UCB, INC., UCB BIOPHARMA SPRL, RESEARCH CORPORATION TECHNOLOGIES, INC., HARRIS FRC CORPORATION, Plaintiffs-Appellees
ACCORD HEALTHCARE, INC., INTAS PHARMACEUTICALS LTD., MYLAN PHARMACEUTICALS INC., MYLAN INC., ZYDUS PHARMACEUTICALS (USA) INC., CADILA HEALTHCARE LIMITED, AMNEAL PHARMACEUTICALS LLC, AMNEAL PHARMACEUTICALS OF NEW YORK, LLC, AUROBINDO PHARMA LTD., AUROBINDO PHARMA USA, INC., BRECKENRIDGE PHARMACEUTICAL, INC., SUN PHARMA GLOBAL FZE, SUN PHARMACEUTICAL INDUSTRIES, LTD., WATSON LABORATORIES, INC. - FLORIDA, NKA ACTAVIS LABORATORIES FL, INC., WATSON PHARMA, INC., NKA ACTAVIS PHARMA, INC., MSN LABORATORIES PVT. LTD., ALEMBIC PHARMACEUTICALS LTD., APOTEX CORP., APOTEX INC., Defendants-Appellants ALEMBIC PHARMA LIMITED, ACTAVIS, INC., NKA ALLERGAN FINANCE, LLC, Defendants
Appeals from the United States District Court for the
District of Delaware in Nos. 1:13-cv-01206-LPS,
1:13-cv-01207-LPS, 1:13-cv-01208-LPS, 1:13-cv-01209-LPS,
1:13-cv-01210-LPS, 1:13-cv-01211-LPS, 1:13-cv-01212-LPS,
1:13-cv-01213-LPS, 1:13-cv-01214-LPS, 1:13-cv-01215-LPS,
1:13-cv-01216-LPS, 1:13-cv-01218-LPS, 1:13-cv-01219-LPS,
1:13-cv-01220-LPS, 1:14-cv-00834-LPS, Chief Judge Leonard P.
Dimitrios T. Drivas, White & Case LLP, New York, NY,
argued for plaintiffs-appellees. Also represented by Adam
Gahtan, Christopher J. Glancy, Eric M. Majchrzak, Laura
Moran, James Trainor; Jack B. Blumenfeld, Megan Dellinger,
Maryellen Noreika, Morris, Nichols, Arsht & Tunnell LLP,
Wilmington, DE; Priscilla Grace Dodson, Jeffrey B. Elikan,
George Frank Pappas, Covington & Burling LLP, Washington,
DC; Alexa Hansen, San Francisco, CA.
Richard G. Greco, Albany, NY, argued for
defendants-appellants Accord Healthcare, Inc., Intas
Pharmaceuticals Ltd. Also represented by John W. Shaw, Shaw
Keller LLP, Wilmington, DE; Gurpreet Singh Walia, Cohen &
Gresser LLP, New York, NY.
Maureen L. Rurka, Winston & Strawn LLP, Chicago, IL,
argued for defendants-appellants Alembic Pharmaceuticals
Ltd., Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of
New York, LLC, Apotex Corp., Apotex Inc., Aurobindo Pharma
Ltd., Aurobindo Pharma USA, Inc., Breckenridge
Pharmaceutical, Inc., Cadila Healthcare Limited, MSN
Laboratories Pvt. Ltd., Mylan Inc., Mylan Pharmaceuticals
Inc., Sun Pharma Global FZE, Sun Pharmaceutical Industries,
Ltd., Watson Laboratories, Inc. - Florida, Watson Pharma,
Inc., Zydus Pharmaceuticals (USA) Inc. Defendants-appellants
Amneal Pharmaceuticals LLC, Amneal Pharmaceuticals of New
York, LLC, Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc.,
Breckenridge Pharmaceutical, Inc., MSN Laboratories Pvt.
Ltd., Sun Pharma Global FZE, Sun Pharmaceutical Industries,
Ltd., Watson Laboratories, Inc. - Florida, Watson Pharma,
Inc., LLC, also represented by George C. Lombardi, John
Reynolds McNair, Samuel S. Park; Charles B. Klein, Eimeric
Reig-Plessis, Washington, DC.
Jeffer Ali, Carlson, Caspers, Vandenburgh, Lindquist &
Schuman, P.A., Minneapolis, MN, for defendant-appellant
Alembic Pharmaceuticals Ltd. Also represented by Sarah
Stensland, Patterson Thuente Pedersen, PA, Minneapolis, MN.
Scott, Taft, Stettinius & Hollister, LLP, Chicago, IL,
for defendants-appellants Apotex Corp., Apotex Inc. Also
represented by Stephen Auten, Richard T. Ruzich.
W. Stafford, Wilson, Sonsini, Goodrich & Rosati, PC,
Austin, TX, for defendants-appellants Mylan Pharmaceuticals
Inc., Mylan Inc. Also represented by Aden M. Allen; Adam
William Burrowbridge, Washington, DC; Joshua B. Kushner, Los
Angeles, CA; David S. Steuer, Palo Alto, CA.
Michael John Gaertner, Locke Lord LLP, Chicago, IL, for
defendants-appellants Zydus Pharmaceuticals (USA) Inc.,
Cadila Healthcare Limited. Also represented by David Brian
Abramowitz, Hugh S. Balsam, Timothy Flynn Peterson; Andrea
Lynn Wayda, New York, NY.
Prost, Chief Judge, Bryson and Stoll, Circuit Judges.
case arises under the Hatch-Waxman Act. Appellees UCB, Inc.;
UCB BioPharma SPRL; Research Corp. Technologies, Inc.; and
Harris FRC Corp. (collectively, "UCB") own and/or
license U.S. Patent No. RE38, 551. The '551 patent covers
lacosamide, an anti-epileptic drug, which treats epilepsy and
other central nervous system disorders. UCB holds New Drug
Applications ("NDAs") that cover its lacosamide
anti-epileptic drug approved by the Food and Drug
Administration ("FDA") and marketed under the
tradename Vimpat®. The '551 patent is
listed in the FDA's Approved Drug Products With
Therapeutic Equivalence Evaluations ("Orange
Book") as covering Vimpat®.
are generic drug manufacturers who filed Abbreviated New Drug
Applications ("ANDAs"), seeking approval for
generic versions of Vimpat®. Pursuant to the
governing Hatch-Waxman provisions, Appellants certified in
their ANDAs that the '551 patent is invalid,
unenforceable, or that their proposed generic lacosamide
products will not infringe the '551 patent. Consequently,
UCB sued Appellants for patent infringement in the United
States District Court for the District of Delaware.
Appellants stipulated to infringement of claims 9, 10, and 13
of the '551 patent but maintained that these claims are
invalid for obviousness-type double patenting, obviousness,
a bench trial, the district court made exhaustive fact
findings based on the trial evidence and concluded that the
asserted claims of the '551 patent are not invalid.
Appellants appeal that decision, arguing that the district
court misapplied the legal standards for obviousness-type
double patenting, obviousness, and anticipation, and that the
prior art anticipates and/or renders the '551 patent
explained more fully below, we hold that the district court
applied the correct legal standards in its obviousness-type
double patenting, obviousness, and anticipation analyses. And
because we discern no clear error in its underlying fact
findings, we affirm the district court's ultimate
conclusion that the asserted claims are not invalid.
'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:
R1, and R3 positions are variables,
representing the many different chemical groups that can be
placed at each position resulting in a vast number of
possible FAA compounds. These groups may be aromatic,
het-eroaromatic, or nonaromatic. Aromatic groups have a
two-dimensional structure, typically organized into rings,
such as benzene. Heteroaromatic groups, such as oxygen or
nitrogen, are also aromatic but contain at least one
heteroatom, i.e., any atom other than carbon. Nonaro-matic
groups have three-dimensional structures and are not
organized into rings.
disclosed in the '551 patent, lacosamide is the
R-enantiomer of N-benzyl-2-acetamido-3-methoxypropion-amide.
See '551 patent col. 3 ll. 65-67, col. 38 ll.
9-40. Enantiomers, a type of stereoisomers, are compounds
that have the same chemical structure-i.e., the same atoms
are connected to each other in the same way-but differ in
orientation in three-dimensional space. These orientations
are designated as either "R" or "S." A
50-50 mixture of two enantiomers is known as a
"racemate" or "racemic mixture."
R, R1, and R3 positions, lacosamide has
an un-substituted benzyl at R, an unsubstituted methyl at
R1, and a nonaromatic methoxymethyl at
R3. The specification teaches that "the R
stereoisomer is unexpectedly more potent than the
corresponding S stereoisomer and the racemic mixture."
Id. col. 23 ll. 31-33.
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.
development of FAAs as anticonvulsants began in the 1980s
with the inventor of the '551 patent, Dr. Kohn. In 1985,
Dr. Kohn first disclosed the anticonvulsant activity of a
compound identified as "AAB, " which provided the
proof of concept for the use of FAAs as anti-epileptic drugs.
In 1987, Dr. Kohn published a paper ("Kohn 1987"),
which disclosed the anticonvulsant activity of different
structural analogs of the parent AAB com- pound. Kohn 1987
reported results of different groups at each of the different
R positions of the general FAA chemical structure. Kohn 1987
showed that the placement of an aromatic group at the
R3 position showed improved anticonvulsant
activity. Relevant to the issues here, the compounds studied
in Kohn 1987 used an unsubstituted benzyl at R and an
unsubstituted methyl at R1. A substituted molecule
replaces one of the hydrogen atoms of the parent molecule
with another atom or structure.
1988, Dr. Kohn also reported data on the racemate and
individual enantiomers of AAB and APB (a similar compound to
AAB except that it contained a phenyl group at
R3). This data showed that the R enantiomers of
AAB and APB were 10 times more potent than their S
enanti-omers. In 1990, this was confirmed by Dr. Kohn in a
study ("Kohn 1990") in which he concluded
"that the anticonvulsant activity [of AAB and APB]
resided primarily in the R stereoisomers." J.A.
3240. In this study, Dr. Kohn also kept the R and
R1 positions constant as benzyl and methyl,
respectively, while testing the effect of different
substituents at the R3 position.
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.
addition to Dr. Kohn's own publications, his research was
disclosed in a 1987 thesis completed by his graduate student,
Philippe LeGall ("LeGall"). LeGall focused on 15
new FAAs and their potential anticonvul-sant activities.
Relevant here, LeGall disclosed compound 107e. Compound 107e
is the racemate of the lacosamide compound claimed in the
'551 patent, meaning that instead of the isolated
R-enantiomer (lacosamide) claimed in the '551 patent,
compound 107e is a mixture of both the R and S enantiomers.
In the study, compound 107e belonged to a class of compounds
called "polar analogues" of a parent compound 68a.
Similar to lacosamide, LeGall replaced the R3
position in compound 107e with a nonaromatic methoxymethyl
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. By comparison, LeGall reported that
other proven anticonvulsants had ED50 values of 14.0, 18.7,
20.1, and 61.0 mg/kg, and some other FAAs had ED50 values of
51.0 and 62.0 mg/kg. Despite not disclosing any
pharmacological data for compound 107e, LeGall speculated
that because of its structural similarities to compound 86b
in the study, which had an ED50 of 62, compound 107e
"may have good anticonvulsant activity." J.A. 5001,
5050. LeGall concluded that the most active compounds studied
had heteroaromatic groups in the R3 position
whereas compound 107e had a nonaromatic group.
Kohn's research led to the filing of U.S. Patent No. 5,
378, 729 in 1991, which is prior art to the '551 patent.
The '729 patent issued to Dr. Kohn in 1995 and discloses
a genus of FAAs. Its specification explains that the claimed
compounds exhibit "central nervous system (CNS) activity
which are useful in the treatment of epi- lepsy and other CNS
disorders." '729 patent col. 111. 30-33. The
compounds of the '729 patent share the following general
at col. 111. 37-43. The '729 patent lists many different
compounds and groups that can be placed at each R position,
which the district court found could form millions of
possible compounds. Important to the issues here, the
'729 patent teaches that "[t]he preferred values of
R is aryl lower alkyl, especially benzyl" and
"[t]he most preferred R1 group is
methyl." Id. at col. 5 11. 17-19. For the
R3 position, the '729 patent lists a number of
preferred heterocyclics and alkyl and lower alkoxy groups but
does not list methoxymethyl. Id. at col. 6 11.
'729 patent also discloses Table 1 containing
pharmacological data for 54 FAAs. None of the compounds
listed in Table 1 are lacosamide, compound 107e disclosed in
LeGall, or any FAA compound with a methoxymethyl group at
R3. All of the compounds listed in Table 1 of the
'729 patent have a methyl at R1 and 49 of them
have an unsubstituted benzyl at R, all with varying potency,
ranging from 3.3 mg/kg to over 300 mg/kg. Of the top ten
compounds with the most potency (i.e., lowest ED50), eight
had heteroaromatic groups at R3 and two had
nitrogen-based groups. Unlike lacosamide, none of the most
potent compounds in Table 1 had a nonaromatic group at
R3. The four compounds with nonaromatic groups at
R3 showed moderate to weak potency.
Patent No. 5, 654, 301 is a continuation-in-part of the
'729 patent and was filed in 1993. The '301 patent is
not prior art to the '551 patent. Appellants rely on the
'301 patent only for their argument that the '551
patent is invalid for obviousness-type double patenting. Like
its parent '729 patent, the '301 patent claims
compounds of a general structure and recites several
different groups that can be placed at the R and
R1 positions. The relevant claims at issue for
purposes of double patenting are claims 39-47 of the '301
patent, which are reproduced below:
39. A compound of the formula
or the pharmaceutically acceptable salts thereof wherein R is
aryl, aryl lower alkyl, heterocyclic, heterocy-clic lower
alkyl, cycloalkyl or lower cycloalkyl lower alkyl, wherein R
is unsubstituted or is substituted with at least one electron
withdrawing group or an electron donating group;
R1 is hydrogen or lower alkyl and R1 is
unsubstituted or substituted with at least one electron
withdrawing group or at least one electron donating group;
A and Q are both O; one of R2 and R3 is
hydrogen and the other is lower alkyl which is substituted
with an electron donating group or a electron withdrawing
group and n is 1-4.
40. The compound according to claim 39 wherein one of
R2 and R3 is hydrogen and the other is
lower alkyl substituted with an electron donating group.
41. The compound according to claim 40 wherein one of
R2 and R3 is alkyl substituted with an
electron donating group wherein alkyl is methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, t-butyl, amyl or hexyl.
42. The compound according to claim 41 wherein one of
R2 and R3 is methyl substituted with an
electron donating group.
43. The compound according to claim 42 wherein the electron
donating group is lower alkoxy.
44. The compound according to claim 43 wherein lower alkoxy
is methoxy. 45. The compound according to any one of claims
39-44 wherein n is 1. 46.An anti-convulsant composition
comprising an anti-convulsant effective amount of a compound
from any one of claim 37-42 and a pharmaceutical carrier
47. A method of treating CNS disorders in an animal
comprising administering to said animal an anti-convulsant
effective amount of a compound of any one of claims 39-44.
'301 patent col. 93 l. 3 - col. 94 l. 21.
claim 39 permits a large number of groups at R,
R1, and R3, where each group can
comprise a large number of substituents and can be either
unsubsti-tuted or substituted. Hence, the district court
found that claim 39 could be thousands, if not millions, of
possible group combinations. Although the specification does
list some of the most preferred groups, the list also
contains generic categories of substituents, creating a large
scope of possible groups. Although lacosamide is not
specifically disclosed in the '301 patent, it is
undisputed that lacosamide falls within the broad genus of
claim 39 of the '301 patent.
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