UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`ACTAVIS, INC., ACTAVIS LABORATORIES FL, INC., ACTAVIS PHARMA,
`INC., AMNEAL PHARMACEUTICALS, LLC, AMNEAL
`PHARMACEUTICALS OF NEW YORK, LLC, AUROBINDO PHARMA LTD.,
`AUROBINDO PHARMA USA, INC., BRECKENRIDGE PHARMACEUTICAL,
`INC., VENNOOT PHARMACEUTICALS, LLC, SANDOZ INC., SUN
`PHARMA GLOBAL FZE, and SUN PHARMACEUTICAL INDUSTRIES, LTD.,
`Petitioner
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner
`
`Case IPR2014-01126
`Patent RE38,551
`
`PATENT OWNER PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`
`DC: 5493200-5
`
`
`
`

`
`IPR2014-01126
`
`029819.0087-US03
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`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`LIST OF EXHIBITS
`
`
`Description
`Richard H. Mattson, Efficacy and Adverse Effects of Established and
`New Antiepileptic Drugs, 36 (Suppl. 2) Epilepsia S13-S26 (1995).
`FDA Approved Labeling Text dated August 27, 2012 for
`FELBATOL® (felbamate) , available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020189s
`027lbl.pdf (last visited Oct. 23, 2014).
`Robert Thornton Morrison & Robert Neilson Boyd, Organic
`Chemistry 120-133 (3d ed. 1973).
`Jerry March, Advanced Organic Chemistry 16-18 (3d ed. 1985).
`Richard H. Mattson, Drug treatment of uncontrolled seizures, in
`Surgical Treatment of Epilepsy 29-35 (William H. Theodore ed.,
`1992).
`John M. Pellock, Standard Approach to Antiepileptic Drug
`Treatment in the United States 35 (Suppl. 4) Epilepsia S11-S18
`(1994).
`Approval Listing dated December 27, 1994 for lamotrigine,
`Approved Drug Products with Therapeutic Equivalence Evaluations
`(Electronic Orange Book),
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Ap
`pl_No=020241&TABLE1=OB_Rx (last visited Oct. 23, 2014).
`The Merck Index 77, 290, 404, 407, 408, 508, 640, 670, 733, 915,
`998, 999, 1020, 1028, 1207, 1246, 1247, 1251, 1259, 1260, 1330,
`1654 (Susan Budavari et al. eds., 12th ed. 1996).
`Approval Listing dated August 5, 1996 for fosphenytoin sodium,
`Approved Drug Products with Therapeutic Equivalence Evaluations
`(Electronic Orange Book),
`http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Ap
`pl_No=020450&TABLE1=OB_Rx (last visited Oct. 23, 2014).
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`Page i
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`IPR2014-01126
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`Description
`FDA Approved Labeling Text dated January 2014 for CEREBYX®
`(fosphenytoin sodium injection) , available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/020450s
`023lbl.pdf (last visited Oct. 23, 2014).
`ChemIDPlus, Toxnet, U.S. Nat’l Library of Medicine, Beclamide,
`http://chem.sis.nlm.nih.gov/chemidplus/rn/501-68-8 (last visited Oct.
`23, 2014).
`ChemIDPlus, Toxnet, U.S. Nat’l Library of Medicine, Phenacemide,
`http://chem.sis.nlm.nih.gov/chemidplus/rn/63-98-9 (last visited Oct.
`23, 2014).
`ChemIDPlus, Toxnet, U.S. Nat’l Library of Medicine, Valproic acid,
`http://chem.sis.nlm.nih.gov/chemidplus/rn/99-66-1 (last visited Oct.
`23, 2014).
`Rogawski & Porter, Antiepileptic Drugs: Pharmacological
`Mechanisms and Clinical Efficacy with Consideration of Promising
`Developmental Stage Compounds, 42(3) Pharmacol. Rev. 223-86
`(1990).
`Bialer et al., Progress report on new antiepileptic drugs: a summary
`of the Sixth Eilat Conference (EILAT VI), 51 Epilepsy Res. 31-71
`(2002).
`
`
`
`
`
`Exhibit
`2010
`
`2011
`
`2012
`
`2013
`
`2014
`
`2015
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`
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`Page ii
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`

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`IPR2014-01126
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`029819.0087-US03
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`TABLE OF CONTENTS
`
`Page(s)
`Introduction ..................................................................................................... 1
`
`The Development of the Inventions and the ‘551 Patent ............................... 5
`
`I.
`
`II.
`
`III. Level of Ordinary Skill in the Art ................................................................ 10
`
`IV. Claim Construction Under “Broadest Reasonable Interpretation” .............. 11
`
`A.
`
`Petitioner’s Implicit Claim Construction of “Compound in the
`R Configuration” is Flawed ................................................................ 11
`
`B.
`
`Therapeutic Composition ................................................................... 13
`
`V.
`
`Petitioner Has Not Shown a Reasonable Likelihood That at Least One
`Claim of the ‘551 Patent Is Unpatentable ..................................................... 15
`
`A.
`
`Petitioner Has Failed to Show That the ‘301 Patent Anticipates
`Any Claim .......................................................................................... 15
`
`1.
`
`2.
`
`3.
`
`Claims 2 and 9 .......................................................................... 21
`
`Claim 10 ................................................................................... 22
`
`Claims 11-13 ............................................................................ 25
`
`B.
`
`C.
`
`Petitioner Has Failed to Show That the LeGall Thesis Is Prior
`Art Under 35 U.S.C. § 102 ................................................................. 27
`
`Petitioner Has Failed to Show That the LeGall Thesis
`Anticipates Any Claim ....................................................................... 30
`
`1.
`
`2.
`
`3.
`
`Claims 2 and 9 .......................................................................... 32
`
`Claim 10 ................................................................................... 34
`
`Claims 11-13 ............................................................................ 36
`
`D.
`
`Petitioner Has Failed to Show That Claims 1-13 are
`Unpatentable Over the LeGall Thesis in View of the ‘729
`Patent and “Other Prior Art” .............................................................. 37
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`Page iii
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`IPR2014-01126
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`1.
`
`2.
`
`Violating PTAB Regulations, The Petition Fails to
`Demonstrate a Reasonable Likelihood of Prevailing .............. 37
`
`The Petition Cherry-Picks From a Multitude of
`Compounds, Contravening Proper Lead Compound
`Analysis .................................................................................... 41
`
`3.
`
`Claims 10 and 11-13 ................................................................ 53
`
`VI. Objective Indicia Confirm That Petitioner Has Not Demonstrated A
`Reasonable Likelihood That At Least One Claim of the ‘551 Patent Is
`Obvious ......................................................................................................... 56
`
`VII. Conclusion .................................................................................................... 59
`
`
`
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`IPR2014-01126
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`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`ArcelorMittal France v. AK Steel Corp.,
`700 F.3d 1314 (Fed. Cir. 2012) .......................................................................... 17
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) .................................................................. 2, 15, 55
`
`Bristol-Meyers Squibb Co. v. Ben Venue Labs., Inc.,
`246 F.3d 1368 (Fed. Cir. 2001) .......................................................................... 32
`
`Cornell Univ. v. Hewlett-Packard Co.
`2008 U.S. Dist. LEXIS 39343 (N.D.N.Y. 2008) .......................................... 28, 29
`
`Daiichi Sankyo Co., Ltd. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .............................................................. 43, 47, 53
`
`Eisai Co. v. Dr. Reddy's Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 42
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 58
`
`Impax Labs., Inc. v. Aventis Pharm. Inc.,
`545 F.3d 1312 (Fed. Cir. 2008) .......................................................................... 34
`
`Impax Labs., Inc. v. Aventis Pharm. Inc.,
`468 F.3d 1366 (Fed. Cir. 2006) .......................................................................... 21
`
`In re Am. Acad. of Sci. Tech Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) .......................................................................... 11
`
`In re Arkley,
`455 F.2d 586 (C.C.P.A. 1972) ............................................................................ 17
`
`In re Baird,
`16 F.3d 380 (Fed. Cir. 1994) ................................................................................ 2
`
`In re Bass,
`314 F.3d 575 (Fed. Cir. 2002) ............................................................................ 11
`Page v
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`In re Cortright,
`165 F.3d 1353 (Fed. Cir. 1999) .......................................................................... 11
`
`In re Cronyn,
`890 F.2d 1158 (Fed. Cir. 1989) .......................................................................... 30
`
`In re Hall,
`781 F.2d 897 (Fed. Cir. 1986) ...................................................................... 28, 29
`
`In re May,
`574 F.2d 1082 (C.C.P.A. 1978) .................................................................... 13, 31
`
`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962) .................................................................. 2, 16, 17
`
`In re Ruschig,
`343 F.2d 965 (C.C.P.A. 1965) .............................................................................. 2
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007) .......................................................................... 57
`
`Pfizer, Inc. v. Ranbaxy Labs. Ltd.,
`405 F. Supp. 2d. 495 (D. Del. 2005) ............................................................. 31, 32
`
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 57
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2009) ....................................... 3, 13, 21, 22, 23, 31, 32
`
`Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd.,
`492 F.3d 1350 (Fed. Cir. 2007) .......................................................................... 42
`
`Statutes
`
`35 U.S.C. § 102 .................................................................................................. 27, 30
`
`35 U.S.C. § 314 .......................................................................................................... 1
`
`35 U.S.C. § 316(e) ..................................................................................................... 1
`
`Other Authorities
`
`37 C.F.R. § 42.6 ....................................................................................... 5, 17, 38, 39
`Page vi
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`37 C.F.R. § 42.22(a)(2) ...................................................................................... 38, 39
`
`37 C.F.R. § 42.100(b) .............................................................................................. 11
`
`37 C.F.R. § 42.104(b) .............................................................................. 5, 16, 38, 39
`
`77 Fed. Reg. 48756 (Aug. 14, 2012)........................................................................ 40
`
`Ex parte Smith, Appeal 2012-00822,
`2013 WL 3339418 (Patent Tr. & App. Bd., May 10, 2013) ........................ 17, 19
`
`IPR2013-00116, Final Written Decision, Paper No. 68,
`(Patent Tr. & App. Bd., June 20, 2014) .............................................................. 24
`
`IPR2014-00454, Decision Denying Institution, Paper No. 12,
`(Patent Tr. & App. Bd., Aug. 29, 2014) ....................................... 5, 17, 38, 39, 41
`
`IPR2014-00514, Decision Denying Institution, Paper No. 18,
`(Patent Tr. & App. Bd., Sept. 9, 2014) ......................................................... 27, 30
`
`NIH Anticonvulsant Screening Program,
`http://www.ninds.nih.gov/research/asp/index.htm ............................................... 7
`
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`IPR2014-01126
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`I.
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`Introduction
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`029819.0087-US03
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`Patent Owner Research Corporation Technologies, Inc. (“Patent Owner”)
`
`provides the following preliminary response to the Petition filed by Actavis, Inc.,
`
`et al. (“Petitioner”), on July 10, 2014, requesting inter partes review of claims 1-13
`
`of U.S. Patent No. RE38,551 (“the ‘551 Patent”). For at least the reasons set forth
`
`below, Patent Owner requests that the Board deny inter partes review as to all
`
`grounds of the Petition.
`
`No matter how often Petitioner tries to twist the facts and the law, it cannot
`
`change the conclusion reached by properly applying bedrock legal principles laid
`
`down by the Federal Circuit: the inventions of the ‘551 Patent are not anticipated
`
`by, or obvious in view of, any of the documents Petitioner cites. The Petitioner has
`
`the burden of proving unpatentability by a preponderance of the evidence, 35
`
`U.S.C. § 316(e), and it has failed to show a reasonable likelihood of prevailing on
`
`any claim in the asserted grounds. 35 U.S.C. § 314.
`
`In the very first sentence of the introduction, the Petition proclaims that
`
`“[t]he ‘551 patent issued only because the Examiner made a basic chemistry
`
`mistake.” Pet., p. 1. The Petition then spends nearly ten pages and a multitude of
`
`diagrams in an attempt to explain its assertion. Pet., pp. 16-26. The Examiner in
`
`fact got the chemistry and the law right that the ‘301 Patent (Ex. 1003) does not
`
`disclose lacosamide.
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`1
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`As to Ground I, the Petition fails to show that the ‘301 Patent anticipates any
`
`claim of the ‘551 Patent. The Petition’s repeated assertions (see, e.g., Pet., pp. 1, 2,
`
`18, and 24) that the ‘301 Patent “expressly discloses lacosamide”1 is wrong and
`
`cannot overturn decades of settled Federal Circuit jurisprudence that there may be
`
`many species encompassed within a genus that are not disclosed by the genus
`
`itself. See, e.g., Atofina v. Great Lakes Chem. Corp., 441 F.3d 991, 999 (Fed. Cir.
`
`2006) (“There may be many species encompassed within a genus that are not
`
`disclosed by a mere disclosure of the genus.”); In re Baird, 16 F.3d 380, 382 (Fed.
`
`Cir. 1994); In re Ruschig, 343 F.2d 965, 974 (C.C.P.A. 1965). Far from “expressly
`
`disclosing lacosamide,” Petitioner’s expert, Dr. Heathcock, conducts a classically
`
`prohibited hindsight analysis of the ‘301 Patent, “picking and choosing” the values
`
`of various variables in the broad genus claims of the ‘301 Patent, which analysis
`
`does not, and cannot, establish that a person skilled in the art would “at once
`
`envisage” a compound claimed by the ‘551 Patent, much less lacosamide in
`
`particular. See, e.g., In re Petering, 301 F.2d 676, 681 (C.C.P.A. 1962).
`
`Moreover, ignoring controlling precedent, Petitioner argues that one of
`
`ordinary skill in the art (referred to in the Petition as a “POSA”) would be able to
`
`obtain “substantially enantiopure” and “90%” pure lacosamide as recited in claims
`
`1 Lacosamide is referred to in the ‘551 Patent as “BAMP.” See Ex. 1001, 24:56-
`
`58.
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`2
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`2 and 9. See, e.g., Pet., pp. 30-31. Nowhere does Petitioner even attempt to
`
`address well settled Federal Circuit precedent that anticipation requires a specific
`
`description of the subject matter at issue, not just its enablement. See, e.g., Sanofi-
`
`Synthelabo v. Apotex, Inc., 550 F.3d 1075, 1084 (Fed. Cir. 2009) (“The knowledge
`
`that enantiomers may be separated is not ‘anticipation’ of a specific enantiomer
`
`that has not been separated, identified, and characterized.”).
`
`With respect to Ground II, the Petition fails to establish that the LeGall
`
`Thesis is prior art. Beyond this, the Petition’s admission that the LeGall Thesis
`
`discloses nothing more than a racemic mixture (“compound 107e”) is fatal under
`
`controlling Federal Circuit case law to the Petition’s Ground II contention that the
`
`LeGall Thesis anticipates any claim of the ‘551 Patent, which are all directed only
`
`to compounds in the R stereoisomer configuration. Sanofi, 550 F.3d at 1084.
`
`Finally, the Ground III argument that the LeGall Thesis, the ‘729 Patent, and
`
`“other prior art” render obvious the claims of the ‘551 Patent, cannot be sustained.
`
`The Petition presents no supportable rationale why a POSA would have selected a
`
`functionalized amino acid (“FAA”) as a lead compound, much less compound
`
`107e of the LeGall Thesis. Thousands of different options included, for example,
`
`structurally different antiepileptic drugs in development, already tested or
`
`approved, and research into compounds with different modes of action.2 The
`
`2 See, e.g., Exs. 2006-2014 and note 3 infra.
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`3
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`Petition impermissibly focuses on structural similarity. It is only through
`
`impermissible hindsight that compound 107e is selected as its lead compound.
`
`The Petition simply ignores critical and well-known facts that would have
`
`led a POSA to select any of a number of other compounds as the lead. Petitioner
`
`fails to mention that, at the priority date of the ‘551 Patent, not one anticonvulsant
`
`marketed in the United States contained an FAA backbone, like lacosamide.3 The
`
`Petition also fails to report that at the time there was no clinical data for any FAA,
`
`in contrast to the data for other approved and differently-structured antiepileptic
`
`drugs (“AEDs”). Rounding out its incomplete description of the landscape of the
`
`art at the time, Petitioner has not attempted to explain why a POSA would pay
`
`attention to a master’s thesis disclosing a racemic compound that had not been
`
`characterized or tested, especially when dozens of other compounds had been
`
`characterized and tested, and especially when subsequent articles co-authored by
`
`that same student did not mention that racemic compound even once.
`
`The Petition also fails to satisfy the requirements of the Board’s regulations
`
`implementing the statute in other important respects. The Petition does not meet
`
`3Exs. 2006-2007 identify 24 antiepileptic drugs marketed in the U.S. prior to the
`
`March 1996 priority date. See Exs. 2008 & 2011-13 (chemical structures). FDA
`
`next approved an antiepileptic drug, also not an FAA, in August 1996. See Exs.
`
`2009, 2010.
`
`4
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`the requirements of 37 C.F.R. § 42.104(b) to “specify where each element of the
`
`claim is found in the prior art patents or printed publications relied upon” and to
`
`provide “the relevance of the evidence to the challenge raised.” For example, as
`
`explained in Section V.D. below, the Petition’s obviousness argument improperly
`
`fails to provide a detailed explanation of the relevance of the numerous “other prior
`
`art” documents it cites, and fails to specify where each element of the challenged
`
`claims is found in the “other prior art.”
`
`The Petition also engages in impermissible incorporation by reference, in
`
`violation of § 42.6(a)(3), by including citations to the Heathcock Declaration (Ex.
`
`1002) to support conclusory statements for which the Petition does not otherwise
`
`provide an argument or explanation. See Sections V.A. and V.D. below; IPR2014-
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`00454, Paper 12, p. 9. This includes an improper incorporation by reference of at
`
`least 50 pages of the Heathcock Declaration.
`
`The Petition does not demonstrate a reasonable likelihood of prevailing with
`
`respect to any challenged claim. The Petition also fails in material and prejudicial
`
`ways to comply with important Board regulations.4 The Petition should be denied.
`
`II. The Development of the Inventions and the ‘551 Patent
`The claimed inventions of the ‘551 Patent -- including the compound
`
`lacosamide, therapeutic compositions comprising lacosamide, and methods of
`
`4 37 C.F.R. §§ 42.6(a)(3), 42.104(b). See Sections V.A. and V.D., infra.
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`5
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`treating central nervous system (“CNS”) disorders, such as epilepsy, by
`
`administering lacosamide -- represent a significant advance that required years of
`
`research. The inventions also met a long-recognized need to find a sufficiently
`
`safe and effective anticonvulsant drug for the chronic treatment of millions of
`
`Americans, and many millions more in other countries, afflicted with epilepsy, and
`
`for whom no currently available antiepileptic drugs effectively treat their
`
`conditions. See, e.g., Exs. 2001, 2005. Each epileptic seizure or convulsion can be
`
`life-threatening, so that people with epilepsy need to take anticonvulsant drugs for
`
`their entire lives, making
`
`the search for anticonvulsant drugs especially
`
`challenging.
`
`As the ‘551 Patent explains (3:14-55), it is not enough for an anticonvulsant
`
`drug to provide high anticonvulsant activity, minimal neurological toxicity, and a
`
`high margin of safety. An anticonvulsant drug also needs to be non-toxic, and safe
`
`relative to its potency, particularly for an anticonvulsant taken during long term,
`
`chronic administration. ‘551 Patent, 3:36-38. In fact, these criteria for being non-
`
`toxic, and safe relative to its potency, may be the most important factors in
`
`determining which anticonvulsant to administer to a patient, especially when
`
`chronic administration is required. Id. at 3:38-41.
`
`The historic failures to find and develop sufficiently safe and effective
`
`antiepileptic drugs prompted the National Institutes of Health in 1975 to establish
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`the Anticonvulsant Screening Program (“ASP”) to facilitate and encourage the
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`discovery of new anticonvulsant agents.5 Yet, as of 1996, the priority date for the
`
`‘551 Patent, only one of the 15,000 compounds screened by NIH -- felbamate --
`
`had gained FDA approval. However, the product was later recognized to have
`
`“restricted value because of hematologic and hepatic toxicity.” Ex. 2001, pp. S21-
`
`S22 (citing FDA Talk Paper, Felbatol update, Sept. 27, 1994). Indeed, just one
`
`year after market entry in 1993, the FDA required the labeling for felbamate to
`
`include a “black box” warning that it “should only be used in patients whose
`
`epilepsy is so severe” that the administering physician concluded that the risk of
`
`liver failure and aplastic anemia was acceptable.6
`
`Dr. Harold Kohn, the inventor of the ‘551 Patent, conceived a new approach
`
`that was outside the mainstream of antiepileptic drug discovery. In the early
`
`1980s, he theorized that modified amino acids known as FAAs may demonstrate
`
`anticonvulsant activity, even though this structure was not contained in any
`
`marketed anticonvulsant compounds. See Section V.D. below; Ex. 1017, p. 568.
`
`When he started his research, Dr. Kohn thus had no evidence that any FAA would
`
`exhibit anticonvulsant activity, low or no neurological toxicity, a high margin of
`
`safety, and minimal adverse effects, such as low liver toxicity, during long term
`
`5 http://www.ninds.nih.gov/research/asp/index.htm
`
`6 FDA Approved Labeling Text dated August 27, 2012 (Ex. 2002).
`
`7
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`chronic administration. Hence, consistent with lead compound analysis, most
`
`researchers in the field had pursued derivatives of compounds which had already
`
`undergone significant clinical testing, such as oxcarbazepine, a close derivative of
`
`the approved antiepileptic carbamazepine. Ex. 2001, S22.
`
`Despite disappointing early results for a number of FAAs from NIH’s
`
`antiepileptic drug screening program, Dr. Kohn persisted. At that time, he focused
`
`primarily on heteroaromatic FAA analogs, a class including at least hundreds of
`
`compounds. One of the most promising of these heteroaromatic analogs contained
`
`a furanyl substituent, and was evaluated with the assistance of the NIH and Eli
`
`Lilly. Despite excellent efficacy and relatively low neurotoxicity, this compound
`
`also produced serious liver toxicity. Ex. 1012, p. 52; Ex. 1001, 36:28-30.
`
`Dr. Kohn forged on. By late-1993, after nearly a decade of research, scores
`
`of experiments and frustrating results, Dr. Kohn tested additional aliphatic analogs,
`
`including (R,S) N-benzyl-2-acetamido-3-methoxypropionamide, after he had
`
`strongly focused on heteroaromatic compounds the years before. This compound
`
`is a racemic mixture of two enantiomers, one of which is lacosamide. Unlike most
`
`of the other aliphatic analogs, but like the heteroaromatic-substituted analogs, this
`
`racemic compound exhibited both efficacy and low neurotoxicity. Synthesis and
`
`testing of its two enantiomers demonstrated that the R enantiomer -- (R) N-benzyl-
`
`8
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`2-acetamido-3-methoxypropionamide, that is, lacosamide -- showed excellent
`
`efficacy with still low neurotoxicity.
`
`Dr. Kohn knew, however, that high efficacy and low neurotoxicity were not
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`enough: low or no liver toxicity over extended periods of administration was also
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`required. This was the criterion that the furanyl analog and so many other
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`compounds had failed to meet. Initial toxicity results lead Dr. Kohn to believe that
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`lacosamide might be the candidate for which he had been looking for so long. As
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`discussed in the ‘551 Patent, lacosamide, unlike other potentially promising FAAs
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`Dr. Kohn had previously investigated, showed virtually no liver toxicity in a 30-
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`day test (Ex. 1001, 36:66-37:25; Table 6; see also Ex. 1012, pp. 61-62), and long
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`term toxicity studies confirmed that lacosamide had no significant adverse effect,
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`such as chronic liver toxicity. See Ex. 2015, p. 43.
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`Many of the pre-lacosamide discoveries resulting from Dr. Kohn’s early
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`years of work are disclosed in broad terms and claimed in U.S. Patent No.
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`5,378,729 (“the ’729 Patent”; Ex. 1008) and its continuation-in-part, U.S. Patent
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`No. 5,654,301 (“the ’301 Patent”; Ex. 1003). Those patents describe amino acid
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`derivatives having the general formula set forth in Fig. 1 below.
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`Fig. 1
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`Those patents also provide examples of the R, R1, R2 and R3 substituents in the
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`
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`general formula shown in Fig. 1, including R3 as methyl, furanyl, azacycle, amino
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`and many others, encompassing hundreds of thousands of compounds within their
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`disclosures and claims. See, e.g., Ex. 1003, 1:35-2:25; Ex. 1008, 1:35-2:20.
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`Neither the ‘301 Patent nor the ‘729 Patent, however, nor any of the
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`documents cited by Petitioner, discloses the specific compound lacosamide
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`(referred to in the ‘551 Patent as “BAMP”; see Ex. 1001, 24:56-58). The ‘551
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`Patent also provides the first teaching that lacosamide, unlike other FAA analogs,
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`exhibits high anticonvulsant efficacy, low neurotoxicity and low liver toxicity,
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`“exhibit[ing] advantages that have not heretofore been realized,” so that
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`lacosamide “can be used in a treatment regimen requiring administration thereof
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`over extended periods of time (chronic administration).” ‘551 Patent, 37:49-51.
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`III. Level of Ordinary Skill in the Art
`As noted above, the inventions of the ‘551 Patent are directed not only to
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`compounds such as lacosamide, but also to therapeutic compositions comprising
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`lacosamide, and methods of treating central nervous system disorders, such as
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`epilepsy, by administering lacosamide. Therefore, one of ordinary skill in the art
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`would need knowledge and experience both in medicinal or organic chemistry, as
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`well as the development of potential drug candidates, suitable for chronic
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`administration, to treat central nervous system disorders, with knowledge and
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`experience in assessing, together with others, the toxicology, pharmacology, and
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`clinical utility of such candidates.
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`IV. Claim Construction Under “Broadest Reasonable Interpretation”
`“[T]he PTO must give claims their broadest reasonable interpretation” (In re
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`Cortright, 165 F.3d 1353, 1358 (Fed. Cir. 1999); 37 C.F.R. § 42.100(b)), which
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`must be “consistent with the specification.” In re Am. Acad. of Sci. Tech Ctr., 367
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`F.3d 1359, 1364 (Fed. Cir. 2004) (internal quotation marks and citation omitted).
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`Furthermore, the broadest reasonable interpretation must “tak[e] into account any
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`definitions presented in the specification.” In re Bass, 314 F.3d 575, 577 (Fed. Cir.
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`2002).
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`A.
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`Petitioner’s Implicit Claim Construction of “Compound in the R
`Configuration” is Flawed
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`The Petition states “that the terms in the claims of the ‘551 patent do not
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`have any special meanings and are presumed to take on their broadest reasonable
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`meaning consistent with the understanding of a person of ordinary skill in the art
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`(‘POSA’) when read in light of the ‘551 patent’s specification.” Pet., p. 8. The
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`only “construction” proffered in the Petition is that “the term ‘compound’ as used
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`in each of claims 1-13 of the ‘551 patent includes the compound known as
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`lacosamide.” Id. However, as Petitioner’s expert, Dr. Heathcock, recognizes, the
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`term to be construed is not “compound,”7 but rather, “compound in the R
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`configuration.” Although Dr. Heathcock includes a construction of this term in his
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`declaration (Ex. 1002, ¶ 37), Petitioner fails to cite Dr. Heathcock in the claim
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`construction section, instead slipping in a cite to ¶ 37 in support of its erroneous
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`argument that the LeGall Thesis anticipates the claims of the ‘551 Patent.
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`Dr. Heathcock’s interpretation of “compound in the R configuration” cannot
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`be correct. According to his declaration, the term “compound in the R
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`configuration” of claim 1 would “include mixtures of enantiomeric compounds of
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`the claimed formula that include any amount of the relevant enantiomer with the R
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`configuration.” Ex. 1002, ¶ 37 (emphasis added). But if a “compound in the R
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`configuration” means “any amount of the relevant enantiomer with the R
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`configuration” as Dr. Heathcock asserts, then a “compound in the R configuration”
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`(e.g., a compound with 90% R and 10% S; see, e.g., Ex. 1001, 5:11-19) would be
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`indistinguishable from a “compound in the S configuration” (e.g., a compound
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`with 90% S and 10% R) and from the racemic mixture (i.e., a compound with
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`equal amounts of R and S; Ex. 2003, p. 127). Such an interpretation would be
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`7 In contrast, the ‘729 Patent (Ex. 1008) and the ‘301 Patent (Ex. 1003) recite just
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`“compound,” and not “compound in the R configuration” as in the ‘551 Patent.
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`inconsistent with well-settled principles of stereochemistry (see, e.g., Ex. 2003),
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`and the specification of the ‘551 Patent (see, e.g., 5:11-19; 5:1-4 and 23:31-33 that
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`distinguish between R stereoisomer, S stereoisomer and the racemic mixture).
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`The law is well settled that an optical isomer (e.g., R or S) of a particular
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`compound is not the same as a racemic mixture of the isomers. In re May, 574
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`F.2d 1082, 1090 (C.C.P.A. 1978) (“the novelty of an optical isomer is not negated
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`by the prior art disclosure of its racemate”); Sanofi, 550 F.3d at 1083–84
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`(disclosure of the racemate is not “a description of the specific dextrorotatory
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`enantiomer”). Dr. Heathcock’s construction therefore improperly fails to treat the
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`R stereoisomer, the S stereoisomer and the racemic mixture as the different
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`compounds that they are.
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`Therapeutic Composition
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`B.
`Claim 10 is directed to a “therapeutic composition” which comprises “a
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`compound according to any one of claims 1-9 and a pharmaceutical carrier
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`therefor.” Patent Owner submits that the broadest reasonable interpretation of
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`“therapeutic composition” consistent with the specification of the ‘551 Patent is
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`“composition suitable for use as a treatment regimen over an extended period of
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`time (chronic administration).”
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`The ’551 Patent repeatedly emphasizes the importance of low toxicity to the
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`patient over the long term, a feature necessary for an antiepileptic drug to be
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`administered chronically. See, e.g., Ex. 1001, 2:62-3:61; 8:62-9:26; 10:29-52;
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`21:13-24; 24:30-29:29; 37:5-51. The specification emphasizes the distinction
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`between two types of treatments -- short-term (e.g., “acute dosing”) and long-term
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`(e.g., “chronic dosing”) -- for epilepsy and related CNS disorders. See, e.g., Ex.
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`1001, 1:45-54. The specification also reports that “[t]he mainstay of treatment for
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`such disorders has been
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`the
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`long-term and