`Filed: May 25, 2016
`
`Filed on behalf of: Mylan Pharmaceuticals Inc.
`By: Steven W. Parmelee
`
`Michael T. Rosato
`
`Jad A. Mills
`WILSON SONSINI GOODRICH & ROSATI
`
`701 Fifth Avenue, Suite 5100
`Seattle, WA 98104-7036
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`
`_____________________________
`
`Case No. IPR2016-01101
`Patent No. RE38,551
`
`_____________________________
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. RE38,551
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`
`MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ............................................. 1
`
`A.
`
`Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1) .......................... 1
`
`B.
`
`C.
`
`Related Matters under 37 C.F.R. § 42.8(b)(2) ..................................... 1
`
`Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3) ..................... 2
`
`D.
`
`Service Information under 37 C.F.R. § 42.8(b)(4) ............................... 2
`
`II.
`
`REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ...................................... 2
`
`A. Grounds For Standing Under 37 C.F.R. § 42.104(a) ........................... 2
`
`B.
`
`Identification of Challenge, 37 C.F.R. § 42.104(b) ............................. 3
`
`III.
`
`SUMMARY OF THE ‘551 PATENT ..................................................................... 6
`
`IV. PREVIOUS PETITION FILED BY OTHER UNRELATED PARTIES ........................... 7
`
`V.
`
`CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3) ............................... 8
`
`A.
`
`“Therapeutic Composition” in Claim 10 ............................................. 8
`
`B.
`
`“A Compound in the R Configuration” in Claim 1 ............................ 10
`
`VI. LEVEL OF SKILL AND KNOWLEDGE IN THE ART ............................................ 12
`
`A.
`
`Cortes (Ex. 1015) .............................................................................. 13
`
`B.
`
`C.
`
`LeGall (1987) (Ex. 1008) .................................................................. 13
`
`Kohn 1991 (Ex. 1012)....................................................................... 14
`
`D.
`
`’729 Patent (1991) (Ex. 1009) ........................................................... 16
`
`E.
`
`F.
`
`Kohn 1993 (Ex. 1017)....................................................................... 17
`
`Choi (1995) (Ex. 1010) ..................................................................... 18
`
`G.
`
`’301 Patent (1995) (Ex. 1019) ........................................................... 19
`
`-i-
`
`
`
`
`VII. CLAIM-BY-CLAIM EXPLANATION OF GROUNDS FOR UNPATENTABILITY ........ 20
`
`A. Ground 1A: Claims 1 and 3-8 Are Anticipated by LeGall ................. 20
`
`1.
`
`2.
`
`New evidence establishes that LeGall is prior art .................... 21
`
`LeGall discloses “racemic lacosamide” and R-lacosamide
`and therefore anticipates claims 1 and 3-8............................... 22
`
`B.
`
`Ground 1B: Claims 2 and 9-13 Are Obvious Over LeGall And
`The ’729 Patent ................................................................................. 23
`
`1.
`
`2.
`
`3.
`
`Claims 2 and 9 to “substantially” or “90%” pure R-
`enantiomer are obvious over LeGall and ’729 patent .............. 23
`
`Claim 10 to a “therapeutic composition” is obvious over
`LeGall and the ’729 patent ...................................................... 27
`
`Claims 11-13 to methods of treatment are obvious over
`LeGall and ’729 patent ............................................................ 29
`
`C.
`
`Ground 2A: Claims 1-9 Are Obvious Over Choi and Kohn
`1991 .................................................................................................. 32
`
`1.
`
`2.
`
`3.
`
`4.
`
`Choi and Kohn 1991 are prior art ............................................ 32
`
`POSA had a reason to select Compound 2d of Choi as a
`lead compound ........................................................................ 32
`
`POSA had a reason to modify the hydroxymethyl
`compound to a “functionalized oxygen” group........................ 38
`
`POSA would have a reasonable expectation of success in
`making raceamic lacosamide and R lacosamide ...................... 39
`
`D. Ground 2B: Claims 10-13 Are Obvious Over Choi, Kohn 1991,
`And ’729 Patent ................................................................................ 40
`
`E.
`
`Ground 3A: Claims 1-9 Are Obvious Over Kohn 1991 and
`Silverman .......................................................................................... 40
`
`1.
`
`Kohn 1991 and Silverman are prior art ................................... 41
`
`-ii-
`
`
`
`2.
`
`Activity data and bioisosterism suggest the change from
`methoxyamino to methoxymethyl (lacosamide) ...................... 41
`
`
`
`F.
`
`Ground 3B: Claims 10-13 Are Obvious Over Kohn 1991,
`Silverman, and ’729 Patent ............................................................... 44
`
`G. Ground 4A: Claims 1-9 Are Obvious Over Cortes and Kohn
`1991 .................................................................................................. 44
`
`1.
`
`2.
`
`3.
`
`Cortes and Kohn 1991 are prior art ......................................... 45
`
`POSA had a reason to select the methyl compound of
`Cortes or Kohn 1991 as a lead compound ............................... 45
`
`POSA had a reason to modify the methyl substituent to a
`methoxymethyl ....................................................................... 46
`
`H. Ground 4B: Claims 10-13 Are Obvious Over Cortes, Kohn
`1991, And ’729 Patent ...................................................................... 48
`
`VIII. THERE ARE NO SECONDARY CONSIDERATIONS OF NONOBVIOUSNESS........... 48
`
`IX. THE CLAIMS ARE NOT ENTITLED TO THE PROVISIONAL FILING DATE ............ 50
`
`X. GROUNDS 1-4 ARE NON-CUMULATIVE OF EACH OTHER................................ 51
`
`XI. THE BOARD SHOULD NOT DECLINE TO INSTITUTE BASED ON ITS
`DISCRETIONARY AUTHORITY UNDER 35 U.S.C. § 325(D) ............................. 52
`
`XII. CLAIMS CHART FOR DEPENDENT CLAIM 2 AND 9-13..................................... 53
`
`XIII. CONCLUSION ............................................................................................... 54
`
`XIV. CERTIFICATE OF COMPLIANCE ...................................................................... 55
`
`XV. PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(A) AND 42.103 ...................... 56
`
`
`
`
`
`
`
`-iii-
`
`
`
`
`
`Mylan Pharmaceuticals Inc. (“Petitioner”) requests that the Board institute
`
`inter partes review (“IPR”) of claims (1-13) of U.S. Patent No. RE 38,551 to Kohn
`
`(“the ’551 patent”) (Ex. 1001), and that these claims be canceled as unpatentable
`
`over the prior art. Inter partes review of claims 1-13 the ’551 patent, was
`
`instituted in IPR2016-00204 on May 23, 2016, based on a petition filed by
`
`Argentum Pharmaceuticals LLC (“Argentum”). For the sake of completeness and
`
`efficiency, the present Petition is a practical copy of the petition in IPR2016-
`
`00204. Petitioner is requesting however, that the Board institute only on the
`
`Grounds instituted in IPR2016-00204, i.e., Grounds 3A and 3B as to claims 1-13,
`
`and not on Grounds 1A, 1B, 2A, 2B, 4A, and 4B. A motion for Joinder with
`
`IPR2016-00204 is being filed concurrently with this Petition.
`
`I. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`A. Real Parties-In-Interest under 37 C.F.R. § 42.8(b)(1)
`
`The following real parties-in-interest are identified: Mylan Pharmaceuticals
`
`Inc., the Petitioner in this matter and a wholly owned subsidiary of Mylan Inc.;
`
`Mylan Inc., which is an indirectly wholly owned subsidiary of Mylan N.V.; and
`
`Mylan N.V.
`
`B. Related Matters under 37 C.F.R. § 42.8(b)(2)
`
`On May 23, 2016, the Board instituted inter partes review of claims 1-13
`
`of the ’551 patent in IPR2016-00204 based on a petition filed by Argentum.
`
`Previously, in IPR2014-01126, the Board denied institution of inter partes
`
`review of the ’551 patent based on a petition filed by Actavis, Inc., Actavis
`
`Laboratories FL, Inc., Actavis Pharma, Inc., Amneal Pharmaceuticals of New
`
`-1-
`
`
`
`
`
`York, LLC, Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc.,
`
`Breckendridge Pharmaceutical, Inc., Vennoot Pharmaceuticals, LLC, Sandoz
`
`Inc., Sun Pharma Global FZE, and Sun Pharmaceutical Industries, Ltd. On July
`
`10, 2013, UCB, Inc. et al. asserted claims for infringement of the ’551 patent in
`
`UCB, Inc. et al. v. Mylan Pharmaceuticals Inc. and Mylan, Inc., Case No. 1:13-cv-
`
`01214, in the District of Delaware, which case was consolidated with UCB, Inc. v.
`
`Accord Healthcare Inc., 1:13-cv-01206 (D. Del. Jul. 10, 2013).
`
`C. Lead and Backup Counsel under 37 C.F.R. § 42.8(b)(3)
`
`Lead Counsel: Steven W. Parmelee (Reg. No. 31,990)
`
`Back-Up Counsel: Michael T. Rosato (Reg. No. 52,182)
`
`Back-Up Counsel: Jad A. Mills (Reg. No. 63,344)
`
`D.
`
`Service Information under 37 C.F.R. § 42.8(b)(4)
`
`Petitioner hereby consents to electronic service.
`
`Email: sparmelee@wsgr.com; mrosato@wsgr.com; jmills@wsgr.com
`
`Post: WILSON SONSINI GOODRICH & ROSATI
`
`701 Fifth Avenue, Suite 5100, Seattle, WA 98104-7036
`
`Tel.: 206-883-2542 Fax: 206-883-2699
`
`II. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104
`
`A. Grounds For Standing Under 37 C.F.R. § 42.104(a)
`
`Petitioner hereby certifies that IPR is available for the ’551 patent and that
`
`Petitioner is not barred or estopped from requesting an IPR challenging the patent
`
`claims on the instituted grounds identified in this petition because a motion for
`
`-2-
`
`
`
`
`
`joinder has been filed to join IPR2016-00204 no later than 1 month after institution
`
`in accordance with 37 C.F.R. § 42.122(b) and 35 U.S.C. §315(c).
`
`B.
`
`Identification of Challenge, 37 C.F.R. § 42.104(b)
`
`Petitioner requests cancellation of claims 1-13 of the ’551 patent on the
`
`following grounds:
`
`
`Ground
`
`Claims
`
`Basis
`
`Reference(s)
`
`1A
`
`1B
`
`2A
`
`2B
`
`3A
`
`3B
`
`4A
`
`4B
`
`1, 3-8
`
`§ 102(b)
`
`LeGall
`
`2, 9-13
`
`§ 103
`
`LeGall and ’729 patent
`
`1-9
`
`§ 103
`
`Choi and Kohn 1991
`
`10-13
`
`§ 103
`
`Choi, Kohn 1991, and ’729 patent
`
`1-9
`
`§ 103
`
`Kohn 1991 and Silverman
`
`10-13
`
`§ 103
`
`Kohn 1991, Silverman, and ’729 patent
`
`1-9
`
`§ 103
`
`Cortes and Kohn 1991
`
`10-13
`
`§ 103
`
`Cortes, Kohn 1991, and ’729 patent
`
`Grounds 1-4 are practical copies of the grounds presented in the petition in
`
`IPR2016-00204, including Grounds 3A-3B that were instituted by the Board,
`
`challenging the same claims over the same prior art and using the same arguments
`
`and expert testimony. Each of Grounds 1-4 identifies a different prior art
`
`compound that independently would have served as a “starting reference point or
`
`points,” from which a person of ordinary skill in the art (“POSA”) would have
`
`easily arrived at lacosamide—the compound claimed in the ’551 patent. Eisai Co.
`
`Ltd. v. Dr. Reddy’s Labs., 533 F.3d 1353, 1359 (Fed. Cir. 2008); see Altana
`
`-3-
`
`
`
`
`
`Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009)
`
`(affirming the selection of up to “18 exemplary compounds” as lead compounds
`
`and rejecting the notion that chemical obviousness requires “only a single lead
`
`compound”).
`
`This case presents a unique set of facts that establish the uncommon instance
`
`in which a patent claim to a compound is anticipated and/or rendered obvious.
`
`Here, the compound lacosamide was first disclosed in the thesis of the graduate
`
`student of the ’551 patent’s named inventor approximately eight years before the
`
`relevant patent application was filed. Even putting aside that novelty destroying
`
`reference, at least three other specific combinations of prior art would have
`
`directed a person of ordinary skill in the art directly to lacosamide and its use. This
`
`is not a case of selecting a single favorable lead compound so that one preordains
`
`the obviousness analysis. Rather, this petition presents four separate examples of
`
`applying clear teachings in the prior art (as summarized in the figure below) to
`
`establish that the claims to lacosamide are unpatentable.
`
`Moreover, the prior art contained repeated statements directing one to use
`
`the R-isomer. The various references stressed that the R-isomer was the
`
`biologically active isomer. Finally, the therapeutic composition and method claims
`
`in the ’551 patent add no specific limitations other than standard, generic
`
`limitations, such as a “pharmaceutical carrier” and “administering to an animal.”
`
`With the prior art data confirming the anticonvulsant activity of the compounds,
`
`those generic limitations cannot render the claimed subject matter patentable.
`
`-4-
`
`
`
`Prior Art Compounds Disclosed in Grounds I - IV
`
`
`
`Petitioner supports its challenges with a Declaration of Dr. Binghe Wang
`
`(“Wang Decl.”) (Ex. 1002) prepared for IPR2016-00204,1 as well as a Declaration
`
`
`
`
`
`1 The Wang Declaration is an exact copy of Dr. Wang’s declaration from
`
`IPR2016-00204, which was relied upon by the Board in that proceeding. Dr.
`
`Wang’s IPR2016-00204 Declaration is cited in this Petition to avoid unnecessary
`
`cost and to advance efficiency in this instance. As mentioned above, this Petition
`
`is presented along with a motion to join IPR2016-00204, and by using the same
`
`Declaration, Petitioner has eliminated the need for analysis of another declaration
`
`or the addition of a new expert.
`
`-5-
`
`
`
`
`
`of Dr. Clayton H. Heathcock (“Heathcock Decl.”) (Ex. 1003) from IPR2014-
`
`01126.
`
`III. SUMMARY OF THE ‘551 PATENT
`
`The ’551 patent lists Harold Kohn as its sole inventor and Research
`
`Corporation Technologies, Inc. as the assignee. The ’551 patent is a reissue of
`
`U.S. Patent No. 5,773,475 (“the ’475 patent”) (Ex. 1005), which issued from U.S.
`
`Patent Application No. 08/818,688 (“the ’688 application”) filed on March 17,
`
`1997, and which claims priority to U.S. Provisional Application No. 60/013,522
`
`filed on March 15, 1996 (the earliest possible effective date). As explained in Part
`
`IX, infra, the ’551 patent is not entitled to the earlier 1996 priority date.
`
`Claim 1 is the sole independent claim in the ’551 patent. Claim 1 reads:
`
`1. A compound in the R configuration having the formula:
`
`wherein
`
`Ar is phenyl which is unsubstituted or substituted with at least one
`
`
`
`halo group;
`
`Q is lower alkoxy, and
`
`Q1 is methyl.
`
`Claims 2-9 are compound claims depending directly or indirectly from claim 1.
`
`Claim 8 is lacosamide, specified by its chemical name: “The compound according
`
`to claim 1 which is (R)-N-Benzyl 2-Acetamido-3-methoxypropion-amide.” The
`
`-6-
`
`
`
`structure of lacosamide is shown below (wherein Ar is benzyl, Q is
`
`methoxymethyl, and Q1 is methyl):
`
`
`
`Claim 10 recites “[a] therapeutic composition comprising an anticonvulsant
`
`effective amount of a compound according to any one of claims 1-9 and a
`
`
`
`pharmaceutical carrier therefor.”
`
`Claims 11-13 are method claims. Claim 11 reads:
`
`11. A method of treating central nervous system disorders in an
`
`animal comprising administering to said animal in need thereof an
`
`anticonvulsant effective amount of a compound according to any one
`
`of claims 1-9.
`
`Claim 12 depends from claim 11 and specifies that the “the animal is a
`
`mammal.” Claim 13 depends from claim 12 and specifies that “the mammal is a
`
`human”.
`
`IV. PREVIOUS PETITION FILED BY OTHER UNRELATED PARTIES
`
`This is the first petition filed against the ’551 patent by Petitioner or its real
`
`parties in interest. As mentioned above, in IPR2016-00204, filed by an unrelated
`
`party, the Board instituted review of claims 1-9 (Ground 3A), based on Kohn 1991
`
`and Silverman, and of claims 10-13 (Ground 3B), based on Kohn 1991, Silverman,
`
`and the ’729 patent. The Board previously declined to institute a review in
`
`IPR2014-01126, filed by parties unrelated to Petitioner. There, Patent Owner
`
`-7-
`
`
`
`
`
`argued that LeGall was not shown to be prior art, and the Board agreed. (Prelim.
`
`Resp. 27-30.) The Board also found that the petition failed to establish a reasonable
`
`likelihood on three asserted grounds of unpatentability: (1) anticipation by the ’301
`
`patent, (2) anticipation by LeGall, and (3) obviousness over LeGall and the ’729
`
`patent. See IPR2014-01126, Paper 22 (“Dec.”). For the first ground (anticipation
`
`by the ’301 patent), the prior petitioners alleged that claims 39-44 of the ’301
`
`patent, together with preferences recited in the ’301 patent, anticipate lacosamide.
`
`The Board disagreed, finding no anticipation based on the preferred genus of
`
`compounds. Dec. 8-9. For the second ground (anticipation by LeGall), the Board
`
`found that LeGall was not shown to be a “printed publication” under § 102(b). Id.
`
`at 12-13. Finally, the third ground was denied for the same reason as the second.
`
`Id. at 14.
`
`V. CLAIM CONSTRUCTION UNDER 37 C.F.R. § 42.104(B)(3)
`
`A.
`
`“Therapeutic Composition” in Claim 10
`
`In the district court litigation, the court construed one term in the ’551
`
`patent: “therapeutic composition,” which appears only in the preamble of claim 10.
`
`To the extent Patent Owner attempts to rely on the district court’s construction, that
`
`construction was unnecessary and, in any event, is not the broadest reasonable
`
`interpretation (“BRI”).
`
`First, claim 10 is a product claim that recites two limitations: an
`
`“anticonvulsant effective amount” of the compound, and a “pharmaceutical
`
`-8-
`
`
`
`
`
`carrier.”2 The body of the claim sets forth all limitations of the claimed invention.
`
`The preamble, “a therapeutic composition,” does not “give life, meaning, and
`
`vitality” to the claim, but merely describes an intended purpose, and is therefore
`
`non-limiting. See Rowe v. Dror, 112 F.3d 473, 478 (Fed. Cir. 1997) (“[W]here a
`
`patentee defines a structurally complete invention in the claim body and uses the
`
`preamble only to state a purpose or intended use for the invention, the preamble is
`
`not a claim limitation.”).
`
`Second, the term “therapeutic composition” does not specify any additional
`
`physical structure or physical components other than the two recited in the body of
`
`the claim. The ’551 patent does not provide a definition of the term “therapeutic
`
`composition.” Nor does the patent use that term in any special manner, other than
`
`introducing the claimed compound in a pharmaceutical carrier. By definition, a
`
`compound within the genus, together with a pharmaceutical carrier, is a therapeutic
`
`composition within the meaning of claim 10.
`
`Third, the BRI of “therapeutic composition” is not confined to the additional
`
`limitations imposed by the district court. Specifically, applying Phillips, the
`
`district court construed the term to mean “[a] composition suitable for use as a
`
`treatment regimen over an extended period of time (chronic administration).” Ex.
`
`1007 at 5. The BRI cannot be limited to only a composition that is administered
`
`
`
`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.”
`
`-9-
`
`
`
`
`
`“over an extended period of time” and for “chronic administration.” Nothing in the
`
`claim limits the composition to “chronic administration.” See Ex. 1001 cols. 9-10
`
`(reciting a litany of acceptable dosage forms and excipients).
`
`Additionally, the claims do not numerically limit the term “anticonvulsant
`
`effective amount.” Applying the BRI, this term should be construed to mean any
`
`amount that could provide an anticonvulsant effective amount of the compound
`
`when administered. The specification again does not define a specific range but
`
`does provide various ranges as guidance. For instance, the ’551 patent states that
`
`“[a] unit dosage form can, for example, contain the principal active compound in
`
`amounts ranging from about 5 to about 1000 mg.” Ex. 1001 at 10:52-59. The ’551
`
`patent also states that the compositions can contain “from about 1 to about 750
`
`mg/ml of carrier,” id. at 10:59, or “preferred . . . between about 5 and 100 mg of
`
`active compound,” id. at 9:25-26, or “at least 1% of active compound,” id. at 9:17-
`
`18. At a minimum, a composition containing about 5 to about 1000 mg of the
`
`claimed compound, and a pharmaceutical carrier, is a “therapeutic composition”
`
`within the meaning of claim 10.
`
`B.
`
`“A Compound in the R Configuration” in Claim 1
`
`Petitioner does not believe that the phrase “a compound in the R
`
`configuration” in claim 1 needs to be construed. Patent Owner, however, put that
`
`phrase into issue in IPR2014-01126. Patent Owner’s preliminary response did not
`
`propose a construction of the term but instead quibbled that the former petitioners’
`
`construction “improperly fails to treat the R stereoisomer, the S stereoisomer and
`
`the racemic mixture as the different compounds that they are.” Prelim. Resp. at 13.
`
`-10-
`
`
`
`
`
`Here, the BRI of “a compound in the R configuration” covers R-isomer
`
`compounds, whether the R-isomer is substantially pure or mixed with the S-
`
`isomer, such as a racemic mixture or isomerically enriched compound. But the
`
`claim does not cover pure S-isomer, which would have no R-isomer. The
`
`declaration of Prof. Wang explains why a POSA would have this understanding.
`
`Ex. 1002 ¶¶ 9-13.
`
`Claim 2 confirms this construction, which further limits claim 1 to
`
`“substantially enantiopure.” Applying claim differentiation, claim 2 further
`
`restricts the amount of S-isomer that is included in the scope of the claim,
`
`specifying that the compound be “substantially enantiopure.” The ’551 patent
`
`explains that “substantially enantiomerically pure” can include at least 10% (w/w)
`
`of the S-isomer. Ex. 1001 at 5:11-16.
`
`Claim 9 also confirms the above construction, which specifies the
`
`“compound according to claim 8”—i.e., (R)-N-benzyl-2-acetamido-3-
`
`methoxypropionamide—“contains at least 90% (w/w) R stereoisomer.” Because
`
`claim 9 depends from claim 1, and because claim 9 includes compositions having
`
`up to 10% (w/w) of the S-isomer, so must claim 1. Moreover, claim 1 does not
`
`limit the amount of R- or S-isomer present in the composition—only that it cannot
`
`be solely S. Nor does the specification provide any lower numerical limit for claim
`
`1, other that it cannot be solely S. To the extent Patent Owner argues that claim 1
`
`requires any level of enantiomeric purity beyond the presence of a single R-isomer
`
`molecule, then claims 2 and 9 are nonsensical and the Board should hold all claims
`
`-11-
`
`
`
`
`
`indefinite under 35 U.S.C. § 112(b). See BlackBerry Corp. v. MobileMedia Ideas
`
`LLC, IPR2013-00036 (Paper 65) (terminating IPR after finding claims indefinite).
`
`VI. LEVEL OF SKILL AND KNOWLEDGE IN THE ART
`
`As of March 15, 1996 (the earliest possible effective date), a hypothetical
`
`POSA would “be aware of all the pertinent prior art” at the time of the alleged
`
`invention. Custom Accessories, Inc. v. Jeffrey-Allan Indus., 807 F.2d 955, 963
`
`(Fed. Cir. 1986). Factors relevant in determining the level of skill include: the
`
`“type of problems encountered in art; prior art solutions to those problems; rapidity
`
`with which innovations are made; sophistication of the technology; and
`
`educational level of active workers in the field.” Id.
`
`The relevant field is medicinal chemistry, and a POSA would have a Ph.D.
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`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
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`drug candidates. Id. With experience in drug development, the POSA would have
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`an appreciation of the diseases and ailments a particular drug candidate is intended
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`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
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`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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`-12-
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`The following prior art references, summarized below, would have further
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`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
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`that N-acetyl-D,L-alanine benzylamide (compound 6d, “AAB”) was “[a]mong
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`the most active compounds.” Id. This compound is the “methyl compound,”
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`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
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`screening,” which yielded “[p]romising results.” Id. at 604. The methyl compound
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`(AAB) of Cortes became the starting point for several projects developing
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`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
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`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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`-13-
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`
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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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`
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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
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`recognize that the structure show discloses both R-lacosamide and S-lacosamide.
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`
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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
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`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
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`-14-
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`
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`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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`
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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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`requirements that exist for maximal anticonvulsant activity in this class of
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`-15-
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`
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`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
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`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
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`inventor, and issued as U.S. Patent No. 5,378,729 (“’729 patent”). The ’729 patent
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`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
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`specific formula applying Kohn’s expressly “preferred” substituents:
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`Ex. 1009, col. 1:30-2:20. The ’729 patent described the preferred substituents as
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`follows: “n is 1,” R is “especially benzyl,” and “[t]he most preferred R1 group is
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`
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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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`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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`-16-
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`
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`As with other prior art references, the ’729 patent reiterates the preference
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`for the R-isomer. Ex. 1002, ¶ 33; Ex. 1009 at 15:31-16:4 (“The D stereoisomer is
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`preferred.”). The ’729 patent also includes data supporting the preference for the
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`R-isomer. Ex. 1009, 58-61, Tbl. 1; Ex. 1002, ¶ 34. The ’729 patent cites known
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`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
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`exhibit excellent anticonvulsant activity,” id. at 16:5-7, that the compounds are
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`administered with a “pharmaceutically acceptable carrier,” id. at 17:53-54, and that
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`“[t]he use of such media and agents for pharmaceutical active substances is well
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`known in the art,” id. at 17:54-58.
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`E. Kohn 1993 (Ex. 1017)
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`In 1993, Dr. Kohn published additional results in the Journal of Medicinal
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`Chemistry providing further information about preferences in the chemical
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`structure of potent anticonvulsants derived from the methyl compound AAB of
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`Cortes. Ex. 1017. The report evaluated an “expanded set of C(α)-heteroaromatic
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`analogs” of the methyl compound AAB as the lead compound. Ex. 1017 at 3350.
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`Based on these studies, a POSA knew that “improved activity resulted by the
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`positioning of a heteroatom two atoms removed from the C(α)-site [i.e., the α -
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`carbon.” Id. at 3354 (emphasis added).
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`Further, the art taught a POSA that oxygen was the best heteroatom to have
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`at that position, i.e., two atoms removed from the a-carbon. Ex. 1002, ¶ 38. Kohn
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`1993 explains prior results demonstrating that “the anticonvulsant activity . . .
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`decreased in proceeding from oxygen to nitrogen to sulfur containing C(α)-
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`-17-
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`
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`
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`heteroaromatic derivatives.” Id. Moreover, Kohn 1993 confirmed that an alkylated
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`heteroatom provided increased activity. Id. (“[I]ncreased anticonvulsant activity
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`generally accompanied the placement of a substituted (alkylated) heteroatom two
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`atoms removed from the amino acid α -carbon.” (emphasis added)). Overall, the
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`teachings in Kohn 1993 would have confirmed that the methoxymethyl group was
`
`a preferred substituent on the α-carbon.
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`F.
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`Choi (1995) (Ex. 1010)
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`In 1995, Kohn and Choi published a report in Tetrahedron Letters (“Choi”
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`Ex. 1010) describing the synthesis of additional derivatives β-halogen amino acid
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`derivatives in one step from the corresponding serine compound and trimethylsilyl
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`halide. Ex. 1010 at 7011, abst. Choi identifies several compounds as being
`
`particularly useful as an intermediate in the formation of new anticonvuslants,
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`including the hydroxymethyl compound 2d (-CH2OH bound to the α-carbon):
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`Hydroxymethyl Compound (Choi 2d)
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`
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`In particular, Choi stated that, “[f]or an ongoing project to prepare bioactive
`
`amino acid derivatives, we needed the β-halogen compounds 2a-2c” (id. at 7011)
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`and that, for this purpose, “(2d) was converted to 2a-2c in acetonitrile” (id. at
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`7012).” Notably, the hydroxymethyl compound (2d) of Choi is the same as
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`compound 49 in Kohn 1993, Ex. 1017 at 335, and compound 107d in LeGall, Ex.
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`-18-
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`1008 at 133, Tbl. 35, to which Choi expressly refers the rea