Mylan Pharm. Inc. v. Research Corp. Techs., Inc.

• Citation: 914 F.3d 1366
• Decision Date: 01 February 2019
• Docket Number: 2017-2088, 2017-2089, 2017-2091
• Parties: MYLAN PHARMACEUTICALS INC., Breckenridge Pharmaceutical, Inc., Alembic Pharmaceuticals Ltd., Appellants v. RESEARCH CORPORATION TECHNOLOGIES, INC., Appellee
• Court: United States Courts of Appeals. United States Court of Appeals for the Federal Circuit

914 F.3d 1366

MYLAN PHARMACEUTICALS INC., Breckenridge Pharmaceutical, Inc., Alembic Pharmaceuticals Ltd., Appellants

v.RESEARCH CORPORATION TECHNOLOGIES, INC., Appellee

2017-2088, 2017-2089, 2017-2091

United States Court of Appeals, Federal Circuit.

Decided: February 1, 2019

Steven William Parmelee, Wilson, Sonsini, Goodrich & Rosati, PC, Seattle, WA, argued for all appellants. Appellant Mylan Pharmaceuticals Inc. also represented by Michael T. Rosato, Jad Allen Mills ; Aden M. Allen, Nicole W. Stafford, Austin, TX.

Matthew L. Fedowitz, Buchanan Ingersoll & Rooney PC, Alexandria, VA, for appellant Breckenridge Pharmaceutical, Inc.

Todd S. Werner, Carlson, Caspers, Vandenburgh, Lindquist & Schuman, PA, Minneapolis, MN, for appellant Alembic Pharmaceuticals Ltd. Also represented by Sarah Stensland, Patterson Thuente Pedersen, PA, Minneapolis, MN.

Jack B. Blumenfeld, Morris, Nichols, Arsht & Tunnell LLP, Wilmington, DE, argued for appellee. Also represented by Alexa Hansen, Covington & Burling LLP, San Francisco, CA; Jennifer L. Robbins, New York, NY; Beth S. Brinkmann, Priscilla Grace Dodson, Evan Smith Krygowski, George Frank Pappas, Washington, DC.

Before Lourie, Bryson, and Wallach, Circuit Judges.

Lourie, Circuit Judge.

Mylan Pharmaceuticals Inc. ("Mylan"), Breckenridge Pharmaceutical, Inc. ("Breckenridge"), and Alembic Pharmaceuticals, Ltd. ("Alembic") (collectively, "Appellants") appeal from the final written decision of the U.S. Patent and Trademark Office Patent Trial and Appeal Board ("the Board") in an inter partes review concluding that claims 1–13 of U.S. Reissue Patent 38,551 ("the ’551 patent") are not unpatentable. See Argentum Pharm. LLC v. Research Corp. Techs., IPR 2016-00204, 2017 WL 1096590, at *1–2 (P.T.A.B. Mar. 22, 2017) (" Decision "). For the reasons detailed below, we affirm.

BACKGROUND

Epilepsy is a neurological disorder that affects about one percent of the human population. It is characterized by two or more unprovoked seizures occurring more than 24 hours apart. Epilepsy can be associated with conditions affecting the structure of the brain, but, for the vast majority of affected individuals, no specific cause can be identified. While there is no known cure for epilepsy, treatment can include both drug therapy and surgery, and most patients are treated via long-term administration of anticonvulsant drugs to prevent seizures. The nature and severity of seizures varies considerably across the patient population, and treatment is typically tailored for each specific patient.

Research Corporation Technologies, Inc. ("RCT") owns the ’551 patent, which discloses and claims enantiomeric compounds and pharmaceutical compositions useful in the treatment of epilepsy and other central nervous system ("CNS") disorders. Claim 1 recites:

1. A compound in the R configuration having the formula:

wherein

Ar is phenyl which is unsubstituted or substituted with at least one halo group;

Q is lower alkoxy, and

Q1 is methyl.

’551 patent col. 38 ll. 8–23.

At issue here are claims 8–13.¹

Claim 8 depends from claim 1 and recites "[t]he compound according to claim 1 which is (R)-N-benzyl-2-acetamido-3-methoxypropionamide," referred to in the patent as "BAMP" and referred to herein as lacosamide:

Claim 9 claims lacosamide in 90 percent or greater purity, claim 10, therapeutic compositions comprising the claimed compounds, and claims 11–13, use of the compounds for treating central nervous system disorders. Id. col. 38 ll. 39–51. Because arguments have not been made concerning the separate claims, we will consider them together, as did the Board.

On November 23, 2015, Argentum Pharmaceuticals LLC ("Argentum") petitioned for inter partes review ("IPR") of the ’551 patent. In its petition, Argentum challenged claims 1–13 on eight grounds. The Board only instituted on two grounds involving three references: (1) obviousness of claims 1–9 over Kohn 1991² and Silverman³ and (2) obviousness of claims 10–13 over Kohn 1991, Silverman, and U.S. Patent 5,378,729 ("the ’729 patent").⁴ The instituted grounds appear in the petition as ground 3A and ground 3B.

In its argument, Argentum advanced a lead compound analysis. It relied on Kohn 1991 for disclosure of compound 3l, its proffered lead compound. Kohn 1991, authored by the named inventor of the ’551 patent, Dr. Harold Kohn, discloses a series of functionalized amino acids ("FAAs") with anticonvulsant activity. Dr. Kohn observed that FAA racemates with N-benzylamide moieties and acetylated amino groups provided potent protection against seizures in mice. For his research presented in the 1991 paper, Dr. Kohn began with (R,S)-2-acetamido-N -benzyl-2-methylacetamide as a lead compound and replaced the a-methyl group, denoted in the structure below as "X," with functionalized nitrogen, oxygen, and sulfur substituents:

Dr. Kohn then evaluated the potency of the compounds in mice, reporting for each the effective dosage for 50 percent of the tested population ("ED₅₀").

Based on the reported ED₅₀ values, Dr. Kohn concluded that "in the most potent analogues (2d, 3l, and 3n), a functionalized oxygen atom existed two atoms removed from the a-carbon atom." J.A. 2407. The most efficacious compound (i.e. , the compound with the lowest ED₅₀) was compound 3l. In compound 3l, NH(OCH₃) is at the a-carbon position. J.A. 2405. Its structure is as follows:

To supply a motivation to modify compound 3l, Argentum relied on Silverman, a book chapter on drug discovery, design, and development. Silverman describes bioisosterism as a "lead modification approach ... useful to attenuate toxicity or to modify ... activity. " J.A. 2430. He specifically defines bioisosteres as "substituents or groups that have chemical or physical similarities, and which produce broadly similar biological properties." Id . As relevant here, Silverman explains that "classical isosteres" are groups with the same number of valence electrons but potentially different atoms. Under the subheading "[b]ivalent atoms and groups," he lists the following compounds as classical isosteres: –CH₂–, –NH–, –O–, –S–, and –Se–. Id.

As a third reference, relevant only to the second instituted ground of review, Argentum cited the ’729 patent, another patent issued to Dr. Kohn and assigned to RCT. The ’729 patent is directed to a genus of FAAs with activity "useful in the treatment of epilepsy and other CNS disorders." ’729 patent, Abstract. Specifically, a method of treating CNS disorders in animals with a racemate of N-benzyl 2-acetamido-3-methoxypropionamide ("racemic lacosamide") is recited in claim 132 of the ’729 patent.

Based on Argentum’s petition, the Board instituted review on (1) obviousness of claims 1–9 over Kohn 1991 and Silverman and (2) obviousness of claims 10–13 over Kohn 1991, Silverman, and the ’729 patent. As for the first ground, the Board was "persuaded that [Argentum] sufficiently articulate[d] reasoning, with adequate rational underpinnings, as to why an ordinary artisan would have chosen derivative 3l from Kohn 1991 as a lead compound for the purposes of making compositions exhibiting anticonvulsant activity." J.A. 367. The Board noted that Kohn 1991 identified compound 3l as "the most potent derivative," and, based on the record at the time, it was not persuaded that "potential synthetic or stability issues" would have counseled against its selection as a lead compound. J.A. 367–68. The Board was also persuaded that "an ordinary artisan reading Silverman would have had reason to substitute the amino group (–NH–) in the X moiety of NH(OCH₃) in derivative 3l from Kohn 1991 with a methylene group," "in an effort to attenuate toxicity, modify activity, or positively affect the metabolism of a compound." J.A. 368. That change would lead to lacosamide.

As for the second ground, the Board concluded that Argentum had adequately supported its contention that an ordinary artisan would have had reason to expect "that compounds falling within claim 132 of the ’729 patent —such as racemic lacosamide and R-lacosamide—would be useful for treating CNS disorders, and would have a reasonable expectation of success in using them for this purpose." J.A. 372.

Three days after the Board instituted Argentum’s petition, Mylan, Breckenridge, and Alembic each filed their own petitions for review with concurrent motions for joinder. Each party had been sued for infringement of the ’551 patent in 2013, more than a year before the petitions were filed.⁵ On October 24, 2016, the Board instituted on each petition and joined each proceeding with the Argentum IPR. In its decision permitting joinder, the Board noted that Mylan, Breckenridge, and Alembic "agree[d] to be limited to an ‘understudy’ role, and limited to evidence and arguments presented in the Argentum Petition in relation to instituted Grounds 3A–3B." J.A. 1463.

Five months later, the Board issued its final written decision, concluding that each challenged claim had not been shown to be unpatentable. Regarding ground one, Petitioners identified two reasons for modifying the methoxyamino moiety of compound 3l in Kohn 1991: (1) that the methoxyamino moiety was not a common moiety in compounds that result in commercial pharmaceutical compounds and (2) that the methoxyamino moiety may present synthetic and stability problems. According to Petitioners, a person of skill in the art would have been motivated to substitute the –NH– group in 3l for a –CH₂– group because it is a more common and acceptable moiety for pharmaceutically active compounds. Further, because Kohn 1991 disclosed a ten-fold higher activity for 3l, which has an R group of –NH(OCH₃), over a compound with an R group of –NH₂, a person of skill in the art would have been motivated to substitute the –CH₃ group with –CH₂ OCH₃.

Contrary to its views in the institution decision, the Board disagreed with Petitioners. It "assum[ed] arguendo , that an ordinary artisan would have selected compound 3l of Kohn 1991 as a lead compound" but found that...