 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
6                      UCB, INC.   v. ACCORD HEALTHCARE, INC.



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 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-
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
8                     UCB, INC.   v. ACCORD HEALTHCARE, INC.



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 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.
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
16                      UCB, INC.   v. ACCORD HEALTHCARE, INC.



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.
UCB, INC.   v. ACCORD HEALTHCARE, INC.                  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
18                     UCB, INC.   v. ACCORD HEALTHCARE, INC.



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
UCB, INC.   v. ACCORD HEALTHCARE, INC.                    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
20                      UCB, INC.   v. ACCORD HEALTHCARE, INC.



hold that the district court’s fact finding of no reasonable
expectation of success is sufficiently supported by the
evidence presented at trial and is not clearly erroneous.
We are not left with “the definite and firm conviction that
a mistake has been made.” Otsuka, 678 F.3d at 1290. We
are satisfied that the district court did not clearly err.
    As the district court found, by the priority date, there
was little to no data from which a person of ordinary skill
in the art could have formed reasonable expectations
about the effect of placing an unsubstituted benzyl at R
and an unsubstituted methyl at R1 in combination with a
methoxymethyl group at R3. Out of all the work per-
formed by Dr. Kohn and others, not a single reference
disclosed any anticonvulsant data for any compound
comprising a methoxymethyl group at R3 let alone la-
cosamide. And most of the FAAs studied prior to the
priority date only experimented with modifying the sub-
stituents at the R3 position while holding constant the
unsubstituted benzyls at R and unsubstituted methyls at
R1. See District Court Opinion, 201 F. Supp. 3d at 504,
531. Thus, the district court reasonably found that the
prior art data studying FAAs did not provide sufficient
insight into the effectiveness of placing benzyl and methyl
at those positions relative to other substituents that could
have been placed at the R and R1 positions. Id. at 531.
This finding was supported by Dr. Roush, who explained
that the prior art was silent as to what role benzyl and
methyl played in the activity of the FAAs studied in the
prior art. The district court buttressed its finding with
the data disclosed in the ’729 patent showing that com-
pounds with benzyl and methyl at R and R1 with different
R3 groups had a varying range of effectiveness. Id. (citing
’729 patent at Table 1). Thus, the trial evidence supports
the district court’s finding that there was no prior art that
would have provided a person of ordinary skill reason to
believe that unsubstituted benzyl and methyl would have
been successful with a methoxymethyl group. Because
UCB, INC.   v. ACCORD HEALTHCARE, INC.                    21



these findings are supported by expert testimony and the
record, we conclude that they are not clearly erroneous.
See Eli Lilly, 689 F.3d at 1378 (affirming the district
court’s obviousness-type double patenting determination
based on its fact finding of no reasonable expectation of
success); see also Amgen, 580 F.3d at 1362–63 (affirming
the district court’s judgment as a matter of law that the
asserted claims were not invalid for obviousness-type
double patenting where the trial evidence supported a
finding of no reasonable expectation of success).
     The dissent states that the district court erred by not
considering LeGall in its primary double-patenting analy-
sis. Dissent Op. at 10. We disagree with the dissent’s
characterization of the district court’s opinion. The dis-
trict court’s fact findings regarding LeGall spanned thir-
teen paragraphs. District Court Opinion, 201 F. Supp. 3d
at 508–09. In what the dissent characterizes as the
district court’s “primary” double patenting analysis, the
district court also relied on Dr. Roush’s expert testimony
specifically discussing LeGall. That portion of Dr. Roush’s
testimony explained that because R and R1 were held
constant in the compounds studied in LeGall, one could
not tell what role benzyl and methyl had in the activity of
the compounds disclosed. Id. at 531–32 (citing Roush Tr.
681–82). Moreover, in its analysis under UCB’s proffered
alternative double patenting test, the district court reject-
ed Appellants’ argument that the claims of the ’551 patent
are indistinguishable from the discussion of compound
107e in LeGall. Id. at 535–536. The district court ex-
plained that LeGall’s reference to compound 107e lacks
any data or discussion that would have motivated a
person of ordinary skill in the art to use a nonaromatic
compound such as a methoxymethyl at R3. Id. at 535–36.
Thus, far from ignoring LeGall, as the dissent suggests,
the district court squarely considered and addressed
LeGall in its double patenting analysis.
22                      UCB, INC.   v. ACCORD HEALTHCARE, INC.



    The “presence or absence of a reasonable expectation
of success is . . . a question of fact,” Par Pharm., 773 F.3d
at 1196, and after considering the prior art and expert
testimony presented at trial, the district court found no
reasonable expectation of success. We cannot reweigh the
evidence, make credibility findings, or find facts. The
district court, relying on LeGall and crediting expert
testimony, made extensive fact findings regarding the
LeGall Thesis. As the district court found, LeGall disclos-
es no data whatsoever for compound 107e or any com-
pound with a methoxymethyl group at the R3 position.
District Court Opinion, 201 F. Supp. 3d at 508. In fact,
the data LeGall did disclose for similar polar analogue
compounds showed little to no potency. Id. The district
court acknowledged that LeGall speculated that com-
pound 107e “may” have good anticonvulsant activity
based on its structural similarity to another compound.
Id. at 509. Dr. Roush testified, however, that a person of
ordinary skill in the art looking to LeGall would have had
no interest in pursuing that compound and that a person
of ordinary skill would not have had a reasonable likeli-
hood of success in pursuing an FAA with a methoxyme-
thyl group at R3 as an anticonvulsant drug. The district
court did not clearly err in crediting this testimony.
    Appellants argue that the ’729 patent’s disclosure that
benzyl is “especially preferred” and that methyl is “most
preferred” for this genus of compounds itself renders the
asserted claims obvious. We disagree. The ’729 patent
describes other possible variants as “preferred com-
pounds,” “preferred embodiments,” or preferred groups for
each position, indicating a large variety of possible com-
pounds. See ’729 patent cols. 5–10. As we held in Eli
Lilly, complex compounds like the FAAs disclosed in the
’729 patent provide for many opportunities for modifica-
tion. As the district court found here, there was no indi-
cation that out of the millions of possible choices, an
unsubstituted benzyl at R and an unsubstituted methyl at
UCB, INC.   v. ACCORD HEALTHCARE, INC.                   23



R1 would have been selected in combination with a meth-
oxymethyl group at R3 to arrive at lacosamide. See Eli
Lilly, 689 F.3d at 1378. Because the district court did not
clearly err in finding that there was no motivation to
modify the ’301 patent’s claims to arrive at lacosamide or
a reasonable expectation of success in doing so, we uphold
the district court’s conclusion that claims 9, 10, and 13 of
the ’551 patent are not invalid for obviousness-type dou-
ble patenting.
    Appellants also argue that the district court erred by
requiring them to prove that benzyl and methyl were the
“best” substituents from which to choose. This is a mis-
characterization of the district court’s decision. The
district court merely quoted Dr. Roush’s expert testimony
that in the prior art “[t]here is no data to say whether
benzyl is best or something else would be the best.”
District Court Opinion, 201 F. Supp. 3d at 532 (quoting
Dr. Roush’s trial testimony). In context, however, it is
clear that the district court merely relied on this testimo-
ny to support its finding that the prior art data demon-
strated a range of effectiveness such that the effectiveness
of prior art compounds could not be attributed to benzyl.
We do not read the district court’s opinion to have re-
quired Appellants to prove that benzyl was the best
selection.
    Appellants further argue that lacosamide falls within
the broad scope of claim 45 of the ’301 patent, and is thus
presumed enabled. Appellants argue that this presump-
tion establishes a reasonable expectation of success as a
matter of law. We disagree. Appellants do not cite any
authority for the proposition that the presumption of an
enabled genus of compounds precludes the district court
from finding that there was no reasonable expectation of
success of creating a species falling within that genus.
Moreover, such a result would have a chilling effect on
genus claiming in the chemical arts as there would be
24                     UCB, INC.   v. ACCORD HEALTHCARE, INC.



double patenting in all chemical compound cases where a
parent patent claims a genus.
     Because we hold that the district court’s finding
regarding no reasonable expectation of success was not
clearly erroneous, we are compelled to affirm the district
court’s conclusion that the asserted claims of the
’551 patent are not invalid for obviousness-type double
patenting.3 Also, for this reason, we need not reach the
district court’s findings regarding secondary considera-
tions and Appellants’ argument that the district court
failed to find a nexus between the asserted secondary
considerations and lacosamide.



     3  We note that the USPTO instituted an ex parte
reexamination and inter partes review of the ’551 patent.
While this appeal was pending, the USPTO issued its
final written decision in the inter partes review, conclud-
ing that the petitioner failed to demonstrate that claims
1–13 of the ’551 patent would have been obvious over
certain prior art, including Kohn 1991 and the ’729 pa-
tent. See Argentum Pharm. LLC v. Research Corp. Techs.,
Inc., IPR2016-00204, 2017 WL 1096590 (PTAB Mar. 22,
2017). The USPTO also recently concluded its reexami-
nation proceeding and confirmed that claims 9, 10, and 13
are not unpatentable for obviousness-type double patent-
ing over the ’301 patent, Kohn 1991, and the ’729 patent.

    The dissent contends that the USPTO did not consid-
er the LeGall Thesis in its reexamination. Dissent Op. 11
n.3. We note, however, that the USPTO did consider
LeGall and determined that LeGall was not prior art
because it was not publically accessible before the priority
date.    See Argentum Pharm., IPR2016-00204, Paper
No. 19 at 12 (PTAB May 23, 2016); District Court Opin-
ion, 201 F.3d at 523.
UCB, INC.   v. ACCORD HEALTHCARE, INC.                  25



                               II
                         OBVIOUSNESS
    Next, we address obviousness. We review the district
court’s ultimate determination that the asserted claims of
the ’551 patent would not have been obvious de novo and
review its underlying fact findings for clear error. Otsu-
ka, 678 F.3d at 1290.
    Appellants assert that claim 9 of the ’551 patent
would have been obvious based on LeGall’s disclosure of
compound 107e as a racemic mixture. Appellants further
assert that LeGall alone, or in combination with the
’729 patent and Kohn 1991, render claim 9 obvious.
Applying a lead compound analysis, the district court
concluded that a person of ordinary skill in the art would
not have selected any FAA, let alone the compounds
disclosed in LeGall and Kohn 1991, as lead compounds in
the lead compound analysis. Relying on our decision in
Aventis Pharma Deutschland GmbH v. Lupin, Ltd.,
499 F.3d 1293 (Fed. Cir. 2007), Appellants argue that the
district court erred by using a lead compound analysis
because this case merely involves purification (not struc-
tural modification) of a known compound. We disagree.
    “In cases involving the patentability of a new chemical
compound, prima facie obviousness under the third Gra-
ham factor generally turns on the structural similarities
and differences between the claimed compound and the
prior art compounds.” Otsuka, 678 F.3d at 1291. We
have held that to demonstrate that a new chemical com-
pound would have been prima facie obvious over a partic-
ular prior art compound based on a lead compound
analysis, the court follows a two-part inquiry. First, “the
court determines whether a chemist of ordinary skill
would have selected the asserted prior art compounds as
lead compounds, or starting points, for further develop-
ment efforts.” Id. Second, the court determines “whether
26                      UCB, INC.   v. ACCORD HEALTHCARE, INC.



the prior art would have supplied one of ordinary skill in
the art with a reason or motivation to modify a lead
compound to make the claimed compound with a reasona-
ble expectation of success.” Id. at 1292. A lead compound
is “a compound in the prior art that would be most prom-
ising to modify in order to improve upon its . . . activity
and obtain a compound with better activity.” Id. at 1291
(quoting Takeda Chem. Indus., Ltd. v. Alphapharm Pty.,
Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)).
    Appellants argue, however, that this court has never
required a lead compound analysis in chemical purifica-
tion cases. Appellants further cite Aventis, where we
addressed whether the pure 5(S) stereoisomer of ramipril,
in a form substantially free of other isomers, would have
been obvious over the prior art disclosing its racemic
mixture. Aventis, 499 F.3d at 1300. There, we held that
the “structural similarity between claimed and prior art
subject matter, proved by combining references or other-
wise, where the prior art gives reason or motivation to
make the claimed compositions, creates a prima facie case
of obviousness.” Id. at 1301. We stated further that
where a claimed composition is a purified form of a mix-
ture that existed in the prior art and “if the prior art
would provide a person of ordinary skill in the art with
reason to believe [it had desirable properties], the purified
compound is prima facie obvious over the mixture even
without an explicit teaching that the ingredient should be
concentrated or purified.” Id. (emphasis added).
    Appellants argue that because Aventis did not apply a
lead compound analysis, no such analysis is required in
this case. We agree. A lead compound analysis is not
required in analyzing obviousness of a chemical com-
pound when, in the inventing process, there was no lead
compound. An inventor may not have tried to improve a
compound known to have desirable properties. See, e.g.,
Otsuka, 678 F.3d at 1291 (“New compounds may be
UCB, INC.   v. ACCORD HEALTHCARE, INC.                   27



created from theoretical considerations rather than from
attempts to improve on prior art compounds.”). And an
obviousness rejection by an examiner, or a challenge in
court, may be based on the closest prior art, which may
not have been a lead compound that the inventor had in
mind.
    We are not aware of any authority holding that a lead
compound analysis is or is not required in cases involving
purifying mixtures. Aventis simply required proving that
a person of ordinary skill in the art would have been
motivated to purify a mixture of compounds based on
some known desirable property. See Aventis, 499 F.3d at
1301 (holding that “if it is known that some desirable
property of a mixture derives in whole or in part from a
particular one of its components, or if the prior art would
provide a person of ordinary skill in the art with reason to
believe that this is so, the purified compound is prima
facie obvious over the mixture”).
     In any event, even if a lead compound analysis is re-
quired here, we hold that the district court did not clearly
err in finding that a person of ordinary skill in the art
would not have selected compound 107e as a lead com-
pound. As we have stated, the district court found that
LeGall contains no data that would have led a person of
ordinary skill in the art to select compound 107e among
the many compounds disclosed in LeGall as a lead com-
pound. The district court further found that the data
provided in LeGall for that class of compounds showed
little potency. Dr. Roush also testified that based on
LeGall’s disclosure, a person of ordinary skill in the art
would not have been motivated to develop compound
107e. We see no clear error in the district court’s factual
findings based on such evidence.
    We also see no clear error in the district court’s fact
finding that a person of ordinary skill in the art would not
28                     UCB, INC.   v. ACCORD HEALTHCARE, INC.



have selected Kohn’s 1991 compound 3l as a lead com-
pound. Kohn’s compound 3l is also a nonaromatic com-
pound like compound 107e, and Dr. Roush testified that
nonaromatic compounds were not of interest as of 1996.
The district court’s fact finding was also supported by
additional expert testimony, which established that
compound 3l had properties making it less stable and that
medicinal chemists would have avoided investigating its
potential use in a pharmaceutical product.
    Based on this evidence, we see no clear error in the
district court’s fact findings and sustain its conclusion
that the asserted claims of the ’551 patent would not have
been obvious.
                            III
                      ANTICIPATION
    Finally, we address anticipation. Only Appellants Ac-
cord Healthcare, Inc. and Intas Pharmaceuticals Ltd. (the
“Accord Appellants”) raise anticipation on appeal. They
argue that because LeGall discloses the chemical struc-
ture of the racemic compound 107e, it necessarily disclos-
es the R-enantiomer (lacosamide) recited in claim 9 of the
’551 patent.
    Relying principally on our decision in Sanofi, 550 F.3d
at 1084, the district court found claim 9 of the ’551 patent
not anticipated, concluding that LeGall discloses neither
the R-enantiomer of compound 107e nor any of its charac-
teristics. Anticipation is also a question of fact, which we
review for clear error. See Sanofi, 550 F.3d at 1082.
    We hold that the district court did not clearly err in
finding that LeGall does not anticipate claim 9 of the
’551 patent. As the district court recognized, we have
held that “[t]he knowledge that enantiomers may be
separated is not ‘anticipation’ of a specific enantiomer
that has not been separated, identified, and character-
ized.” Id. at 1084. We have also stated that “the novelty
UCB, INC.   v. ACCORD HEALTHCARE, INC.                   29



of an optical isomer is not negated by the prior art disclo-
sure of its racemate.” In re May, 574 F.2d 1082, 1090
(CCPA 1978). Although LeGall discloses the chemical
structure of the racemic compound 107e, it does not
disclose its separation into individual enantiomers nor
does it disclose any pharmaceutical data of the R enanti-
omer recited in claim 9 of the ’551 patent. As the Accord
Appellants point out, LeGall expressly stated that he
“prepare[d] the racemic amino acid derivatives rather
than the individual enantiomers,” and that “[i]n each
case, the functionalized amino acid racemate was pre-
pared rather than the individual enantiomers.” J.A. 4942;
J.A. 5030 (emphasis added). Thus, we discern no clear
error in the district court’s finding of no anticipation.
                          CONCLUSION
    We have considered the parties’ remaining arguments
and find them unpersuasive. For the foregoing reasons,
we affirm the district court’s judgment that the asserted
claims of the ’551 patent are not anticipated, obvious, or
invalid for obviousness-type double patenting.
                         AFFIRMED
                            COSTS
    Costs to Appellees.
 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.
                 ______________________

PROST, Chief Judge, dissenting.
    Because I believe that the district court clearly erred
when it found there would not have been a reasonable
expectation of success in selecting unsubstituted benzyl
for R and unsubstituted methyl for R1, I disagree with the
majority that the asserted claims of the ’551 patent are
patentably distinct from the reference patent claims. I
therefore respectfully dissent.
                             I
    The parties focused their double-patenting presenta-
tions to the district court on whether claim 9 of the ’551
patent (asserted claim) is invalid for obviousness-type
double patenting over claims 44 and 45 of the ’301 patent
(reference claims). UCB, Inc. v. Accord Healthcare, Inc.,
201 F. Supp. 3d 491, 528 (D. Del. 2016) (“District Court
Opinion”). Reference claim 45 covers a genus of com-
pounds known as functionalized amino acids (“FAA”)
having the following general structure of the formula:
UCB, INC.   v. ACCORD HEALTHCARE, INC.                    3




Id. at 512.
    In this formula, R, R1, and R3 are variables, meaning
that different elements or compounds can be placed at
each of these three sites. When claim 45 is limited to
depending from claim 44, the R3 group is defined as
methoxymethyl. Id. The definition of R includes unsub-
stituted benzyl and the definition of R1 includes unsubsti-
tuted methyl. Id. at 516.
    Lacosamide is one species of this genus. Id. at 512.
Lacosamide has a methoxymethyl group at R3, id. at 503,
unsubstituted benzyl at R, and unsubstituted methyl at
R1, id. at 530. Asserted claim 9 claims lacosamide. Id. at
502. It “fills in the variables of the claim 44/45 equation,
so as to narrow the genus of claims 44 and 45 to the
species of a single compound, lacosamide.” Id. at 515. In
other words, claim 9 “selects substituents for R (benzyl)
and R1 (methyl) that fall within the scope of claims 44/45.”
Id. at 516. These differences are depicted below:




Id.
                               II
   With respect to the district court’s double-patenting
analysis, much like the majority, I would leave undis-
4                       UCB, INC.   v. ACCORD HEALTHCARE, INC.



turbed nearly all of the district court’s findings. To the
extent, however, the district court found that a person of
ordinary skill in the art would not have had a reasonable
expectation of success in selecting an unsubstituted
benzyl for R and an unsubstituted methyl for R1, it clearly
erred.
    The obviousness-type double-patenting analysis in-
volves determining whether the differences between the
claims in the reference patent and the claims in the
asserted patent render the claims patentably distinct.
AbbVie Inc. v. Mathilda & Terence Kennedy Inst. of
Rheumatology Tr., 764 F.3d 1366, 1374 (Fed. Cir. 2014).
This part of the obviousness-type double-patenting analy-
sis is analogous to an obviousness analysis under 35
U.S.C. § 103. Amgen Inc. v. F. Hoffman-La Roche Ltd.,
580 F.3d 1340, 1361 (Fed. Cir. 2009). An obviousness
determination requires that a skilled artisan would have
perceived a reasonable expectation of success in making
the invention in light of the prior art. Id. at 1362. This is
a question of fact, which we review for clear error follow-
ing a bench trial. Par Pharm., Inc. v. TWI Pharm., Inc.,
773 F.3d 1186, 1198 (Fed. Cir. 2014). “A factual finding is
clearly erroneous if, despite some supporting evidence,
‘the reviewing court on the entire evidence is left with the
definite and firm conviction that a mistake has been
committed.’” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1359 (Fed. Cir. 2007) (quoting United States v. U.S.
Gypsum Co., 333 U.S. 364, 395 (1948)).
                             A
    The district court found that a person of ordinary skill
in the art would not have had a reasonable expectation of
success in selecting an unsubstituted benzyl for R and an
unsubstituted methyl for R1. It based this finding largely
on a lack of data showing the effect of placing these
substituents at their respective positions. District Court
Opinion, 201 F. Supp. 3d at 532. The court stated that
UCB, INC.   v. ACCORD HEALTHCARE, INC.                   5



“given how unpredictable drug development is, and the
high likelihood that any formulation will prove unsuccess-
ful, the lack of data strongly contributes to the [c]ourt’s
finding.” Id. (citations omitted).
    Although we cannot reject the district court’s finding
that drug development is unpredictable, “obviousness
cannot be avoided simply by a showing of some degree of
unpredictability in the art so long as there was a reasona-
ble probability of success.” Pfizer, 480 F.3d at 1364. In
reality, “there were many tests conducted on FAAs with
benzyl at R and methyl at R1.” District Court Opinion,
201 F. Supp. 3d at 531. And indeed, as the district court
found, 75% of Dr. Kohn’s experimental compounds con-
tained benzyl at R and methyl at R1, and most of these
were unsubstituted. Id. As I detail below, the district
court’s findings of fact as to the prior art provided ample
evidence showing that a person of skill in the art would
have had a reasonable expectation of success in creating
an FAA with anticonvulsant activity by selecting an
unsubstituted benzyl for R and an unsubstituted methyl
for R1. While it is true that there may be some evidence
supporting the district court’s view, given the overwhelm-
ing evidence to the contrary, I am “left with the definite
and firm conviction that a mistake has been committed.”
Pfizer, 480 F.3d at 1359 (quoting U.S. Gypsum, 333 U.S.
at 395).
    In 1985, Dr. Kohn published the anticonvulsant activ-
ity of his first FAA compound, AAB. District Court Opin-
ion, 201 F. Supp. 3d at 505. AAB contained a benzyl at R,
and a methyl at R1. Id. According to Dr. Kohn, AAB
demonstrated the “proof of concept” for FAAs. Id. Two
years later, Dr. Kohn reported on the anticonvulsant
activity of sixteen structural analogues of AAB. Id. The
paper used unsubstituted benzyl at R and unsubstituted
methyl at R1 as a “reference point,” and considered five
possible modifications of the unsubstituted benzyl at R
6                      UCB, INC.   v. ACCORD HEALTHCARE, INC.



and three modifications of the unsubstituted methyl at R1.
Id. at 506.
    In Dr. Kohn’s 1990 paper, he also kept “R1 constant
and R constant” as methyl and benzyl, respectively. Id. at
509. He reported that the most potent compound was 2g,
which had benzyl at R and methyl at R1. Id. Unlike
lacosamide, 2g had an aromatic 2-furanyl structure at R3.
Id. Compound 2g “was found to be significantly more
potent than APB [described in a 1988 paper], and at the
time in 1990 when this paper was published this was the
most potent compound in the FAA family.” Id.
    Dr. Kohn then summarized his prior FAA work in a
1991 paper. Id. All twenty-six compounds reported in
that paper had unsubstituted benzyl at R and unsubsti-
tuted methyl at R1 with different compounds at the R3
group. Id. at 506–07. Dr. Kohn explained in this paper
that “you get potent protection if you have a benzyl on one
end [at R] and a methyl on the other [at R1].” Id. at 506.
The 1991 paper also identified compound 3l, which pos-
sessed “the best activity to date” for any FAA racemate.
Id. at 507. Compound 3l had unsubstituted benzyl at R
and unsubstituted methyl at R1 with methoxyamino at R3.
Id.
    Dr. Kohn continued to explore and publish data for
many other compounds with different groups at R3. Id. at
506. In a 1993 paper, Dr. Kohn published the results of
an experiment investigating modifications of the 2-
furanyl group at R3 with other heteroaromatic groups.
Once again, the “starting point” was benzyl at R and
methyl at R1. Id.
    On this record it is clear that Dr. Kohn’s extensive
study of FAAs provides copious amounts of information
from which a person of ordinary skill would form a rea-
sonable expectation that the selection of an unsubstituted
benzyl for R and an unsubstituted methyl for R1 would
lead to the successful creation of an FAA with anticonvul-
UCB, INC.   v. ACCORD HEALTHCARE, INC.                     7



sant activity. Indeed, Dr. Kohn described unsubstituted
benzyl for R and an unsubstituted methyl for R1 as the
“starting point” or “reference point” for nearly every
experiment he published. Dr. Kohn himself explained in
his 1991 paper (where all 26 compounds reported had
unsubstituted benzyl at R and unsubstituted methyl at
R1) that “you get potent protection if you have a benzyl on
one end [at R] and a methyl on the other [at R1].”1 Id. at
506.
    The district court recognized that “there were many
tests conducted on FAAs with benzyl at R and methyl at
R1.” Id. at 531. But it dismissed the resulting data
because “[m]ost of these tests kept the structures at R and
R1 constant in order to assess changes made at the R3
position” and so “any changes (whether increases or
decreases) observed in anticonvulsant behavior and/or
neurotoxicity would be attributed to the structure at R3
rather than to the benzyl at R or the methyl at R1.” Id.
In dismissing the data resulting from these tests, the
court clearly erred. Although the experiments may have
been designed to assess changes made at the R3 position,
by using unsubstituted benzyl for R and an unsubstituted
methyl for R1 as the “starting point” or “reference point”
for these tests, the prior art showed, without question,
that those substituents would work at those positions.
And not only did the prior art show that unsubstituted
benzyl works at R and that unsubstituted methyl works




    1   Additionally, I find it significant that unsubstitut-
ed benzyl and unsubstituted methyl were most often used
together at R and R1, respectively. In other words, they
are presented throughout the prior art as a pair. Thus, a
person of ordinary skill would not need to independently
select benzyl for R and then separately select methyl for
R1, as the district court posited.
8                       UCB, INC.   v. ACCORD HEALTHCARE, INC.



at R1, the prior art showed that FAAs with these substit-
uents so positioned demonstrate anticonvulsant activity.
    It was clear error for the district court to require test-
ing to provide “insight into the effectiveness of benzyl and
methyl relative to other structures that could be placed at
R and R1.” Id. Where the prior art teaches that the
selected substituent will work, even when it is selected
from thousands of compounds, an inability to predict how
any one substituent will work in the composition and a
need for testing will not render that selection nonobvious.
See In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985)
(“Although [the inventor] declared that it cannot be
predicted how any candidate will work in a detergent
composition, but that it must be tested, this does not
overcome [the prior art’s] teaching that hydrated zeolites
will work.”); Pfizer, 480 F.3d at 1364.
    Further, if, as the district court found, all the testing
focused on R3 and a person of ordinary skill would attrib-
ute anticonvulsant behavior to R3, once R3 was fixed in
the ’301 reference patent genus, plugging in unsubstitut-
ed benzyl at R and unsubstituted methyl at R1 (which had
remained largely constant throughout the prior art test-
ing) would be viewed simply as a trivial selection. Indeed,
because the ’301 claim is a genus claim, with only two
variables R and R1, a person of ordinary skill would know
to select a substituent for each variable. A person of
ordinary skill would certainly have a reasonable expecta-
tion of success when deciding which substituents to select
if she copied the “75% of Dr. Kohn’s compounds [which]
contained benzyl at R and methyl at R1, and most of these
were unsubstituted.” District Court Opinion, 201 F. Supp.
3d at 531.
    In dismissing the data resulting from the many tests
conducted with unsubstituted benzyl at R and unsubsti-
tuted methyl at R1 and in relying so heavily on what it
saw as a lack of data, the district court clearly erred.
UCB, INC.   v. ACCORD HEALTHCARE, INC.                    9



                               B
    The district court also erred when it found that the
limited data that did exist at the time would not have led
a person of ordinary skill to place an unsubstituted benzyl
at R or an unsubstituted methyl at R1. Id. at 532. In-
deed, the data that were available showed that unsubsti-
tuted benzyl at R and an unsubstituted methyl at R1 were
comparable to, if not better than, any other substituents
tested.
    For example, Dr. Kohn, in his 1985 paper, used un-
substituted benzyl at R and unsubstituted methyl at R1 as
a “reference point,” and considered five possible modifica-
tions of the unsubstituted benzyl at R and three modifica-
tions of the unsubstituted methyl at R1. Id. at 506. With
respect to the R position, only one of the five R modifica-
tions showed activity comparable to unsubstituted benzyl
at R. Id. The others showed decreased activity. Id. For
the R1 position, each of the three modifications decreased
anticonvulsant activity when compared to unsubstituted
methyl. Id.
    Dr. Kohn also considered, in his 1990 paper, the effect
of replacing an unsubstituted benzyl at R and found that
placing a fluoro-substituted benzyl at R yielded only a
comparable anticonvulsant effect. Id. Fluoro-substituted
benzyl at R did, however, provide a “far superior” protec-
tive index. Id. Yet, this must be balanced against Dr.
Kohn’s 1991 paper (where all 26 compounds reported had
unsubstituted benzyl at R and unsubstituted methyl at
R1) explaining that “you get potent protection if you have a
benzyl on one end [at R] and a methyl on the other [at
R1].” Id. (emphasis added).
    Thus, the data that were available showed that un-
substituted benzyl at R and an unsubstituted methyl at
R1 were comparable, if not better, than any other substit-
uents that were tested with respect to anticonvulsant
activity. Despite the test that demonstrated fluoro-
10                     UCB, INC.   v. ACCORD HEALTHCARE, INC.



substituted benzyl’s “far superior” protective index, these
tests provide strong evidence that a person of ordinary
skill would have a reasonable expectation of success in
selecting these substituents in order to create an FAA
having an anticonvulsant effect. This is especially so with
respect to selecting unsubstituted methyl for R1 as it was
the most successful substituent tested. Although these
data might have shown that there was no guarantee that
unsubstituted benzyl at R would provide the greatest
protective index as compared to other possible substitu-
ents, “only a reasonable expectation of success, not a
guarantee, is needed.” Pfizer, 480 F.3d at 1364.
    Accordingly, the district court clearly erred when it
found that the data specific to R and R1 that did exist at
the time would not have led a person of ordinary skill to
place an unsubstituted benzyl at R or an unsubstituted
methyl at R1.
                             C
     Finally, and perhaps most importantly, the district
court erred when it did not consider the LeGall Thesis in
its primary double-patenting analysis.2 See District Court
Opinion, 201 F. Supp. 3d at 530–35. For purposes of this



     2   The majority takes issue with my characterization
of the district court’s opinion on this point. I do not mean
to imply that the district court did not make any findings
of fact as to the LeGall Thesis. The court certainly did in
its introductory “Findings of Fact” section. District Court
Opinion, 201 F. Supp. 3d at 508–09. But I maintain that
the district court determined in its primary double-
patenting analysis that there was no reasonable expecta-
tion of success without considering the teachings of this
reference. A citation to two pages of Dr. Roush’s trial
testimony, stripped of any reference to the LeGall Thesis,
cannot cure this deficiency.
UCB, INC.   v. ACCORD HEALTHCARE, INC.                   11



litigation, the parties agree that the LeGall Thesis consti-
tutes a “printed publication” within the meaning of 35
U.S.C. § 102(b).3 Id. at 508.
    Importantly, the LeGall Thesis disclosed compound
107e which, exactly like lacosamide, has a methoxymethyl
group at R3, an unsubstituted benzyl at R, and an unsub-
stituted methyl at R1. Id. Compound 107e is identical to
lacosamide except that it contains both the R- and S-
enantiomers in a mixture, rather than just the R-
enantiomer. Id. Although he did not have data for com-
pound 107e, LeGall hypothesized that structural similari-
ties between compound 107e and another compound for
which he did have data, 86b, suggested that compound
107e “may have good anticonvulsant activity.” Id. at 509.
    The LeGall Thesis is highly relevant to the obvious-
ness analysis. For example, the majority concluded that
“the trial evidence supports the district court’s finding
that there was no prior art that would have provided a
person of ordinary skill reason to believe that unsubsti-
tuted benzyl and methyl would have been successful with
a methoxymethyl group.” Majority Op. 20. Not so. The
thesis disclosed a compound having, like lacosamide, a
methoxymethyl group at R3 together with an unsubstitut-
ed benzyl at R and an unsubstituted methyl at R1 and it
provided a reasonable hypothesis, based on structural
similarities to other compounds, that this compound “may
have good anticonvulsant activity.” District Court Opin-
ion, 201 F. Supp. 3d at 509. Again, “only a reasonable


    3    The majority, in support of its conclusion, notes
that the USPTO instituted an ex parte reexamination of
the ’551 patent and concluded that claims 9, 10, and 13
were not unpatentable for obviousness-type double pa-
tenting over the ’301 patent, Kohn 1991, and the ’729
patent. Crucially, however, the USPTO did not institute
trial as to grounds relying on the LeGall Thesis.
12                     UCB, INC.   v. ACCORD HEALTHCARE, INC.



expectation of success, not a guarantee, is needed.”
Pfizer, 480 F.3d at 1364. Thus, to the extent the district
court found that there was no indication in the prior art
that benzyl and methyl would have been successful with a
methoxymethyl group, it clearly erred.
    Certainly this evidence, especially when considered
along with the other evidence before the district court,
would have strongly contributed to a person of ordinary
skill in the art’s having a reasonable expectation of suc-
cess in creating an FAA with anticonvulsant activity by
selecting an unsubstituted benzyl for R and an unsubsti-
tuted methyl for R1.
                         *   *     *
    Considering all of the evidence, despite some support-
ing evidence identified by the district court, I am “left
with the definite and firm conviction” that the district
court made a mistake. Id. at 1359 (quoting U.S. Gypsum,
333 U.S. at 395). Thus, I conclude that the district court
clearly erred in finding that one skilled in the art would
not have had a reasonable expectation of success with
unsubstituted benzyl at R and unsubstituted methyl at
R1. Taking the district court’s clear error together with
the remainder of its fact findings, I would have concluded
that claims 9, 10, and 13 of the asserted ’551 patent are
not patentably distinct from the reference claims. Thus, I
would reverse the district court’s conclusion and hold that
the asserted claims of the ’551 patent are invalid for
obviousness-type double patenting. I therefore respectful-
ly dissent.
