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UCB, Inc. v. Accord Healthcare, Inc.

United States Court of Appeals, Federal Circuit

May 23, 2018

UCB, INC., UCB BIOPHARMA SPRL, RESEARCH CORPORATION TECHNOLOGIES, INC., HARRIS FRC CORPORATION, Plaintiffs-Appellees
v.
ACCORD HEALTHCARE, INC., INTAS PHARMACEUTICALS LTD., MYLAN PHARMACEUTICALS INC., MYLAN INC., ZYDUS PHARMACEUTICALS (USA) INC., CADILA HEALTHCARE LIMITED, AMNEAL PHARMACEUTICALS LLC, AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, AUROBINDO PHARMA LTD., AUROBINDO PHARMA USA, INC., BRECKENRIDGE PHARMACEUTICAL, INC., SUN PHARMA GLOBAL FZE, SUN PHARMACEUTICAL INDUSTRIES, LTD., WATSON LABORATORIES, INC. - FLORIDA, NKA ACTAVIS LABORATORIES FL, INC., WATSON PHARMA, INC., NKA ACTAVIS PHARMA, INC., MSN LABORATORIES PVT. LTD., ALEMBIC PHARMACEUTICALS LTD., APOTEX CORP., APOTEX INC., Defendants-Appellants ALEMBIC PHARMA LIMITED, ACTAVIS, INC., NKA ALLERGAN FINANCE, LLC, Defendants

          Appeals from the United States District Court for the District of Delaware in Nos. 1:13-cv-01206-LPS, 1:13-cv-01207-LPS, 1:13-cv-01208-LPS, 1:13-cv-01209-LPS, 1:13-cv-01210-LPS, 1:13-cv-01211-LPS, 1:13-cv-01212-LPS, 1:13-cv-01213-LPS, 1:13-cv-01214-LPS, 1:13-cv-01215-LPS, 1:13-cv-01216-LPS, 1:13-cv-01218-LPS, 1:13-cv-01219-LPS, 1:13-cv-01220-LPS, 1:14-cv-00834-LPS, Chief Judge Leonard P. Stark.

          Dimitrios T. Drivas, White & Case LLP, New York, NY, argued for plaintiffs-appellees. Also represented by Adam Gahtan, Christopher J. Glancy, Eric M. Majchrzak, Laura Moran, James Trainor; Jack B. Blumenfeld, Megan Dellinger, Maryellen Noreika, Morris, Nichols, Arsht & Tunnell LLP, Wilmington, DE; Priscilla Grace Dodson, Jeffrey B. Elikan, George Frank Pappas, Covington & Burling LLP, Washington, DC; Alexa Hansen, San Francisco, CA.

          Richard G. Greco, Albany, NY, argued for defendants-appellants Accord Healthcare, Inc., Intas Pharmaceuticals Ltd. Also represented by John W. Shaw, Shaw Keller LLP, Wilmington, DE; Gurpreet Singh Walia, Cohen & Gresser LLP, New York, NY.

          Maureen L. Rurka, Winston & Strawn LLP, Chicago, IL, argued for defendants-appellants Alembic Pharmaceuticals Ltd., Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of New York, LLC, Apotex Corp., Apotex Inc., Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc., Breckenridge Pharmaceutical, Inc., Cadila Healthcare Limited, MSN Laboratories Pvt. Ltd., Mylan Inc., Mylan Pharmaceuticals Inc., Sun Pharma Global FZE, Sun Pharmaceutical Industries, Ltd., Watson Laboratories, Inc. - Florida, Watson Pharma, Inc., Zydus Pharmaceuticals (USA) Inc. Defendants-appellants Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of New York, LLC, Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc., Breckenridge Pharmaceutical, Inc., MSN Laboratories Pvt. Ltd., Sun Pharma Global FZE, Sun Pharmaceutical Industries, Ltd., Watson Laboratories, Inc. - Florida, Watson Pharma, Inc., LLC, also represented by George C. Lombardi, John Reynolds McNair, Samuel S. Park; Charles B. Klein, Eimeric Reig-Plessis, Washington, DC.

          M. Jeffer Ali, Carlson, Caspers, Vandenburgh, Lindquist & Schuman, P.A., Minneapolis, MN, for defendant-appellant Alembic Pharmaceuticals Ltd. Also represented by Sarah Stensland, Patterson Thuente Pedersen, PA, Minneapolis, MN.

          Ian Scott, Taft, Stettinius & Hollister, LLP, Chicago, IL, for defendants-appellants Apotex Corp., Apotex Inc. Also represented by Stephen Auten, Richard T. Ruzich.

          Nicole W. Stafford, Wilson, Sonsini, Goodrich & Rosati, PC, Austin, TX, for defendants-appellants Mylan Pharmaceuticals Inc., Mylan Inc. Also represented by Aden M. Allen; Adam William Burrowbridge, Washington, DC; Joshua B. Kushner, Los Angeles, CA; David S. Steuer, Palo Alto, CA.

          Michael John Gaertner, Locke Lord LLP, Chicago, IL, for defendants-appellants Zydus Pharmaceuticals (USA) Inc., Cadila Healthcare Limited. Also represented by David Brian Abramowitz, Hugh S. Balsam, Timothy Flynn Peterson; Andrea Lynn Wayda, New York, NY.

          Before Prost, Chief Judge, Bryson and Stoll, Circuit Judges.

          OPINION

          STOLL, CIRCUIT JUDGE

         This case arises under the Hatch-Waxman Act. Appellees UCB, Inc.; UCB BioPharma SPRL; Research Corp. Technologies, Inc.; and Harris FRC Corp. (collectively, "UCB") own and/or license U.S. Patent No. RE38, 551. The '551 patent covers lacosamide, an anti-epileptic drug, which treats epilepsy and other central nervous system disorders. UCB holds New Drug Applications ("NDAs") that cover its lacosamide anti-epileptic drug approved by the Food and Drug Administration ("FDA") and marketed under the tradename Vimpat®. The '551 patent is listed in the FDA's Approved Drug Products With Therapeutic Equivalence Evaluations ("Orange Book") as covering Vimpat®.

         Appellants are generic drug manufacturers who filed Abbreviated New Drug Applications ("ANDAs"), seeking approval for generic versions of Vimpat®. Pursuant to the governing Hatch-Waxman provisions, Appellants certified in their ANDAs that the '551 patent is invalid, unenforceable, or that their proposed generic lacosamide products will not infringe the '551 patent. Consequently, UCB sued Appellants for patent infringement in the United States District Court for the District of Delaware. Appellants stipulated to infringement of claims 9, 10, and 13 of the '551 patent but maintained that these claims are invalid for obviousness-type double patenting, obviousness, and anticipation.

         Following a bench trial, the district court made exhaustive fact findings based on the trial evidence and concluded that the asserted claims of the '551 patent are not invalid. Appellants appeal that decision, arguing that the district court misapplied the legal standards for obviousness-type double patenting, obviousness, and anticipation, and that the prior art anticipates and/or renders the '551 patent obvious.

         As explained more fully below, we hold that the district court applied the correct legal standards in its obviousness-type double patenting, obviousness, and anticipation analyses. And because we discern no clear error in its underlying fact findings, we affirm the district court's ultimate conclusion that the asserted claims are not invalid.

         Background

         A.

         The '551 patent discloses and claims lacosamide, the active ingredient in Vimpat®. Lacosamide belongs to a class of compounds known as functionalized amino acids ("FAAs") having the following general structure:

         (Image Omitted)

         The R, R1, and R3 positions are variables, representing the many different chemical groups that can be placed at each position resulting in a vast number of possible FAA compounds. These groups may be aromatic, het-eroaromatic, or nonaromatic. Aromatic groups have a two-dimensional structure, typically organized into rings, such as benzene. Heteroaromatic groups, such as oxygen or nitrogen, are also aromatic but contain at least one heteroatom, i.e., any atom other than carbon. Nonaro-matic groups have three-dimensional structures and are not organized into rings.

         As disclosed in the '551 patent, lacosamide is the R-enantiomer of N-benzyl-2-acetamido-3-methoxypropion-amide. See '551 patent col. 3 ll. 65-67, col. 38 ll. 9-40. Enantiomers, a type of stereoisomers, are compounds that have the same chemical structure-i.e., the same atoms are connected to each other in the same way-but differ in orientation in three-dimensional space. These orientations are designated as either "R" or "S." A 50-50 mixture of two enantiomers is known as a "racemate" or "racemic mixture."

         For its R, R1, and R3 positions, lacosamide has an un-substituted benzyl at R, an unsubstituted methyl at R1, and a nonaromatic methoxymethyl at R3. The specification teaches that "the R stereoisomer is unexpectedly more potent than the corresponding S stereoisomer and the racemic mixture." Id. col. 23 ll. 31-33.

         As of the March 1996 effective filing date of the '551 patent, no FAA had been approved as an anti-epileptic drug nor had any FAA advanced to clinical trials. Also, prior to the '551 patent, there was no public disclosure of pharmacological efficacy or safety data to support the use of any FAA as an anti-epileptic or anti-convulsant drug. To date, Vimpat® remains the only approved FAA for the treatment of epilepsy.

         The development of FAAs as anticonvulsants began in the 1980s with the inventor of the '551 patent, Dr. Kohn. In 1985, Dr. Kohn first disclosed the anticonvulsant activity of a compound identified as "AAB, " which provided the proof of concept for the use of FAAs as anti-epileptic drugs. In 1987, Dr. Kohn published a paper ("Kohn 1987"), which disclosed the anticonvulsant activity of different structural analogs of the parent AAB com- pound. Kohn 1987 reported results of different groups at each of the different R positions of the general FAA chemical structure. Kohn 1987 showed that the placement of an aromatic group at the R3 position showed improved anticonvulsant activity. Relevant to the issues here, the compounds studied in Kohn 1987 used an unsubstituted benzyl at R and an unsubstituted methyl at R1. A substituted molecule replaces one of the hydrogen atoms of the parent molecule with another atom or structure.

         In 1988, Dr. Kohn also reported data on the racemate and individual enantiomers of AAB and APB (a similar compound to AAB except that it contained a phenyl group at R3). This data showed that the R enantiomers of AAB and APB were 10 times more potent than their S enanti-omers. In 1990, this was confirmed by Dr. Kohn in a study ("Kohn 1990") in which he concluded "that the anticonvulsant activity [of AAB and APB] resided primarily in the R stereoisomers." J.A. 3240. In this study, Dr. Kohn also kept the R and R1 positions constant as benzyl and methyl, respectively, while testing the effect of different substituents at the R3 position.

         Finally, in 1991, Dr. Kohn evaluated "compound 3l, " a racemate ("Kohn 1991"). Compound 3l contained a meth-oxyamino group at R3 and exhibited superior anticonvul-sant properties. Notably, like lacosamide, compound 3l contained a nonaromatic group at R3. Compound 3l had instability problems, however, which were of concern for pharmaceutical formulations.

         In addition to Dr. Kohn's own publications, his research was disclosed in a 1987 thesis completed by his graduate student, Philippe LeGall ("LeGall"). LeGall focused on 15 new FAAs and their potential anticonvul-sant activities. Relevant here, LeGall disclosed compound 107e. Compound 107e is the racemate of the lacosamide compound claimed in the '551 patent, meaning that instead of the isolated R-enantiomer (lacosamide) claimed in the '551 patent, compound 107e is a mixture of both the R and S enantiomers. In the study, compound 107e belonged to a class of compounds called "polar analogues" of a parent compound 68a. Similar to lacosamide, LeGall replaced the R3 position in compound 107e with a nonaromatic methoxymethyl group.

         LeGall discloses and provides anticonvulsant efficacy data for all 15 compounds except for compound 107e. The class of compounds to which compound 107e belonged all contained nonaromatic groups, and as a class, these compounds showed little to no potency, resulting in ED50 values ranging from above 100 mg/kg to above 300 mg/kg.[1] By comparison, LeGall reported that other proven anticonvulsants had ED50 values of 14.0, 18.7, 20.1, and 61.0 mg/kg, and some other FAAs had ED50 values of 51.0 and 62.0 mg/kg. Despite not disclosing any pharmacological data for compound 107e, LeGall speculated that because of its structural similarities to compound 86b in the study, which had an ED50 of 62, compound 107e "may have good anticonvulsant activity." J.A. 5001, 5050. LeGall concluded that the most active compounds studied had heteroaromatic groups in the R3 position whereas compound 107e had a nonaromatic group.

         Dr. Kohn's research led to the filing of U.S. Patent No. 5, 378, 729 in 1991, which is prior art to the '551 patent. The '729 patent issued to Dr. Kohn in 1995 and discloses a genus of FAAs. Its specification explains that the claimed compounds exhibit "central nervous system (CNS) activity which are useful in the treatment of epi- lepsy and other CNS disorders." '729 patent col. 111. 30-33. The compounds of the '729 patent share the following general formula:

         (Image Omitted)

         Id. at col. 111. 37-43. The '729 patent lists many different compounds and groups that can be placed at each R position, which the district court found could form millions of possible compounds. Important to the issues here, the '729 patent teaches that "[t]he preferred values of R is aryl lower alkyl, especially benzyl" and "[t]he most preferred R1 group is methyl." Id. at col. 5 11. 17-19. For the R3 position, the '729 patent lists a number of preferred heterocyclics and alkyl and lower alkoxy groups but does not list methoxymethyl. Id. at col. 6 11. 13-31.

         The '729 patent also discloses Table 1 containing pharmacological data for 54 FAAs. None of the compounds listed in Table 1 are lacosamide, compound 107e disclosed in LeGall, or any FAA compound with a methoxymethyl group at R3. All of the compounds listed in Table 1 of the '729 patent have a methyl at R1 and 49 of them have an unsubstituted benzyl at R, all with varying potency, ranging from 3.3 mg/kg to over 300 mg/kg. Of the top ten compounds with the most potency (i.e., lowest ED50), eight had heteroaromatic groups at R3 and two had nitrogen-based groups. Unlike lacosamide, none of the most potent compounds in Table 1 had a nonaromatic group at R3. The four compounds with nonaromatic groups at R3 showed moderate to weak potency.

         U.S. Patent No. 5, 654, 301 is a continuation-in-part of the '729 patent and was filed in 1993. The '301 patent is not prior art to the '551 patent. Appellants rely on the '301 patent only for their argument that the '551 patent is invalid for obviousness-type double patenting. Like its parent '729 patent, the '301 patent claims compounds of a general structure and recites several different groups that can be placed at the R and R1 positions. The relevant claims at issue for purposes of double patenting are claims 39-47 of the '301 patent, which are reproduced below:

39. A compound of the formula
(Image Omitted)
or the pharmaceutically acceptable salts thereof wherein R is aryl, aryl lower alkyl, heterocyclic, heterocy-clic lower alkyl, cycloalkyl or lower cycloalkyl lower alkyl, wherein R is unsubstituted or is substituted with at least one electron withdrawing group or an electron donating group;
R1 is hydrogen or lower alkyl and R1 is unsubstituted or substituted with at least one electron withdrawing group or at least one electron donating group;
A and Q are both O; one of R2 and R3 is hydrogen and the other is lower alkyl which is substituted with an electron donating group or a electron withdrawing group and n is 1-4.
40. The compound according to claim 39 wherein one of R2 and R3 is hydrogen and the other is lower alkyl substituted with an electron donating group.
41. The compound according to claim 40 wherein one of R2 and R3 is alkyl substituted with an electron donating group wherein alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or hexyl.
42. The compound according to claim 41 wherein one of R2 and R3 is methyl substituted with an electron donating group.
43. The compound according to claim 42 wherein the electron donating group is lower alkoxy.
44. The compound according to claim 43 wherein lower alkoxy is methoxy. 45. The compound according to any one of claims 39-44 wherein n is 1. 46.An anti-convulsant composition comprising an anti-convulsant effective amount of a compound from any one of claim 37-42 and a pharmaceutical carrier therefor.
47. A method of treating CNS disorders in an animal comprising administering to said animal an anti-convulsant effective amount of a compound of any one of claims 39-44.

'301 patent col. 93 l. 3 - col. 94 l. 21.

         Independent claim 39 permits a large number of groups at R, R1, and R3, where each group can comprise a large number of substituents and can be either unsubsti-tuted or substituted. Hence, the district court found that claim 39 could be thousands, if not millions, of possible group combinations. Although the specification does list some of the most preferred groups, the list also contains generic categories of substituents, creating a large scope of possible groups. Although lacosamide is not specifically disclosed in the '301 patent, it is undisputed that lacosamide falls within the broad genus of claim 39 of the '301 patent.

         Claim 45, which depends from claim 44, recites that R3 is a methoxymethyl group, which is the substituent at R3 in lacosamide and claimed in the '551 patent. Claim 45 does not recite the molecules at R and R1, however. As stated above, claim 45 depends ...


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