Burwell, No. 14-1850-KBJ (D.D.C.), is DENIED; and Defendants' and Defendant-Intervenors' cross-motions for summary judgment in Elliott Associates, L.P. v. Burwell, No. 14-1850-KBJ (D.D.C.), are GRANTED. This Court issued a separate order consistent with this opinion on January 9, 2015.


The instant dispute involves two drug products, both of which have the active ingredient colchicine, which is a pharmacological substance that has been used historically for the treatment of gout.[2] Plaintiffs have a financial interest in Colcrys-- an FDA-approved 0.6 mg single-ingredient oral colchicine tablet--and they have brought this challenge to Defendant FDA's recent approval of Intervenors' Mitigare, which is a 0.6 mg single-ingredient oral colchicine capsule. In order to understand the Plaintiffs' challenge fully, some background information about both colchicine itself and FDA's prior approval of Plaintiff's Colcrys, is necessary. The underlying facts are not in dispute.

A. Colchicine: A Drug For The Treatment Of Gout

Doctors have used colchicine--an agent derived from the Colchicum Autumnale plant--to treat gout for centuries. ( See Admin. R. (hereinafter, " AR" ) at 3 (" The

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first use of colchicine as a selective treatment for gout is attributed to the Byzantine physician Alexander of Tralles in 6 A.D." ).) Colchicine can be used both for the targeted treatment of gout flares (" acute treatment" ) and for longer-term maintenance treatment that is aimed at preventing flares (" prophylaxis" ). ( See id. at 4, 116-17, 157, 204.) However, there is a relatively small window of doses in which colchicine provides therapeutic benefits without causing severe complications. ( See AR at 202.) This " narrow therapeutic index" means that minor dosing changes can have a grave effect on patient outcomes because toxic levels of colchicine can be reached relatively quickly and " can result in serious life-threatening adverse events and death." ( Id.; see also id. at 117 (noting that, although colchicine is therapeutic " at doses of approximately 0.015 mg/kg," the drug is " toxic in doses greater than 0.1 mg/kg, and typically lethal at doses of approximately 0.8 mg/kg" ).) Even doses of colchicine that are within the normal therapeutic range can be toxic if colchicine is used concomitantly with certain other drugs called " CYP3A4 and P-gp inhibitors." ( Id. at 202.)

Consistent with colchicine's long history, drug manufacturers in the United States marketed a variety of forms and dosages of colchicine for decades prior to Congress's 1962 enactment of amendments to the FDCA that required FDA to " approve" a drug-- i.e., to make findings that a drug is safe, effective, and properly labeled--prior to marketing. ( See AR at 50, 255); see also Peter Barton Hutt, et al., Food and Drug Law 577 (3rd ed. 2007).[3] After Congress passed the 1962 amendments that established a premarket approval requirement, FDA reviewed a number of drugs that were already on the market, including ColBenemid, which is a combination tablet that contains both 0.5 mg of colchicine and 500 mg of probenecid. ( See AR at 4, 668.) FDA determined that ColBenemid was " effective for the treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout," 37 Fed.Reg. 15189-02 (July 28, 1972) ( see also AR at 50), and approved that product for, " essentially, prophylactic treatment of gout flares" (AR at 668). It subsequently approved a generic version of ColBenemid--known as Col-Probenecid--that is also a tablet with 0.5 mg of colchicine and 500 mg of probenecid and is still on the market today. ( See id. 4, 349, 353.) Other drug manufacturers have relied upon FDA's findings that colchicine and probenecid effectively treat gout in the context of the agency's approval of ColBenemid and Col-Probenecid, including the two drug companies that have sponsored the colchicine drug products at issue in the instant case. ( See id. at 4, 8).

Just as combination colchicine products were legally marketed and sold for many years in the pre-approval era, " [s]ingle-ingredient colchicine tablets" --tablets that contain only colchicine and are not combined with another drug--" were available for decades as marketed but unapproved products, in 0.6 mg strength." ( Id. at 668.) The practice of marketing single-ingredient colchicine products as an unapproved drug continued even after Congress required premarket approval of drugs ( see id. at 421), and it persisted until at least 2006, when " FDA announced a new drug safety initiative to remove unapproved marketed drugs from the market" ( id. at 349). FDA undertook this initiative with

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the knowledge that " [f]or historical reasons, some drugs are available in the United States that lack required FDA approval for marketing[,]" FDA Ctr. For Drug Evaluation & Research, Guidance for FDA Staff and Indus.: Marketed Unapproved Drugs--Compliance Policy Guide Sec. 440.100: Marketed New Drugs Without Approved NDAs & ANDAs 2 (June 2006, as revised Sept. 2011), and with the intent to bring all prescription drug products into compliance with an FDA approval process that Congress had adopted in 1984, as part of a statute that is formally named the " Drug Price Competition and Patent Term Restoration Act of 1984" and is commonly referred to as the " Hatch-Waxman Amendments." Pub. L. No. 98-417, 98 Stat. 1585 (1984), codified at 21 U.S.C. § 355.

B. FDA's Drug Approval Framework: The Hatch-Waxman Amendments

In brief, Hatch-Waxman requires drug manufacturers seeking to market a new drug to first obtain FDA approval via one of three different application pathways: (1) a full New Drug Application (" NDA" ); (2) an Abbreviated New Drug Application (" ANDA" ); or (3) an intermediate process known as a Section 505(b)(2) NDA. See 21 U.S.C. § 355; see also, e.g., Ethypharm S.A. France v. Abbott Labs, 707 F.3d 223, 226-27 (3d Cir. 2013) (describing the three different approval methods).

1. NDAs, ANDAs, and 505(b)(2) NDAs

The full NDA process, see 21 U.S.C. § 355(b)(1), requires the manufacturer to submit detailed safety and efficacy data for the drug, including, among other things, " full reports of investigations which have been made to show whether or not such drug is safe for use and whether such drug is effective in use" ( i.e., clinical trials); all components of the drug; the methods used for the drug's manufacture, processing, and packing; examples for proposed labeling for the drug; and any patents claimed in relation to the drug. See 21 U.S.C. § § 355(b)(1)(A), (B), (D), (F), (G). This path is used by drug manufacturers for ...

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