Paper No. ____
`Filed: June 22, 2016
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`Filed on behalf of Alembic Pharmaceuticals, Ltd.
`By:
`Jeffer Ali
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`Gary J. Speier
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`CARLSON, CASPERS, VANDENBURGH, LINDQUIST & SCHUMAN, P.A.
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`225 South Sixth St., Suite 4200
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`Minneapolis, MN 55402
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ALEMBIC PHARMACEUTICALS, LTD., Petitioner
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`v.
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`RESEARCH CORPORATION TECHNOLOGIES, INC., Patent Owner
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`
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`Case No. Unassigned
`Patent No. RE38,551
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`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. RE38,551
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`TABLE OF CONTENTS
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`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................... 1
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................. ..1
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`TABLE OF CONTENTS
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`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1) .......................... 1
`A.
`Real Parties—In—Interest under 37 C.F.R. § 42.8(b)(1) ........................ ..1
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`B. Related Matters under 37 C.F.R. § 42.8(b)(2) ...................................... 1
`B.
`Related Matters under 37 C.F.R. § 42.8(b)(2) .................................... ..1
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`C. Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3)...................... 2
`C.
`Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3) .................... ..2
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`D. Service Information under 37 C.F.R. § 42.8(b)(4) ................................ 2
`D.
`Service Information under 37 C.F.R. § 42.8(b)(4) .............................. ..2
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`II. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ............................ 3
`REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 .......................... ..3
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`A. Grounds for Standing Under 37 C.F.R. § 42.104(a) ............................. 3
`A.
`Grounds for Standing Under 37 C.F.R. § 42.104(a) ........................... ..3
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`B.
`B.
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`Identification of Challenge, 37 C.F.R. § 42.104(b) .............................. 3
`Identification of Challenge, 37 C.F.R. § 42.104(b) ............................ ..3
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`III.
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`III. SUMMARY OF THE ’551 PATENT ............................................................. 6
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`SUMMARY OF THE ’55 1 PATENT ........................................................... ..6
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`IV. PREVIOUS PETITION FILED BY OTHER UNRELATED PARTIES ....... 8
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`PREVIOUS PETITION FILED BY OTHER UNRELATED PARTIES ..... ..8
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`IV.
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`V. CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) .................... 9
`CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) .................. ..9
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`A.
`A.
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`B.
`B.
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`“Therapeutic Composition” in Claim 10 ............................................... 9
`“Therapeutic Composition” in Claim 10 ............................................. ..9
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`“A Compound in the R Configuration” in Claim 1 ............................11
`“A Compound in the R Configuration” in Claim 1 .......................... ..11
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`VI.
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`VI. LEVEL OF SKILL AND KNOWLEDGE IN THE ART .............................13
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`LEVEL OF SKILL AND KNOWLEDGE IN THE ART ........................... .. 13
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`A. Cortes (Ex. 1015) ................................................................................14
`A.
`Cortes (Ex. 1015) .............................................................................. ..14
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`B. LeGall (1987) (Ex. 1008) ....................................................................15
`B.
`LeGall (1987) (Ex. 1008) .................................................................. ..15
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`C. Kohn 1991 (Ex. 1012) .........................................................................16
`C.
`Kohn 1991 (Ex. 1012) ....................................................................... ..16
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`D.
`D.
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`’729 Patent (1991) (Ex. 1009) .............................................................18
`’729 Patent (1991) (Ex. 1009) ........................................................... ..18
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`E. Kohn 1993 (Ex. 1017) .........................................................................19
`E.
`Kohn 1993 (Ex. 1017) ....................................................................... ..19
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`F. Choi (1995) (Ex. 1010) .......................................................................20
`F.
`Choi (1995) (Ex. 1010) ..................................................................... ..20
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`G.
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`’301 Patent (1995) (Ex. 1019) .............................................................21
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`VII. CLAIM-BY-CLAIM EXPLANATION OF GROUNDS FOR
`UNPATENTABILITY ..................................................................................23
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`A. Ground 1A: Claims 1 and 3-8 Are Anticipated by LeGall .................23
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`1. New evidence establishes that LeGall is prior art ....................23
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`2.
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`LeGall discloses “racemic lacosamide” and R-lacosamide
`and therefore anticipates claims 1 and 3-8 ................................25
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`B. Ground 1B: Claims 2 and 9-13 Are Obvious Over LeGall and
`The ’729 Patent ...................................................................................26
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`1. Claims 2 and 9 to “substantial” or “90%” pure
`R-enantiomer are obvious over LeGall and ’729 patent ...........26
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`2. Claim 10 to a “therapeutic composition” is obvious over
`LeGall and the ’729 patent ........................................................30
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`3. Claims 11-13 to methods of treatment are obvious over
`LeGall and ’729 patent ..............................................................33
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`C. Ground 2A: Claims 1-9 Are Obvious Over Choi and Kohn 1991 ......36
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`1. Choi and Kohn 1991 are prior art .............................................36
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`2.
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`3.
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`4.
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`POSA had a reason to select Compound 2d of Choi as
`a lead compound .......................................................................37
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`POSA had a reason to modify the hydroxymethyl
`compound to a “functionalized oxygen” group ........................42
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`POSA would have a reasonable expectation of success
`in making racemic lacosamide and R lacosamide ....................44
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`D. Ground 2B: Claims 10-13 Are Obvious Over Choi, Kohn 1991,
`And ’729 Patent ...................................................................................45
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`E. Ground 3A: Claims 1-9 Are Obvious Over Kohn 1991 and
`Silverman .............................................................................................45
`ii
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`1. Kohn 1991 and Silverman are prior art ....................................45
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`2. Activity data and bioisosterism suggest the change from
`methoxyamino to methoxymethyl (lacosamide) ......................46
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`F. Ground 3B: Claims 10-13 Are Obvious Over Kohn 1991,
`Silverman, and ’729 Patent .................................................................49
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`G. Ground 4A: Claims 1-9 Are Obvious Over Cortes and
`Kohn 1991 ...........................................................................................50
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`1. Cortes and Kohn 1991 are prior art ..........................................50
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`2.
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`3.
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`POSA had a reason to select the methyl compound of
`Cortes or Kohn 1991 as a lead compound ................................50
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`POSA had a reason to modify the methyl substituent to
`a methoxymethyl .......................................................................51
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`H. Ground 4B: Claims 10-13 Are Obvious Over Cortes,
`Kohn 1991, And ’729 Patent ...............................................................53
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`VIII. THERE ARE NO SECONDARY CONSIDERATIONS OF
`NONOBVIOUSNESS ...................................................................................54
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`IX. THE CLAIMS ARE NOT ENTITLED TO THE PROVISIONAL
`FILING DATE ...............................................................................................56
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`X. GROUNDS 1-4 ARE NON-CUMULATIVE OF EACH OTHER ..............58
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`XI. THE BOARD SHOULD NOT DECLINE TO INSTITUTE
`BASED ON ITS DISCRETIONARY AUTHORITY UNDER
`35 U.S.C. § 325(D) ........................................................................................58
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`XII. CLAIMS CHART FOR DEPENDENT CLAIM 2 AND 9-13 .....................59
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`XIII. CONCLUSION ..............................................................................................60
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`XIV. CERTIFICATE OF COMPLIANCE ............................................................61
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`XV. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103..........62
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`iii
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`EXHIBIT LIST ........................................................................................................63
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`EXHIBIT LIST ...................................................................................................... ..63
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`CERTIFICATE OF SERVICE ................................................................................66
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`CERTIFICATE OF SERVICE .............................................................................. ..66
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`iv
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`Alembic Pharmaceuticals, Ltd. (“Petitioner”) requests that Board institute
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`inter partes review (“IPR”) of claims (1-13) of U.S. Patent No. RE 38,551 to Kohn
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`(“the ’551 patent”) (Ex. 1001), and that these claims be canceled as unpatentable
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`over the prior art. Inter partes review of claims 1-13 the ’551 patent, was
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`instituted in IPR2016-00204 on May 23, 2016, based on a petition filed by
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`Argentum Pharmaceuticals LLC (“Argentum”). For the sake of completeness and
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`efficiency, the present Petition is a practical copy of the petition in IPR2016-
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`00204. Petitioner is requesting however, that the Board institute only on the
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`Grounds instituted in IPR2016-00204, i.e., Grounds 3A and 3B as to claims 1-13,
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`and not on Grounds 1A, 1B, 2A, 2B, 4A, and 4B. A motion for Joinder with
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`IPR2016-00204 is being filed concurrently with this Petition.
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`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
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`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1)
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`The following real parties-in-interest are identified: Alembic
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`Pharmaceuticals, Ltd., the Petitioner in this matter.
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`B. Related Matters under 37 C.F.R. § 42.8(b)(2)
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`On May 23, 2016, the Board instituted inter partes review of claims 1-13 of
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`the ’551 patent in IPR2016-00204 based on a petition filed by Argentum.
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`Previously, in IPR2014-01126, the Board denied institution of inter partes review
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`of the ’551 patent based on a petition filed by Actavis, Inc., Actavis Laboratories
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`FL, Inc., Actavis Pharma, Inc., Amneal Pharmaceuticals of New York, LLC,
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`Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc., Breckendridge
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`Pharmaceutical, Inc., Vennoot Pharmaceuticals, LLC, Sandoz Inc., Sun Pharma
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`Global FZE, and Sun Pharmaceutical Industries, Ltd. On July 10, 2013, UCB, Inc.
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`et al. asserted claims for infringement of the ’551 patent in UCB, Inc. et al. v.
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`Alembic Pharmaceuticals, Ltd., 1:13-cv-01207, in the District of Delaware, which
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`case was consolidated with UCB, Inc. v. Accord Healthcare Inc., 1:13-cv-01206
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`(D. Del. Jul. 10, 2013).
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`C. Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3)
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`Lead Counsel: Jeffer Ali (Reg. No. 46,359)
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`Back-Up Counsel: Gary J. Speier (Reg. No. 45,458)
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`D.
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`Service Information under 37 C.F.R. § 42.8(b)(4)
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`Petitioner hereby consents to electronic service.
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`Email: jali@carlsoncaspers.com; gspeier@carlsoncaspers.com
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`Post: CARLSON, CASPERS, VANDENBURGH, LINDQUIST &
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`SCHUMAN, P.A.
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`225 South Sixth Street, Suite 4200, Minneapolis, MN 55402
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`Tel.: 612-436-9600 Fax: 612-436-9605
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`2
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`II. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104
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`A. Grounds for Standing Under 37 C.F.R. § 42.104(a)
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`Petitioner hereby certifies that IPR is available for the ’551 patent and that
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`Petitioner is not barred or estopped from requesting an IPR challenging the patent
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`claims on the instituted grounds identified in this petition because a motion for
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`joinder has been filed to join IPR2016-00204 no later than 1 month after institution
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`in accordance with 37 C.F.R. § 42.122(b) and 35 U.S.C. § 315(c).
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`B.
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`Identification of Challenge, 37 C.F.R. § 42.104(b)
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`Petitioner requests cancellation of claims 1-13 of the ’551 patent on the
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`following grounds:
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`Ground
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`Claims
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`Basis
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`1A
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`1B
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`2A
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`2B
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`3A
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`3B
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`4A
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`4B
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`1, 3-8
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`2, 9-13
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`1-9
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`10-13
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`1-9
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`10-13
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`1-9
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`10-13
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`§ 102(b)
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`§ 103
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`§ 103
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`§ 103
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`§ 103
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`§ 103
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`§ 103
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`§ 103
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`Reference(s)
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`LeGall
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`LeGall and ’729 patent
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`Choi and Kohn 1991
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`Choi, Kohn 1991, and ’729 patent
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`Kohn 1991 and Silverman
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`Kohn 1991, Silverman, and ’729 patent
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`Cortes and Kohn 1991
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`Cortes, Kohn 1991, and ’729 patent
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`3
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`Grounds 1-4 are practical copies of the grounds presented in the petition in
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`IPR2016-00204, including Grounds 3A-3B that were instituted by the Board,
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`challenging the same claims over the same prior art and using the same arguments
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`and expert testimony. Each of Grounds 1-4 identifies a different prior art
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`compound that independently would have served as a “starting reference point or
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`points,” from which a person of ordinary skill in the art (“POSA”) would have
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`easily arrived at lacosamide—the compound claimed in the ’551 patent. Eisai Co.
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`Ltd. v. Dr. Reddy’s Labs., 533 F.3d 1353, 1359 (Fed. Cir. 2008); see Altana
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`Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009)
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`(affirming the selection of up to “18 exemplary compounds” as lead compounds
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`and rejecting the notion that chemical obviousness requires “only a single lead
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`compound”).
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`This case presents a unique set of facts that establish the uncommon instance
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`in which a patent claim to a compound is anticipated and/or rendered obvious.
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`Here, the compound lacosamide was first disclosed in the thesis of the graduate
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`student of the ’551 patent’s named inventor approximately eight years before the
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`relevant patent application was filed. Even putting aside that novelty destroying
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`reference, at least three other specific combinations of prior art would have
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`directed a person of ordinary skill in the art directly to lacosamide and its use. This
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`is not a case of selecting a single favorable lead compound so that one preordains
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`4
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`the obviousness analysis. Rather, this petition presents four separate examples of
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`applying clear teachings in the prior art (as summarized in the figure below) to
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`establish that the claims to lacosamide are unpatentable.
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`Moreover, the prior art contained repeated statements directing one to use
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`the R-isomer. The various references stressed that the R-isomer was the
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`biologically active isomer. Finally, the therapeutic composition and method claims
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`in the ’551 patent add no specific limitations other than standard, generic
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`limitations, such as a “pharmaceutical carrier” and “administering to an animal.”
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`With the prior art data confirming the anticonvulsant activity of the compounds,
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`those generic limitations cannot render the claimed subject matter patentable.
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`Prior Art Compounds Disclosed in Grounds I - IV
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`5
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`Petitioner supports its challenges with a Declaration of Dr. Binghe Wang
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`(“Wang Decl.”) (Ex. 1002) prepared for IPR2016-00204,1 as well as a Declaration
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`of Dr. Clayton H. Heathcock (“Heathcock Decl.”) (Ex. 1003) from IPR2014-
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`01126.
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`III. SUMMARY OF THE ’551 PATENT
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`The ’551 patent lists Harold Kohn as its sole inventor and Research
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`Corporation Technologies, Inc. as the assignee. The ’551 patent is a reissue of
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`U.S. Patent No. 5,773,475 (“the ’475 patent”) (Ex. 1005), which issued from U.S.
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`Patent Application No. 08/818,688 (“the ’688 application”) filed on March 17,
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`1997, and which claims priority to U.S. Provisional Application No. 60/013,522
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`filed on March 15, 1996 (the earliest possible effective date). As explained in Part
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`IX, infra, the ’551 patent is not entitled to the earlier 1996 priority date.
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`Claim 1 is the sole independent claim in the ’551 patent. Claim 1 reads:
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`1 The Wang Declaration is an exact copy of Dr. Wang’s declaration from IPR2016-
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`00204, which was relied upon by the Board in that proceeding. Dr. Wang’s
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`IPR2016-00204 Declaration is cited in this Petition to avoid unnecessary cost and
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`to advance efficiency in this instance. As mentioned above, this Petition is
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`presented along with a motion to join IPR2016-00204, and by using the same
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`Declaration, Petitioner has eliminated the need for analysis of another declaration
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`or the addition of a new expert.
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`6
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`1. A compound in the R configuration having the formula:
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`wherein
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`Ar is phenyl which is unsubstituted or substituted with at least one
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`halo group;
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`Q is lower alkoxy, and
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`Q1 is methyl.
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`Claims 2-9 are compound claims depending directly or indirectly from claim 1.
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`Claim 8 is lacosamide, specified by its chemical name: “The compound according
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`to claim 1 which is (R)-N-Benzyl 2-Acetamido-3-methoxypropion-amide.” The
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`structure of lacosamide is shown below (wherein Ar is benzyl, Q is
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`methoxymethyl, and Q1 is methyl):
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`7
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`Claim 10 recites “[a] therapeutic composition comprising an anticonvulsant
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`effective amount of a compound according to any one of claims 1-9 and a
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`pharmaceutical carrier therefor.”
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`Claim 11-13 are method claims. Claim 11 reads:
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`11. A method of treating central nervous system disorders in an
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`animal comprising administering to said animal in need thereof an
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`anticonvulsant effective amount of a compound according to any one
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`of claims 1-9.
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`Claim 12 depends from claim 11 and specifies that the “the animal is a
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`mammal.” Claim 13 depends from claim 12 and specifies that “the mammal is a
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`human”.
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`IV. PREVIOUS PETITION FILED BY OTHER UNRELATED PARTIES
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`This is the first petition filed against the ’551 patent by Petitioner or its real
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`parties in interest. As mentioned above, in IPR2016-00204, filed by an unrelated
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`party, the Board instituted review of claims 1-9 (Ground 3A), based on Kohn 1991
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`and Silverman, and of claims 10-13 (Ground 3B), based on Kohn 1991, Silverman,
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`and the ’729 patent. The Board previously declined to institute a review in
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`IPR2014-01126, filed by parties unrelated to Petitioner. There, Patent Owner
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`argued that LeGall was not shown to be prior art, and the Board agreed. (Prelim.
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`Resp. 27-30.) The Board also found that the petition failed to establish a
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`8
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`reasonable likelihood on three asserted grounds of unpatentability: (1) anticipation
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`by the ’301 patent, (2) anticipation by LeGall, and (3) obviousness over LeGall and
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`the ’729 patent. See IPR2014-01126, Paper 22 (“Dec.”). For the first ground
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`(anticipation by the ’301 patent), the prior petitioners alleged that claims 39-44 of
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`the ’301 patent, together with preferences recited in the ’301 patent, anticipate
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`lacosamide. The Board disagreed, finding no anticipation based on the preferred
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`genus of compounds. Dec. 8-9. For the second ground (anticipation by LeGall),
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`the Board found that LeGall was not shown to be a “printed publication” under §
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`102(b). Id. at 12-13. Finally, the third ground was denied for the same reason as
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`the second. Id. at 14.
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`V. CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3)
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`A.
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`“Therapeutic Composition” in Claim 10
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`In the district court litigation, the court construed one term in the ’551
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`patent: “therapeutic composition,” which appears only in the preamble of claim 10.
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`To the extent Patent Owner attempts to rely on the district court’s construction,
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`that construction was unnecessary and, in any event, is not the broadest reasonable
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`interpretation (“BRI”).
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`First, claim 10 is a product claim that recites two limitations: an
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`“anticonvulsant effective amount” of the compound, and a “pharmaceutical
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`9
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`carrier.”2 The body of the claim sets forth all limitations of the claimed invention.
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`The preamble, “a therapeutic composition,” does not “give life, meaning, and
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`vitality” to the claim, but merely describes an intended purpose, and is therefore
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`non-limiting. See Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997) (“[W]here a
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`patentee defines a structurally complete invention in the claim body and uses the
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`preamble only to state a purpose or intended use for the invention, the preamble is
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`not a claim limitation.”).
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`Second, the term “therapeutic composition” does not specify any additional
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`physical structure or physical components other than the two recited in the body of
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`the claim. The ’551 patent does not provide a definition of the term “therapeutic
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`composition.” Nor does the patent use that term in any special manner, other than
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`introducing the claimed compound in a pharmaceutical carrier. By definition, a
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`compound within the genus, together with a pharmaceutical carrier, is a therapeutic
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`composition within the meaning of claim 10.
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`Third, the BRI of “therapeutic composition” is not confined to the additional
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`limitations imposed by the district court. Specifically, applying Phillips, the
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`district court construed the term to mean “[a] composition suitable for use as a
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`treatment regimen over an extended period of time (chronic administration).” Ex.
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`2 Claim 10 reads in full: “A therapeutic composition comprising [1] an
`anticonvulsant effective amount of a compound according to any one of claims 1-9
`and [2] a pharmaceutical carrier therefor.”
`10
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`1007 at 5. The BRI cannot be limited to only a composition that is administered
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`“over an extended period of time” and for “chronic administration.” Nothing in
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`the claim limits the composition to “chronic administration.” See Ex. 1001 cols. 9-
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`10 (reciting a litany of acceptable dosage forms and excipients).
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`Additionally, the claims do not numerically limit the term “anticonvulsant
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`effective amount.” Applying the BRI, this term should be construed to mean any
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`amount that could provide an anticonvulsant effective amount of the compound
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`when administered. The specification again does not define a specific range but
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`does provide various ranges as guidance. For instance, the ’551 patent states that
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`“[a] unit dosage form can, for example, contain the principal active compound in
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`amounts ranging from about 5 to about 1000 mg.” Ex. 1001 at 10:52-59. The ’551
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`patent also states that the compositions can contain “from about 1 to about 750
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`mg/ml of carrier,” id. at 10:59, or “preferred . . . between about 5 and 100 mg of
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`active compound,” id. at 9:25-26, or “at least 1% of active compound,” id. at 9:17-
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`18. At a minimum, a composition containing about 5 to about 1000 mg of the
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`claimed compound, and a pharmaceutical carrier, is a “therapeutic composition”
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`within the meaning of claim 10.
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`B.
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`“A Compound in the R Configuration” in Claim 1
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`Petitioner does not believe that the phrase “a compound in the R
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`configuration” in claim 1 needs to be construed. Patent Owner, however, put that
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`11
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`phrase into issue in IPR2014-01126. Patent Owner’s preliminary response did not
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`propose a construction of the term but instead quibbled that the former petitioners’
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`construction “improperly fails to treat the R stereoisomer, the S stereoisomer and
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`the racemic mixture as the different compounds that they are.” Prelim. Resp. at 13.
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`Here, the BRI of “a compound in the R configuration” covers R-isomer
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`compounds, whether the R-isomer is substantially pure or mixed with the S-
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`isomer, such as a racemic mixture or isomerically enriched compound. But the
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`claim does not cover pure S-isomer, which would have no R-isomer. The
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`declaration of Prof. Wang explains why a POSA would have this understanding.
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`Ex. 1002 ¶¶ 9-13.
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`Claim 2 confirms this construction, which further limits claim 1 to
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`“substantially enantiopure.” Applying claim differentiation, claim 2 further
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`restricts the amount of S-isomer that is included in the scope of the claim,
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`specifying that the compound be “substantially enantiopure.” The ’551 patent
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`explains that “substantially enantiomerically pure” can include at least 10% (w/w)
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`of the S-isomer. Ex. 1001 at 5:11-16.
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`Claim 9 also confirms the above construction, which specifies the
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`“compound according to claim 8”—i.e., (R)-N-benzyl-2-acetamido-3-
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`methoxypropionamide—“contains at least 90% (w/w) R stereoisomer.” Because
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`claim 9 depends from claim 1, and because claim 9 includes compositions having
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`up to 10% (w/w) of the S-isomer, so must claim 1. Moreover, claim 1 does not
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`limit the amount of R- or S-isomer present in the composition—only that it cannot
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`be solely S. Nor does the specification provide any lower numerical limit for claim
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`1, other that it cannot be solely S. To the extent Patent Owner argues that claim 1
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`requires any level of enantiomeric purity beyond the presence of a single R-isomer
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`molecule, then claims 2 and 9 are nonsensical and the Board should hold all claims
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`indefinite under 35 U.S.C. § 112(b). See BlackBerry Corp. v. MobileMedia Ideas
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`LLC, IPR2013-00036 (Paper 65) (terminating IPR after finding claims indefinite).
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`VI. LEVEL OF SKILL AND KNOWLEDGE IN THE ART
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`As of March 15, 1996 (the earliest possible effective date), a hypothetical
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`POSA would “be aware of all the pertinent prior art” at the time of the alleged
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`invention. Custom Accessories, Inc. v. Jeffrey-Allan Indus., 807 F.2d 955, 963
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`(Fed. Cir. 1986). Factors relevant in determining the level of skill include: the
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`“type of problems encountered in art; prior art solutions to those problems; rapidity
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`with which innovations are made; sophistication of the technology; and
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`educational level of active workers in the field.” Id.
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`The relevant field is medicinal chemistry, and a POSA would have a Ph.D.
`
`in organic or medicinal chemistry and at least a few years of experience in
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`medicinal chemistry, including in the development of potential drug candidates.
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`Ex. 1002, ¶ 13. The POSA would also include a person having a Bachelor’s or
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`Master’s degree (organic chemistry or medicinal chemistry) if such a person had
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`more years of experience in medicinal chemistry and the development of potential
`
`drug candidates. Id. With experience in drug development, the POSA would have
`
`an appreciation of the diseases and ailments a particular drug candidate is intended
`
`to treat, but would not necessarily be a medical doctor or clinician. The POSA
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`would know how to evaluate the physical and biological properties of chemical
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`compounds and would be able to conduct, or otherwise have access to resources
`
`that could conduct, in vitro and in vivo evaluations of biological and toxicity
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`properties of chemical compounds. Id.
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`The following prior art references, summarized below, would have further
`
`informed a POSA’s skill and understanding of the art.
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`A. Cortes (Ex. 1015)
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`In 1985, Sergio Cortes co-authored an article with Dr. Harold Kohn which
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`reported the synthesis and anticonvulsant activity four amino acid derivatives (as
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`well as nitrogen-containing compounds). Ex. 1015 at 601 abstr. Cortes reported
`
`that N-acetyl-D,L-alanine benzylamide (compound 6d, “AAB”) was “[a]mong the
`
`most active compounds.” Id. This compound is the “methyl compound,” depicted
`
`below:
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`Methyl Compound (AAB)
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`With its favorable data, the methyl compound (AAB) was “slated for additional
`
`screening,” which yielded “[p]romising results.” Id. at 604. The methyl
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`compound (AAB) of Cortes became the starting point for several projects
`
`developing additional anticonvulsant agents. Ex. 1002, ¶¶ 120-128.
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`B.
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`LeGall (1987) (Ex. 1008)
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`LeGall (Ex. 1008) (also referred to as the “LeGall Thesis”) is a 1987
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`master’s thesis by Philippe LeGall, a student of inventor Dr. Harold Kohn. LeGall
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`describes the synthesis and anticonvulsant activity of “analogues of the potent
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`anticonvulsant agent” AAB, i.e., the methyl compound, from Cortes, thus
`
`conducting the “additional screening” that Cortes recommended. Ex. 1008 at 42,
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`132, 173 n.102. LeGall synthesized five compounds 107a-e that were “selected as
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`polar analogues of the potent anticonvulsant” lead methyl compound (AAB,
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`compound 68a. The data for those compounds is provided in the following table:
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`15
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`Id. at 133, Tbl. 35. Compound 107e depicts racemic lacosmaide, whose R
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`substituent is methoxymethyl (-CH2OCH3), and which includes both the R- and S-
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`isomers. Ex. 1002, ¶¶ 20, 57-59. Furthermore, a POSA would immediately
`
`recognize that the structure show discloses both R-lacosamide and S-lacosamide.
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`Id.
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`LeGall taught an express preference for the R configuration, i.e., the “D-
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`enantiomer,” of the methyl compound (AAB), observing that the R-isomer is
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`“thirteen times more active” than the S stereoisomer and “more potent and less
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`toxic than the corresponding racemates.” Ex. 1008 at 42, 164; Ex. 1002, ¶ 26.
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`C. Kohn 1991 (Ex. 1012)
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`In 1991, Kohn and LeGall (along with others) published a paper in the
`
`Journal of Medicinal Chemistry which adopted Cortes’s suggestion to make
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`analogues of the highly potent lead, the methyl compound (AAB) (compound 2a in
`
`Kohn 1991). Ex. 1012 at 2444. Kohn 1991 tested numerous methyl compound
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`derivatives which retained the core structure and varied only the R group on the α-
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`carbon (shown as “X” below):
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`
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`Id. at 2445, Tbl. I.
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`Of the multiple compounds that were prepared and tested, Kohn 1991
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`reported that the most active was the methoxyamino compound (3l), whose
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`structure is shown below:
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`
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`Id. at 2444, abstr.; id. at 2445, Tbl. I. The methoxymethyl compound had an
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`ED50 6.2 mg/kg. A close analogue, the methoxy(methyl)amino (3n) was also quite
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`potent, with an ED50 of 6.7 mg/kg. Id. at 2445, Tbl. I.
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`Reviewing the potency of all tested compounds, Kohn 1991 taught “several
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`important observations” about the structure-activity relationships for compounds
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`based on the lead methyl compound AAB. First, Kohn 1991 explained that amino
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`compound “displayed anticonvulsant activit[y] comparable to that observed for the
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`α-methyl analogue.” Ex. 1002, ¶ 30. Second, there are “stringent steric
`
`
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`17
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`requirements that exist for maximal anticonvulsant activity in this class of
`
`compounds,” referring specifically to the size of the group on the α-carbon. Third,
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`in the most potent analogues, “a functionalized oxygen atom existed two atoms
`
`removed from the α-carbon atom.” Id. at 2447.
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`D.
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`’729 Patent (1991) (Ex. 1009)
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`In 1991, a U.S. patent application was filed which named Dr. Kohn as an
`
`inventor, and issued as U.S. Patent No. 5,378,729 (“’729 patent”). The ’729 patent
`
`discloses a genus of anticonvulsant compounds covering lacosamide. Ex. 1009;
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`Ex. 1002, ¶ 32. The general structure is depicted below, along with the more
`
`specific formula applying Kohn’s expressly “preferred” substituents:
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`
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`Ex. 1009, col. 1:30-2:20. The ’729 patent described the preferred substituents as
`
`follows: “n is 1,” R is “especially benzyl,” and “[t]he most preferred R1 group is
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`methyl.” Id. at 5:14-19.
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`The above genus of the ’729 patent covers lacosamide. Lacosamide is the
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`R-enantiomer of the claimed compound, where R is “aryl lower alkyl,” i.e., the
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`“especially [preferred] benzyl,” id. at 5:17-18, R1 is “lower alkyl,” i.e., the “most
`
`
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`18
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`preferred . . . methyl,” id. at 5:17-19, and one of R2 and R3 is “hydrogen” and the
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`other “lower alkyl,” i.e., methylene, “substituted with . . . at least one electron
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`donating substituent,” i.e., “methoxy,” id. at 4:37.
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`As with other prior art references, the ’729 patent reiterates the preference
`
`for the R-isomer. Ex. 1002, ¶ 33; Ex. 1009 at 15:31-16:4 (“The D stereoisomer is
`
`preferred.”). The ’729 patent also includes data supporting the preference for the
`
`R-isomer. Ex. 1009, 58-61, Tbl. 1; Ex. 1002, ¶ 34. The ’729 patent cites known
`
`techniques for synthesizing and separating stereoisomers. Ex. 1009, 15:31-16:4.
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`Finally, the ’729 patent discloses that “compounds of the present invention
`
`exhibit excellent anticonvulsant activity,” id. at 16:5-7, that the compounds are
`
`administered with a “pharmaceutically acceptable carrier,” id. at 17:53-54, and that
`
`“[t]he use of such media and agents for pharmaceutical active substances is well
`
`known in the art,” id. at 17:54-58.
`
`E. Kohn 1993 (Ex. 1017)
`
`In 1993, Dr. Kohn published additional results in the Journal of Medicinal
`
`Chemistry providing further information about preferences in the chemical
`
`structure of potent anticonvulsants derived from the methyl compound AAB of
`
`Cortes. Ex. 1017. The report evaluated an “expanded set of C(α)