IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`
`Case No. IPR2016-00204
`Patent No. RE 38,551
`
`PATENT OWNER PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
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`IPR2016-00204
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`029819.0100-US03
`
`Exhibit
`2001
`
`2002
`
`2003
`
`2004
`
`2005
`2006
`
`2007
`2008
`
`2009
`2010
`
`2011
`
`2012
`
`LIST OF EXHIBITS
`
`Description
`Richard H. Mattson, Efficacy and Adverse Effects of Established and
`New Antiepileptic Drugs, 36 (Suppl. 2) Epilepsia S13-S26 (1995).
`Richard H. Mattson, Drug Treatment of Uncontrolled Seizures, in
`Surgical Treatment of Epilepsy 29-35 (William H. Theodore ed.,
`1992).
`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 Feb. 2, 2016).
`Judith D. Conley & Harold Kohn, Functionalized DL-Amino Acid
`Derivatives. Potent New Agents for the Treatment of Epilepsy, 30 J.
`Med. Chem. 567-574 (1987).
`U.S. Provisional Patent Application No. 60/013,522.
`Bialer et al., Progress report on new antiepileptic drugs: a summary
`of the Sixth Eilat Conference (EILAT VI), 51 Epilepsy Res. 31-71
`(2002).
`Jerry March, Advanced Organic Chemistry 94-96 (4th ed. 1992).
`Decision Denying Institution of Inter Partes Review, IPR2014-
`01126, Paper 22.
`Curriculum Vitae of Dr. Farrokh Mistree, September 2014.
`Marcy Barge & W.T. Ingram, Inverse Limits on [0,1] Using Logistic
`Bonding Maps, 72 Topology and its Applications 159-72 (1996).
`Jack McBryde Jr., Inverse Limits on Arcs Using Certain Logistic
`Maps as Bonding Maps, Master’s Thesis, University of Houston,
`(1987).
`Trial Testimony of Dr. Clayton Heathcock, UCB, Inc., et al., v.
`Accord Healthcare, Inc., et. al., No. 13-1206-LPS (D. Del., Nov. 9,
`2015).
`
`Page i
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`IPR2016-00204
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`029819.0100-US03
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`Exhibit
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`2018
`
`2019
`
`2020
`
`Description
`FDA Approved Labeling Text dated July 9, 2015 for VIMPAT®
`(lacosamide), available at
`http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/022253s
`030,022254s022,022255s016lbl.pdf (last visited Feb. 2, 2016).
`Wolfgang Löscher & Dieter Schmidt, Strategies in Antiepileptic
`Drug Development: Is Rational Drug Design Superior to Random
`Screening and Structural Variation?, 17 Epilepsy Research 95-134
`(1994).
`Michael A. Rogawski & Roger J. Porter, Antiepileptic Drugs:
`Pharmacological Mechanisms and Clinical Efficacy with
`Consideration of Promising Developmental Stage Compounds, 42(3)
`Pharmacological Reviews 223-86 (1990).
`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 Feb. 2, 2016).
`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 Feb. 2, 2016).
`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 Feb. 2, 2016).
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`Page ii
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`IPR2016-00204
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`029819.0100-US03
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`Description
`ChemIDPlus, Toxnet, U.S. Nat’l Library of Medicine, Beclamide,
`http://chem.sis.nlm.nih.gov/chemidplus/rn/501-68-8 (last visited Feb.
`2, 2016).
`ChemIDPlus, Toxnet, U.S. Nat’l Library of Medicine, Phenacemide,
`http://chem.sis.nlm.nih.gov/chemidplus/rn/63-98-9 (last visited Feb.
`2, 2016).
`ChemIDPlus, Toxnet, U.S. Nat’l Library of Medicine, Valproic acid,
`http://chem.sis.nlm.nih.gov/chemidplus/rn/99-66-1 (last visited Feb.
`2, 2016).
`Portfolio − Mont Alto Capital,
`http://www.montaltocapital.com/portfolio/ (last visited Feb. 23,
`2016)
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`
`
`Exhibit
`2021
`
`2022
`
`2023
`
`2024
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`Page iii
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`IPR2016-00204
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`029819.0100-US03
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`TABLE OF CONTENTS
`
`Page(s)
`
`I.
`
`II.
`
`Introduction ..................................................................................................... 1
`
`The Development of the Inventions and the ‘551 Patent ............................... 4
`
`III. Level of Ordinary Skill in the Art .................................................................. 9
`
`IV. Claim Construction Under “Broadest Reasonable Interpretation” ................ 9
`
`A.
`
`B.
`
`“A Compound In the R Configuration” ............................................. 10
`
`“Therapeutic Composition” ................................................................ 13
`
`V.
`
`Petitioner Fails to Demonstrate a Reasonable Likelihood That at Least
`One Claim of the ‘551 Patent Is Unpatentable ............................................. 17
`
`A. Grounds 1A and 1B Should be Denied Under 35 U.S.C. §
`325(d) ................................................................................................. 17
`
`B.
`
`C.
`
`1.
`
`2.
`
`The Board Has Already Decided That the LeGall Thesis
`Does Not Qualify as a Printed Publication .............................. 18
`
`The Petition Provides No Credible Evidence of Public
`Accessibility of the LeGall Thesis To Justify Reversal of
`the Board’s Prior Ruling .......................................................... 19
`
`Ground 1A: Petitioner Fails to Show That the LeGall Thesis
`Anticipates Any of Claims 1 and 3-8 ................................................. 23
`
`Ground 1B: Petitioner Fails to Show That Claims 2 and 9-13
`are Unpatentable Over the LeGall Thesis and the ‘729 Patent .......... 26
`
`1.
`
`2.
`
`3.
`
`Claims 2 and 9 .......................................................................... 26
`
`Claim 10 ................................................................................... 36
`
`Claims 11-13 ............................................................................ 38
`
`D. Grounds 2A and 2B: Petitioner Fails to Show That Claims 1-13
`are Unpatentable Over Choi, Kohn 1991, and the ‘729 Patent .......... 40
`
`Page iv
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`IPR2016-00204
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`029819.0100-US03
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`1.
`
`2.
`
`3.
`
`Claim 1 ..................................................................................... 40
`
`Claims 2-9 ................................................................................ 44
`
`Claims 10-13 ............................................................................ 45
`
`E.
`
`Grounds 3A and 3B: Petitioner Fails to Show That Claims 1-13
`are Unpatentable Over Kohn 1991, Silverman, and the ‘729
`Patent .................................................................................................. 46
`
`1.
`
`2.
`
`3.
`
`Claim 1 ..................................................................................... 46
`
`Claims 2-9 ................................................................................ 50
`
`Claims 10-13 ............................................................................ 50
`
`F.
`
`Grounds 4A and 4B: Petitioner Fails to Show That Claims 1-13
`are Unpatentable Over Cortes, Kohn 1991, and the ‘729 Patent ....... 50
`
`1.
`
`2.
`
`3.
`
`Claim 1 ..................................................................................... 50
`
`Claims 2-9 ................................................................................ 53
`
`Claims 10-13 ............................................................................ 53
`
`VI. Objective Indicia Confirm That Petitioner Has Not Demonstrated A
`Reasonable Likelihood That At Least One Claim of the ‘551 Patent Is
`Obvious ......................................................................................................... 54
`
`VII. The Claims Are Entitled to the Provisional Application Filing Date .......... 58
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`Page v
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`IPR2016-00204
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`029819.0100-US03
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`TABLE OF AUTHORITIES
`
`Cases
`Apple Inc. v. DSS Tech. Mgmt., Inc.,
`IPR2015-00369, Paper 14 (P.T.A.B. Aug. 12, 2015) ......................................... 19
`
`Page(s)
`
`Computer Docking Station Corp. v. Dell, Inc.,
`519 F.3d 1366 (Fed. Cir. 2008) .......................................................................... 15
`
`Conopco, Inc. v. Procter & Gamble Co.,
`IPR2014-00506, Paper 25 (P.T.A.B. Dec. 10, 2014) ......................................... 18
`
`In re Cuozzo Speed Techs., LLC,
`793 F.3d 1268 (Fed. Cir. 2015) ............................................................................ 9
`
`Daiichi Sankyo Co. v. Matrix Labs., Ltd.,
`619 F.3d 1346 (Fed. Cir. 2010) .......................................................................... 27
`
`Deere & Co. v. Bush Hog, LLC,
`703 F.3d 1349 (Fed. Cir. 2012) .......................................................................... 15
`
`Eisai Co. v. Dr. Reddy's Labs., Ltd.,
`533 F.3d 1353 (Fed. Cir. 2008) .......................................................................... 27
`
`Flir Sys., Inc. v. Canvs Corp.,
`IPR2014-00773, Paper 7 (P.T.A.B. Sept. 4, 2014)............................................... 3
`
`Glaxo Wellcome, Inc. v. Impax Labs., Inc.,
`356 F.3d 1348 (Fed. Cir. 2004) .......................................................................... 15
`
`Gold Seal Importers v. Westerman-Rosenberg, Inc,
`133 F.2d 192 (2d Cir. 1943) ............................................................................... 20
`
`Johns Manville Corp. v. Knauf Insulation, Inc.,
`IPR2015-01527, Paper 17 (P.T.A.B. Dec. 17, 2015) ......................................... 19
`
`In re May,
`574 F.2d 1082 (C.C.P.A. 1978) .................................................................... 24, 25
`
`Otsuka Pharm. Co. v. Sandoz, Inc.,
`678 F.3d 1280 (Fed. Cir. 2012) ...................................................................passim
`
`Page vi
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`

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`IPR2016-00204
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`029819.0100-US03
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`In re Petering,
`301 F.2d 676 (C.C.P.A. 1962) ............................................................................ 25
`
`Pfizer, Inc. v. Ranbaxy Labs. Ltd.,
`405 F. Supp. 2d. 495 (D. Del. 2005) ................................................................... 24
`
`Poly-Am., L.P. v. GSE Lining Tech., Inc.,
`383 F.3d 1303 (Fed. Cir. 2004) .......................................................................... 15
`
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ............................................................................ 56
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) .............................................................. 23, 24, 25
`
`Scripps Clinic & Research Found. v. Genentech, Inc.,
`927 F.2d 1565 (Fed. Cir. 1991) .......................................................................... 23
`
`Seay v. Int'l Ass'n of Machinists,
`360 F. Supp. 123 (C.D. Cal. 1973) ..................................................................... 20
`
`Spectrum Pharms. Inc. v. Sandoz Inc.,
`802 F.3d 1326 (Fed. Cir. 2015) .......................................................................... 36
`
`Square, Inc. v. Think Comput. Corp.,
`CBM2015-00067, Paper 20 (P.T.A.B. Nov. 27, 2015) ...................................... 18
`
`In re Suitco Surface, Inc.,
`603 F.3d 1255 (Fed. Cir. 2010) .................................................................... 10, 17
`
`Travelocity.com L.P., et al. v. Cronos Techs., LLC,
`CBM2015-00047, Paper 7 (P.T.A.B. June 15, 2015) ......................................... 18
`
`Vizio, Inc. v. Int’l Trade Comm’n,
`605 F.3d 1330 (Fed. Cir. 2010) .......................................................................... 15
`
`Windsurfing Int’l, Inc. v. AMF, Inc.,
`782 F.2d 995 (Fed. Cir. 1986) ............................................................................ 56
`
`In re Wyer,
`655 F.2d 221 (C.C.P.A. 1981) ............................................................................ 21
`
`Page vii
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`

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`IPR2016-00204
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`Statutes
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`029819.0100-US03
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`35 U.S.C. § 102 ............................................................................................ 17, 19, 20
`
`35 U.S.C. § 311(b) ............................................................................................. 17, 19
`
`35 U.S.C. § 313 ........................................................................................................ 21
`
`35 U.S.C. § 314 ........................................................................................................ 21
`
`35 U.S.C. § 325(d) ............................................................................................. 17, 18
`
`American Inventors Protection Act of 1999, § 4801(d) (codified at 35
`U.S.C. § 119(e)(3)) ............................................................................................. 58
`
`Other Authorities
`
`37 C.F.R. § 1.78(a)(3) (1996) .................................................................................. 58
`
`37 C.F.R. § 42.22(a)(2) ............................................................................................ 45
`
`37 C.F.R. § 42.100(b) ................................................................................................ 9
`
`37 C.F.R. § 42.104(b)(4) .......................................................................................... 45
`
`77 Fed. Reg. 48,756 (Aug. 14, 2012)....................................................................... 45
`
`
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`Page viii
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`

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`IPR2016-00204
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`I.
`
`Introduction
`
`029819.0100-US03
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`Patent Owner Research Corporation Technologies, Inc. (“Patent Owner”)
`
`provides the following preliminary response to the petition filed by Argentum
`
`Pharmaceuticals LLC (“Petitioner” or “Argentum”), on November 23, 2015,
`
`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.
`
`In light of Petitioner’s recently-filed Updated Mandatory Notices addressing
`
`additional parties, Patent Owner continues to investigate the real parties-in-interest,
`
`including, inter alia, Mont Alto Capital, that should be named in the present
`
`petition. Not only is Mont Alto Capital located at the same address as Petitioner,
`
`Argentum is one of Mont Alto Capital’s portfolio companies in which it takes an
`
`active “founding, board, investment, or advisory role.” Ex. 2024, pp. 1-2, 5.
`
`The ‘551 Patent claims the compound lacosamide, therapeutic compositions
`
`comprising lacosamide, and methods of treating central nervous system (“CNS”)
`
`disorders such as epilepsy by administering lacosamide. The Petitioner does not
`
`and cannot dispute that the ‘551 Patent provides the first disclosure of lacosamide
`
`and its low liver toxicity, coupled with its strong anticonvulsant activity and low
`
`neurotoxicity, that make it ideal for the long-term administration needed for the
`
`treatment of epilepsy.
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`1
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`IPR2016-00204
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`029819.0100-US03
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`Petitioner fails to establish a reasonable likelihood that any claim of the ‘551
`
`Patent is unpatentable. First, like the earlier petition in Actavis, Inc., et al. v.
`
`Research Corp. Techs., Inc., IPR2014-01126, which the Board denied (the
`
`“Actavis Petition”), the petition1 here relies on the LeGall Thesis (Ex. 1008), but
`
`provides no basis for the Board to revisit its prior decision on the merits that the
`
`LeGall Thesis has not been shown to qualify as a “printed publication.”
`
`Second, the disclosure of a racemate (“compound 107e”) in the LeGall
`
`Thesis is the only basis for Petitioner’s argument that the R-enantiomer is
`
`anticipated. And even if the LeGall Thesis were a “printed publication,” Petitioner
`
`fails to cite, much less distinguish, controlling Federal Circuit precedent holding
`
`that the disclosure of a racemic compound does not disclose its individual
`
`stereoisomers. Thus, Petitioner’s anticipation argument cannot withstand the
`
`straightforward application of controlling legal principles. In addition, Petitioner
`
`fails to report inconsistent trial testimony from Dr. Heathcock,2 one of two
`
`
`1 The citations to the petition contained herein, “Pet. at __,” are identical for the as-
`
`filed petition and Ex. 1036 correcting the typographical error in the figure label on
`
`page 34. See Paper No. 8.
`
`2 Dr. Heathcock submitted a declaration in the prior IPR proceeding (IPR2014-
`
`01126), and Petitioner here relies on Dr. Heathcock as well, submitting the same
`
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`2
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`IPR2016-00204
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`declarants on whom Petitioner relies (Ex. 1003), explaining the difference between
`
`the prior art and the claimed compounds, thus destroying Petitioner’s anticipation
`
`argument.
`
`Third, Petitioner’s obviousness arguments and lead compound analysis are
`
`anchored in impermissible hindsight. By the 1996 priority date, not one
`
`antiepileptic drug (“AED”) approved by the FDA had the functionalized amino
`
`acid (“FAA”) backbone found in lacosamide, and no FAA compound, including
`
`lacosamide, had ever been administered to a human. And critically, Petitioner
`
`turns a blind eye to the absence of any pharmacological data for compound 107e or
`
`
`Heathcock declaration in support of its challenge. Ex. 1003; Pet. at 5; see also
`
`Declaration of Dr. Binghe Wang , Ex. 1002, ¶¶ 140-153 (discussing the Heathcock
`
`Declaration). Ex. 2012 is the November 9, 2015 direct, cross, and redirect trial
`
`testimony of Dr. Heathcock (appearing on behalf of defendants, including Actavis
`
`petitioners) in the consolidated Delaware litigation involving the ‘551 Patent
`
`(UCB, Inc., et al. v. Accord Healthcare, Inc., et al., No. 13-1206 (LPS) (D. Del.)).
`
`Because Dr. Heathcock testified before the filing of the present petition, and his
`
`testimony was not taken specifically for the purpose of the present proceeding, it is
`
`not “new testimony evidence,” and the Board can, and should, consider it. See Flir
`
`Sys., Inc. v. Canvs Corp., IPR2014-00773, Paper 7 at 2 (P.T.A.B. Sept. 4, 2014).
`
`3
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`IPR2016-00204
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`any FAA with a methoxymethyl at R3 prior to the ‘551 Patent.
`
`The state of the art in 1996 demonstrates why a POSA would not have
`
`selected an FAA as a lead, and why a POSA, even if given an FAA as a lead,
`
`would not have modified any such compound to synthesize lacosamide with a
`
`reasonable expectation of success. This leaves Petitioner with arguments based on
`
`unsupported conclusory statements that fail repeatedly to account for contradictory
`
`data and documents, and that engage repeatedly in impermissible hindsight. The
`
`Petitioner has failed to show a reasonable likelihood of prevailing on any claim in
`
`the asserted grounds.
`
`II. The Development of the Inventions and the ‘551 Patent
`
`The claimed inventions of the ‘551 Patent represent significant advances
`
`based on years of research. The inventions also met a long-recognized need to find
`
`a sufficiently safe and effective anticonvulsant drug for the long-term treatment of
`
`millions of patients afflicted with epilepsy for whom no available antiepileptic
`
`drugs could effectively treat their conditions. See, e.g., Exs. 2001, 2002.
`
`The discovery and development of antiepileptic drugs (“AEDs”) are
`
`difficult. As the ‘551 Patent explains, an antiepileptic drug should ideally do more
`
`than provide high anticonvulsant activity, minimal neurological toxicity, and a
`
`high margin of safety after acute administration. Ex. 1001, 3:14-55. Because each
`
`epileptic seizure or convulsion can be life-threatening, people with epilepsy need
`
`4
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`to take anticonvulsant drugs for their entire lives. An AED therefore also should be
`
`non-toxic, and safe relative to its potency, particularly during long-term, chronic
`
`administration. Id. at 3:36–38. Epilepsy is a heterogeneous disease, and each
`
`patient has different treatment needs, thus making the development of an effective
`
`and safe AED particularly challenging.
`
`The historic failures to find and develop sufficiently safe and effective
`
`antiepileptic drugs prompted the National Institutes of Health (“NIH”) in 1975 to
`
`establish the Anticonvulsant Screening Program (“ASP”) to facilitate and
`
`encourage the discovery of new anticonvulsant agents.3 Yet, as of 1996, the
`
`priority date of the ‘551 Patent, only one of the 16,000 compounds screened –
`
`felbamate – had gained FDA approval. But that product was later recognized to
`
`have “restricted value because of hematologic and hepatic toxicity.” Ex. 2001, pp.
`
`S21-S22. 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.4
`
`Dr. Harold Kohn, the inventor of the ‘551 Patent, conceived a new approach
`
`
`3 http://www.ninds.nih.gov/research/asp/index.htm
`
`4 FDA Approved Labeling Text dated August 27, 2012 (Ex. 2003).
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`5
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`IPR2016-00204
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`that was outside the mainstream of antiepileptic drug discovery. In the early 1980s,
`
`he theorized that a class of modified amino acids which he called “functionalized
`
`amino acids,” or “FAAs,” may demonstrate anticonvulsant activity, even though
`
`no known medical drug had this structure. See § V.C, infra; Ex. 2004, p. 568.
`
`When Dr. Kohn started his research, he 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
`
`chronic administration. Indeed, consistent with conventional lead compound
`
`analysis, no other researchers in the field had paid the least attention to FAAs.
`
`Most had instead pursued derivatives of compounds which had already undergone
`
`significant clinical testing, such as oxcarbazepine, a close derivative of the
`
`approved antiepileptic carbamazepine. Ex. 2001, p. S22.
`
`Despite disappointing early results for a number of FAAs from NIH’s
`
`antiepileptic drug screening program, Dr. Kohn persisted. After several years of
`
`research, he began to focus 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. While this compound had excellent efficacy
`
`and relatively low neurotoxicity, it also produced serious liver toxicity. Ex. 2005,
`
`p. 52; Ex. 1001, 36:28–30.
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`6
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`Dr. Kohn nevertheless continued his research. By late-1993, after nearly a
`
`decade of research, scores of experiments and frustrating results, Dr. Kohn tested
`
`additional FAAs, including (R,S) N-benzyl-2-acetamido-3-methoxypropionamide,
`
`a racemic compound. Unlike most of the other aliphatic analogs, this racemic
`
`compound exhibited surprising efficacy and
`
`low neurotoxicity. He
`
`then
`
`synthesized the two enantiomers of that compound in May of 1994. Subsequent
`
`testing of the two enantiomers demonstrated that the R enantiomer − (R) N-benzyl-
`
`2-acetamido-3-methoxypropionamide, that is, lacosamide − showed excellent
`
`efficacy with low neurotoxicity.
`
`Dr. Kohn knew, however, that high efficacy and low neurotoxicity are not
`
`enough: low or no liver toxicity over extended periods of administration is a
`
`critical property for antiepileptic drugs. As discussed in the ‘551 Patent,
`
`lacosamide, unlike other potentially promising FAAs Dr. Kohn had investigated,
`
`showed high efficacy and virtually no liver toxicity in a 30-day test (Ex. 1001,
`
`36:66–37:25; Table 6; see also Ex. 2005, pp. 51–52). Long-term toxicity studies
`
`confirmed that lacosamide had no significant adverse effects such as liver toxicity.
`
`See Ex. 2006, p. 43.
`
`Many of the pre-lacosamide discoveries resulting from Dr. Kohn’s early
`
`years of work are disclosed and claimed in broad terms in U.S. Patent No.
`
`5,378,729 (“the ‘729 Patent”; Ex. 1009) and its continuation-in-part, U.S. Patent
`
`7
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`IPR2016-00204
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`029819.0100-US03
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`No. 5,654,301 (“the ’301 Patent”; Ex. 1019). 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
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`the general formula shown in Fig. 1, including R3 as methyl, furanyl, azacycle,
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`amino and many others, encompassing virtually millions of compounds within
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`their disclosures and claims. See, e.g., Ex. 1019, 1:35-2:25; Ex. 1009, 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 the combination of high anticonvulsant efficacy, low neurotoxicity and
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`low liver toxicity. The ‘551 Patent also reports that this combination of
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`“advantages . . . have not heretofore been realized,” so that lacosamide “can be
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`used in a treatment regimen requiring administration thereof over extended periods
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`of time (chronic administration).” Ex. 1001, 37:47–51.
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`III. Level of Ordinary Skill in the Art
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`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”
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`“In an inter partes review, claim terms . . . are interpreted according to their
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`broadest reasonable construction in light of the specification of the patent in which
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`they appear.” In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275–79 (Fed. Cir.
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`2015)5; 37 C.F.R. § 42.100(b). “[C]laims should always be read in light of the
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`specification and teachings in the underlying patent” when determining their
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`5 reh’g en banc denied, 793 F.3d 1297 (Fed. Cir. 2015), cert. granted, 2016 WL
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`205946 (S. Ct. Jan. 15, 2016). Should the Supreme Court change the standard,
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`Patent Owner may at that time request leave to address the impact of such a ruling.
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`IPR2016-00204
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`broadest reasonable construction. In re Suitco Surface, Inc., 603 F.3d 1255, 1260
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`(Fed. Cir. 2010).
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`A.
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`“A Compound In the R Configuration”
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`Claim 1 recites “[a] compound in the R configuration” having the structural
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`formula recited in the claim. The broadest reasonable interpretation of “a
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`compound in the R configuration” is a compound containing greater than 50% of
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`the R-enantiomer. Such a construction, unlike Petitioner’s construction, is
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`consistent with the specification and the understanding in the art. The proper
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`interpretation of “a compound in the R configuration” is readily apparent from the
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`use of the term in the specification of the ‘551 Patent itself:
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`
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`As indicated by the asterisk in formula I, the compounds of the
`present invention contain at least one asymmetric carbon. The
`stereochemistry of the asymmetric carbon at the asterisk is in the R
`configuration. The inventor has found that the R stereoisomer at the
`asymmetric carbon at the asterisk is significantly more efficacious
`than the corresponding S enantiomer or a racemic mixture thereof.
`Ex. 1001, 4:1–9, 65–5:4 (emphases added); see also id. at 23:31–33.
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`The ‘551 Patent also explains that “melting point, optical rotation and 1H NMR
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`IPR2016-00204
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`upon addition of an organic acid in the R-configuration, such as R(–)-mandelic
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`acid” can determine the level of enantiopurity. Id. at 6:13-16. It further reports
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`that preferred compounds of the present invention are “substantially free from the
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`corresponding S enantiomer.” Id. at 5:11-19. Together, these statements from the
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`‘551 Patent − wholly ignored by Petitioner − leave no doubt that “a compound in
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`the R configuration” of claim 1 is a compound containing greater than 50% R
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`enantiomer.
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`This interpretation is also consistent with the fact that compounds in the R
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`configuration (having greater than 50% R enantiomer), compounds in the S
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`configuration (having greater than 50% S enantiomer), and racemic compounds
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`(having equal amounts of R and S enantiomer) have different chemical and
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`physical properties. See Ex. 2007 (explaining properties “such as melting points,
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`solubilities, and heats of fusion, are often different” for the racemate when
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`compared to the individual enantiomers); Ex. 1001, Table 1 (comparing melting
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`point of the racemate (R, S) in Comp. Ex. 9 to melting points of each enantiomer
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`(R) and (S) in Ex. 1, 2 and Comp. Ex. 11, respectively). The specification,
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`moreover, confirms that compounds of the ‘551 Patent in the R configuration, in
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`the S configuration, and racemates have different biological properties. See., e.g,
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`Ex. 1001 at 4:65-5:4 (different antiepileptic activity); Table 1 (different
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`antiepileptic activities and different neurotoxicities).
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`Rather than addressing these disclosures in the specification, Petitioner
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`argues instead that “a compound in the R configuration” includes compounds with
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`any amount of R-isomer. See Pet. at 10; Ex. 1002, ¶¶ 9–13. Thus, according to
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`Petitioner, “a compound in the R configuration” includes racemic compounds with
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`equal amounts of R and S enantiomer, as well as compounds that are substantially
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`enantiopure S enantiomer (e.g., compounds containing 99% S and only 1% R). See
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`Pet. at 10-11.
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`Under Petitioner’s construction, the term “in the R configuration” relays no
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`information about the relative amount of each enantiomer: the compound could
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`contain more R than S, more S than R, or equal amounts of R and S. Under the
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`Petitioner’s approach, each of these compounds could also be identified as “in the
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`S configuration.” A construction that equates a compound “in the R configuration”
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`with one “in the S configuration” is incorrect on its face, and is inconsistent with
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`the specification of the ‘551 Patent, which expressly discloses that the “racemic
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`mixture” (8:58–59) is not the final “R-product” (7:36). Rather, the racemic
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`mixture must be “resolved into the R isomer” (8:59) to arrive at “[t]he compounds
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`of the present invention in the R form” (5:20) or “in the R configuration” (4:65–
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`5:1). In other words, the specification is clear that the racemic compound is not “a
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`compound in the R configuration.”
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`Petitioner’s attempt to mischaracterize Patent Owner’s proposal in fact
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`demonstrates how the claims of the ‘551 Patent make perfect sense. Petitioner
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`asserts that, “[t]o the extent Patent Owner argues that claim 1 requires any level of
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`enantiomeric purity beyond the presence of a single R-isomer molecule, then
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`claims 2 and 9 are nonsensical. . . .” Pet. at 11. But claim 1 only requires a
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`compound “in the R configuration,” which means a compound having more R than
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`S enantiomer, ranging from a very small amount more to a great deal more R than
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`S. Claim 2 requires substantial enantiopurity, which the specification defines as
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`substantially free from the S enantiomer, meaning substantially more R tha