`
`United States Court of Appeals
`for the Federal Circuit
`______________________
`
`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
`______________________
`
`
`

`

`
`2
`
` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`2016-2610, 2016-2683, 2016-2685, 2016-2698, 2016-2710,
`2017-1001
`______________________
`
`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.
`______________________
`
`Decided: May 23, 2018
`______________________
`
` 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 defend-
`
`ants-appellants Accord Healthcare, Inc., Intas Pharma-
`ceuticals 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 Pharmaceu-
`ticals Ltd., Amneal Pharmaceuticals LLC, Amneal Phar-
`maceuticals of New York, LLC, Apotex Corp., Apotex Inc.,
`Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc.,
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`3
`
`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 Pharmaceuti-
`cals (USA) Inc. Defendants-appellants Amneal Pharma-
`ceuticals LLC, Amneal Pharmaceuticals of New York,
`LLC, Aurobindo Pharma Ltd., Aurobindo Pharma USA,
`Inc., Breckenridge Pharmaceutical, Inc., MSN Laborato-
`ries Pvt. Ltd., Sun Pharma Global FZE, Sun Pharmaceu-
`tical 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 de-
`fendant-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, Washing-
`ton, 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.
`
`

`

`
`4
`
` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`______________________
`
`Before PROST, Chief Judge, BRYSON and STOLL, Circuit
`Judges.
`Opinion for the court filed by Circuit Judge STOLL.
`Dissenting opinion filed by Chief Judge PROST.
`STOLL, Circuit Judge.
`This case arises under the Hatch-Waxman Act. Ap-
`pellees 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, unenforce-
`able, 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. Appel-
`lants 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, obvious-
`ness, and anticipation.
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`5
`
`Following a bench trial, the district court made ex-
`haustive 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 dis-
`trict court applied the correct legal standards in its obvi-
`ousness-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:
`
`
`
`
`
`
`
`
`The R, R1, and R3 positions are variables, represent-
`ing 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
`
`

`

` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`r 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 orienta-
`tions 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 specifica-
`tion 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 provid-
`ed 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-
`
`
`
`6 o
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`7
`
`pound. Kohn 1987 reported results of different groups at
`each of the different R positions of the general FAA chem-
`ical 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 substi-
`tuted 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 primar-
`ily 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 re-
`search 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
`
`

`

` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`n 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 prov-
`en 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 pharma-
`cological 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 pa-
`tent. 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-
`
`1 Anticonvulsant activity, i.e., efficacy, is deter-
`mined based on ED50, which in LeGall represents the dose
`at which half of the animals tested did not have a convul-
`sion. A lower ED50 value represents higher potency.
`Conversely, a higher ED50 value represents lower potency.
`
`
`
`8 i
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`9
`
`lepsy and other CNS disorders.” ’729 patent col. 1 ll. 30–
`33. The compounds of the ’729 patent share the following
`general formula:
`
`
`
`Id. at col. 1 ll. 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 mil-
`lions 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 pre-
`ferred R1 group is methyl.” Id. at col. 5 ll. 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 ll. 13–31.
`The ’729 patent also discloses Table 1 containing
`pharmacological data for 54 FAAs. None of the com-
`pounds listed in Table 1 are lacosamide, compound 107e
`disclosed in LeGall, or any FAA compound with a meth-
`oxymethyl 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
`
`

`

`
`10
`
` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`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
`
`
`
`
`
`
`
`or the pharmaceutically acceptable salts thereof
`wherein
`R is aryl, aryl lower alkyl, heterocyclic, heterocy-
`clic lower alkyl, cycloalkyl or lower cycloalkyl low-
`er alkyl, wherein R
`is unsubstituted or
`is
`substituted with at least one electron withdraw-
`ing group or an electron donating group;
`R1 is hydrogen or lower alkyl and R1 is unsubsti-
`tuted or substituted with at least one electron
`withdrawing group or at least one electron donat-
`ing group;
`A and Q are both O;
`one of R2 and R3 is hydrogen and the other is low-
`er alkyl which is substituted with an electron do-
`nating group or a electron withdrawing group and
`n is 1–4.
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`11
`
`40. The compound according to claim 39 wherein
`one of R2 and R3 is hydrogen and the other is low-
`er 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 elec-
`tron 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 an-
`imal 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
`
`

`

`
`12
`
` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`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 lacosa-
`mide 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 from claim 39, which
`recites a genus of groups that can be located at R and R1.
`B.
`The asserted ’551 patent discloses and claims lacosa-
`mide, a species of the genus disclosed in the ’729 and ’301
`patents. The claims of the ’551 patent at issue in this
`case are claims 9, 10, and 13, which are reproduced below
`along with the claims from which they depend.
`1. A compound in the R configuration having the
`formula:
`
`
`wherein
`Ar is phenyl which is unsubstituted or substi-
`tuted with at least one halo group;
`Q is lower alkoxy, and
`Q1 is methyl.
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`13
`
`8. The compound according to claim 1 which is (R)
`N-Benzyl 2-Acetamido-3-methoxypropionamide.
`9. The compound according to claim 8 which con-
`tains at least 90% (w/w) R stereoisomer.
`10. A therapeutic composition comprising an anti-
`convulsant effective amount of a compound ac-
`cording to any one of claims 1–9 and a
`pharmaceutical carrier therefor.
`11. A method of treating central nervous system
`disorders in an animal comprising administering
`to said animal in need thereof an anticonvulsant
`effective amount of a compound according to any
`one of claims 1–9.
`12. The method according to claim 11 wherein the
`animal is a mammal.
`13. The method according to claim 12 wherein the
`mammal is a human.
`Claim 9 recites the lacosamide compound with 90% or
`greater purity. For its R positions, lacosamide has an
`unsubstituted benzyl at R, an unsubstituted methyl at R1,
`and a nonaromatic methoxymethyl group at R3.2
`C.
`Before the district court, Appellants asserted that
`claims 9, 10, and 13 of the ’551 patent are invalid for
`obviousness-type double patenting, alleging that they are
`
`2 As shown in the formula of claim 1, the ’551 pa-
`tent uses “Ar”, “Q”, and “Q1” to designate the location of
`substituent groups corresponding to the “R”, “R1”, and
`“R3” positions in the asserted art. For ease of compari-
`son, we use the R, R1, and R3 designations in discussing
`corresponding substituents in lacosamide.
`
`

`

`
`14
`
` UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`not patentably distinct from claims 44–47 of the ’301
`patent. Appellants argued that the compound described
`in the asserted claims of the ’551 patent is merely an
`obvious species of the genus claimed in the ’301 patent.
`Following a bench trial, the district court found that
`the differences between claim 45 of the ’301 patent and
`the asserted claims of the ’551 patent rendered the claims
`patentably distinct. See UCB, Inc. v. Accord Healthcare,
`Inc., 201 F. Supp. 3d 491, 530–36 (D. Del. 2016) (“District
`Court Opinion”). Relying on, among other things, the lack
`of supporting efficacy data investigating the impact of
`placing an unsubstituted benzyl and methyl at R and R1,
`the district court concluded that it would not have been
`obvious to a person of ordinary skill in the art to make
`lacosamide by placing an unsubstituted benzyl at R or an
`unsubstituted methyl at R1 in combination with methox-
`ymethyl at R3. Id.
`Appellants also asserted that LeGall’s disclosure of
`the racemic mixture compound 107e alone, or in combina-
`tion with the ’729 patent’s disclosure of the genus of FAAs
`and Kohn 1991’s disclosure of compound 3l rendered the
`asserted claims of the ’551 patent obvious. Id. at 540.
`The district court applied a lead compound analysis and
`concluded that, as of March 1996, a skilled artisan would
`not have selected any FAA, let alone compound 107e
`(LeGall) or compound 3l (Kohn 1991), as a lead compound.
`Id. at 542–43. The district court based this finding on the
`complete lack of data to support that these compounds
`were effective and Kohn 1991’s disclosure that nonaro-
`matic compounds were generally disfavored. Id.
`Finally, Appellants asserted that the ’551 patent was
`anticipated by LeGall’s disclosure of the racemic mixture
`of compound 107e, which necessarily discloses the enanti-
`omers of that mixture, including the R enantiomer (la-
`cosamide). Id. at 544. Relying on our decision in Sanofi-
`Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1084 (Fed. Cir.
`
`

`

`UCB, INC. v. ACCORD HEALTHCARE, INC.
`
`15
`
`2008), the district court held that LeGall does not antici-
`pate the asserted claims because, while it discloses the
`racemic mixture compound 107e, it does not explicitly
`disclose the R-enantiomer or its characteristics. Id.
`Appellants appeal the district court’s fact findings and
`conclusions on double patenting, obviousness, and antici-
`pation. Invalidity under any of these three theories must
`be established by clear and convincing evidence. Mi-
`crosoft Corp. v. i4i Ltd. P’ship, 564 U.S. 91, 95 (2011).
`Thus, in order to prevail on appeal, Appellants must show
`that the district court clearly erred in failing to find clear
`and convincing evidence of invalidity. We have jurisdic-
`tion pursuant to 28 U.S.C. § 1295 (a)(1).
`I
`OBVIOUSNESS-TYPE DOUBLE PATENTING
`We first address Appellants’ argument that the dis-
`trict court erred in holding that the asserted claims of the
`’551 patent are not invalid for obviousness-type double
`patenting.
`By statute, only a single patent may issue for the
`same invention. See 35 U.S.C. § 101 (“Whoever invents or
`discovers any new and useful process, machine, manufac-
`ture, or composition of matter, or any new and useful
`improvement thereof, may obtain a patent therefor . . . .”)
`(emphasis added); In re Lonardo, 119 F.3d 960, 965
`(Fed. Cir. 1997) (“[Section 101] thus permits only one
`patent to be obtained for a single invention, and the
`phrase ‘same invention’ refers to an invention drawn to
`substantially identical subject matter.”).
`Nonstatutory double patenting, however, is a judicial-
`ly-created doctrine, which “prohibits an inventor from
`obtaining a second patent for claims that are not patenta-
`bly distinct from the claims of the first patent.” Id. at
`965. It “prevent[s] the extension of the term of a patent,
`even where an express statutory basis for the rejection is
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` UCB, INC. v. ACCORD HEALTHCARE, INC.
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`missing, by prohibiting the issuance of the claims in a
`second patent not patentably distinct from the claims of
`the first patent.” Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280, 1297 (Fed. Cir. 2012) (quoting In re Longi,
`759 F.2d 887, 892 (Fed. Cir. 1985)) (alteration in original).
`The obviousness-type double patenting analysis in-
`volves two steps: “First, the court ‘construes the claim[s]
`in the earlier patent and the claim[s] in the later patent
`and determines the differences.’ Second, the court ‘de-
`termines whether those differences render the claims
`patentably distinct.’” AbbVie Inc. v. Mathilda & Terence
`Kennedy Inst. of Rheumatology Tr., 764 F.3d 1366, 1374
`(Fed. Cir. 2014) (quoting Sun Pharm. Indus., Ltd. v. Eli
`Lilly & Co., 611 F.3d 1381, 1385 (Fed. Cir. 2010)). The
`second part of this analysis is analogous to the obvious-
`ness inquiry under 35 U.S.C. § 103 in the sense that if an
`earlier claim renders obvious or anticipates a later claim,
`the later claim is not patentably distinct and is thus
`invalid for obviousness-type double patenting.
` Id.
`at 1378–79. In chemical cases, the double patenting
`inquiry is not whether a person of ordinary skill in the art
`would select the earlier compound as a lead compound,
`but rather whether the later compound would have been
`an obvious or anticipated modification of the earlier
`compound. Otsuka, 678 F.3d at 1297. Unlike in an
`obviousness analysis, the underlying patent in the double
`patenting analysis need not be prior art to the later claim.
`See id.
`We review the district court’s ultimate legal conclu-
`sion of obviousness-type double patenting de novo and
`review its underlying fact findings for clear error. AbbVie,
`764 F.3d at 1372. “A factual finding is clearly erroneous
`if, despite some supporting evidence, we are left with the
`definite and firm conviction that a mistake has been
`made.” Otsuka, 678 F.3d at 1290.
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`UCB, INC. v. ACCORD HEALTHCARE, INC.
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`17
`
`A.
`Before the district court, the parties disagreed as to
`the correct legal test for obviousness-type double patent-
`ing. Appellants argued that only the differences between
`claims 44–47 of the ’301 patent and claims 9, 10, and 13 of
`the asserted ’551 patent are to be considered. UCB ar-
`gued that the claims as a whole should be considered,
`including the commonalities between the claims and
`whether a person of ordinary skill in the art would have
`been motivated to also modify any of those commonalities
`when modifying the differences between the claims.
`Specifically, UCB argued that the court should consider
`whether the commonly shared R3 methoxymethyl group in
`the ’301 and ’551 patents would have been substituted
`with another substituent when considering which sub-
`stituents to place at the R and R1 positions. The district
`court adopted Appellants’ theory, but held that the as-
`serted claims are not invalid for obviousness-type double
`patenting under either theory.
`We agree with Appellants that the obviousness-type
`double patenting inquiry requires consideration of the
`differences between
`the
`claims
`in
`the
`reference
`’301 patent and the ’551 patent. As we stated above, the
`focus of the double patenting analysis entails determining
`the differences between the compounds claimed in the
`reference and asserted patents and then “determin[ing]
`whether those differences render the claims patentably
`distinct.” AbbVie, 764 F.3d at 1374 (emphasis added). In
`this case, both claims recite a methoxymethyl group at R3.
`Thus, the double patenting analysis requires determining
`whether the claims’ differences, i.e., unsubstituted benzyl
`and methyl at R and R1, would have been obvious to one
`of skill in the art.
`At the same time, as we explained in Eli Lilly & Co. v.
`Teva Parenteral Medicines, Inc., 689 F.3d 1368 (Fed. Cir.
`2012), “those differences [between the claims] cannot be
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` UCB, INC. v. ACCORD HEALTHCARE, INC.
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`considered in isolation—the claims must be considered as
`a whole.” Id. at 1377. Indeed, “just as § 103(a) requires
`asking whether the claimed subject matter ‘as a whole’
`would have been obvious to one of skill in the art, so too
`must the subject matter of the [asserted claims] be con-
`sidered ‘as a whole’ to determine whether the [reference
`patent] would have made those claims obvious for purpos-
`es of obviousness-type double patenting.” Id. at 1377
`(quoting Gen. Foods Corp. v. Studiengesellschaft Kohle
`mbH, 972 F.2d 1272, 1278 (Fed. Cir. 1992)). Thus, the
`district court did not err by focusing its double patenting
`analysis on the claims’ differences, as well as the claims
`as a whole.
`
`B.
`We turn next to the district court’s double patenting
`analysis. Appellants assert that claims 9, 10, and 13 of
`the ’551 patent are not patentably distinct from claims
`44–47 of the ’301 patent and are thus invalid for obvious-
`ness-type double patenting. Because these claims only
`have a common methoxymethyl group at the R3 position,
`the question before us is whether a person of ordinary
`skill in the art, starting with claim 45 of the ’301 patent,
`would have been motivated to place an unsubstituted
`benzyl at R and an unsubstituted methyl at R1 in combi-
`nation with the methoxymethyl group at R3 with a rea-
`sonable expectation of success. We acknowledge that this
`is a close case, but because we discern no clear error in
`the district court’s underlying fact finding that there
`would have been no reasonable expectation of success in
`placing an unsubstituted benzyl and methyl in the
`claimed combination, we agree with the district court that
`the asserted claims of the ’551 patent are patentably
`distinct from the ’301 patent.
`The differences between claim 45 of the ’301 patent
`and claim 9 of the ’551 patent are that: (1) unlike claim 45
`of the ’301 patent, claim 9 of the ’551 patent requires the
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`UCB, INC. v. ACCORD HEALTHCARE, INC.
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`19
`
`R-enantiomer with 90% or greater purity; (2) while claim
`45 of the ’301 patent allows for any substituted or unsub-
`stituted “aryl, aryl lower alkyl, heterocyclic, heterocyclic
`lower alkyl, cycloalkyl, or lower cycloalkyl lower alkyl,” at
`R, the ’551 patent requires an unsubstituted benzyl at R;
`and (3) while claim 45 of the ’301 patent allows R1 to be a
`substituted or unsubstituted hydrogen or lower alkyl with
`at least one electron withdrawing or donating group, the
`’551 patent requires R1 to be an unsubstituted methyl.
`Compare ’301 patent col. 93 l. 3 – col. 94 l. 15, with
`’557 patent col. 38 ll. 8–39.
`Focusing on these differences, the district court found
`that as of the priority date, a person of ordinary skill in
`the art would not have had a reasonable expectation that
`placing an unsubstituted benzyl at R or an unsubstituted
`methyl at R1 with a methoxymethyl group at R3 would
`have yielded an efficacious anticonvulsant FAA. The
`district court recognized that in the context of drug devel-
`opment, “‘predictability is a vital consideration in the
`obviousness analysis,’ including obviousness-type double
`patenting.” District Court Opinion, 201 F. Supp. 3d at
`531 (quoting Otsuka, 678 F.3d at 1298). We agree that
`proving that a claim is invalid for obviousness-type double
`patenting “requires identifying some reason that would
`have led a chemist to modify the earlier compound to
`make the later compound with a reasonable expectation of
`success.” Eli Lilly, 689 F.3d at 1378 (emphasis added)
`(quoting Otsuka, 678 F.3d at 1297); see also Amgen Inc. v.
`F. Hoffman-La Roche Ltd, 580 F.3d 1340, 1362 (Fed. Cir.
`2009) (“An obviousness determination requires that a
`skilled artisan would have perceived a reasonable expec-
`tation of success in making the invention in light of the
`prior art.”). Here, the district court, relying on the prior
`art and expert evidence, found no reasonable expectation
`of success. That is a fact finding that we review for clear
`error following a bench trial. Par Pharm., Inc. v. TWI
`Pharm., Inc., 773 F.3d 1186, 1196 (Fed. Cir. 2014). We
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