UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`ACTAVIS, INC., ACTAVIS LABORATORIES FL, INC.,
`ACTAVIS PHARMA, INC., AMNEAL PHARMACEUTICALS, LLC,
`AMNEAL PHARMACEUTICALS OF NEW YORK, LLC,
`AUROBINDO PHARMA LTD., AUROBINDO PHARMA USA, INC.,
`BRECKENRIDGE PHARMACEUTICAL, INC., VENNOOT
`PHARMACEUTICALS, LLC, SANDOZ INC., SUN PHARMA GLOBAL FZE,
`and SUN PHARMACEUTICAL INDUSTRIES, LTD.,
`Petitioners
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner
`
`
`
`Case: IPR2014-01126
`
`
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. RE 38,551
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, Virginia 22313–1450
`Submitted Electronically via the Patent Review Processing System
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`TABLE OF CONTENTS
`
`
`Page
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 ................................... 4
`A. Real Parties-In-Interest ............................................................................ 4
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2) ........................................ 5
`C. Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3) .................... 5
`D. Service Information ................................................................................. 6
`
`III.
`
`PAYMENT OF FEES – 37 C.F.R. § 42.103 ................................................... 6
`
`IV. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104 ............................ 6
`A. Grounds For Standing Under 37 C.F.R. § 42.104(a) ............................... 6
`B.
`Identification Of Challenge Under 37 C.F.R. § 42.104(b) And
`Relief Requested ...................................................................................... 7
`C. Claim Construction Under 37 C.F.R. §§ 42.100(b), 42.104(b)(3) .......... 7
`
`V.
`
`SUMMARY OF THE ’551 PATENT ............................................................. 8
`
`VI. LEVEL OF ORDINARY SKILL IN THE ART ...........................................12
`
`B.
`
`VII. BACKGROUND ...........................................................................................13
`A.
`In 1985, Dr. Kohn Co-Authors Prior Art That Discloses The
`Precursor To Lacosamide. ..................................................................... 13
`In 1987, Dr. Kohn’s Student (LeGall) Modifies The Preferred
`Compound Of Cortes And Discloses The Chemical Structure Of
`Lacosamide. ........................................................................................... 14
`In 1991, Dr. Kohn And A Colleague Disclose Compounds That
`Include Lacosamide. .............................................................................. 16
`In 1993, Drs. Kohn And Watson Apply For What Became The
`’301 Patent, Which Expressly Discloses Lacosamide As A
`Preferred Antiepileptic Compound. ....................................................... 18
`
`C.
`
`D.
`
`i
`
`

`

`E.
`
`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`In 1998, The Examiner Issues The ’551 Patent Based On A
`Mistaken Belief That The ’301 Patent Does Not Disclose
`Lacosamide. ........................................................................................... 21
`F. The Patentee Concedes That The ’301 Patent Does Disclose
`Lacosamide. ........................................................................................... 24
`
`VIII. ANALYSIS OF GROUNDS FOR TRIAL ...................................................26
`A. Ground 1: The ’301 Patent Anticipates All Claims Of The ’551
`Patent. ..................................................................................................... 26
`1. The ’301 Patent Is § 102(e) Prior Art. ........................................... 27
`2. Each And Every Limitation Of The ’551 Patent Is Found In
`The Prior Art ’301 Patent. .............................................................. 27
`3. A POSA Would Have At Once Envisaged Lacosamide From
`Claim 44 Of The ’301 Patent. ........................................................ 29
`4. The ’301 Patent Would Have Enabled A POSA To Practice
`All Claims Of The ’551 Patent. ..................................................... 30
`a) The ’301 Patent Enabled A POSA To Obtain
`“Substantially” And “90%” Pure Lacosamide. ...................... 30
`b) The ’301 Patent Enabled A POSA To Prepare A
`Therapeutic Composition For Lacosamide. ........................... 32
`c) The ’301 Patent Enabled A POSA To Use Lacosamide
`To Treat CNS Disorders. ........................................................ 33
`B. Ground 2: The LeGall Thesis Anticipates All Claims Of The
`’551 Patent. ............................................................................................ 33
`1. The LeGall Thesis Is Prior Art Under § 102(b). ............................ 34
`2. The LeGall Thesis Discloses Lacosamide And Thus
`Anticipates Claims 1 And 3-8. ....................................................... 36
`3. The LeGall Thesis Directs A POSA To The Pure R
`Stereoisomer And Thus Anticipates Claims 2 And 9. ................... 37
`4. The LeGall Thesis Discloses Lacosamide’s “Good
`Anticonvulsant Activity” And Thus Anticipates Claim 10 Of
`The ’551 Patent. ............................................................................. 39
`5. The LeGall Thesis Discloses Lacosamide’s “Clinical
`Applications” And Thus Anticipates Claims 11-13 Of The
`’551 Patent...................................................................................... 40
`
`ii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`C. Ground 3: Claims 1-13 Are Obvious Over The LeGall Thesis In
`View Of The ’729 Patent And Other Prior Art...................................... 41
`1. Claims 1 And 3-8, Which Claim The Racemate Including
`Lacosamide, Are Obvious Over The LeGall Thesis, The
`’729 Patent, And Other Prior Art. .................................................. 42
`2. Claims 2 And 9, Which Claim “Substantially” Or “90%”
`Pure Lacosamide, Are Obvious Over The LeGall Thesis,
`The ’729 Patent And Other Prior Art. ............................................ 44
`3. Claim 10, Which Covers A Therapeutic Composition
`Comprising Lacosamide, Is Obvious Over The LeGall
`Thesis, The ’729 Patent And Other Prior Art. ............................... 47
`4. Method Claims 11-13 Are Obvious Over The LeGall Thesis,
`The ’729 Patent And Other Prior Art. ............................................ 48
`
`IX. ANY SECONDARY CONSIDERATIONS FAIL TO OVERCOME THE
`SHOWING OF OBVIOUSNESS. .................................................................49
`A. Lacosamide Produced No Relevant Unexpected Results. ..................... 50
`B. The ’551 Patent Satisfied No Long-Felt But Unmet Need. ................... 51
`C. Copying By Generic Drug Makers Is Irrelevant.................................... 52
`
`X.
`
`
`
`
`CONCLUSION ..............................................................................................53
`
`
`
`iii
`
`

`

`Exhibit
`
`1001
`
`1002
`
`1003
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`1010
`
`1011
`
`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`EXHIBITS
`
`Description
`
`U.S. Patent No. RE 38,551 to Kohn (“’551 patent”)
`(reissue of U.S. Patent No. 5,773,475 (“’475 patent”))
`
`Declaration of Clayton H. Heathcock, Ph.D.
`
`U.S. Patent No. 5,654,301 to Kohn and Watson
`(“’301 patent”)
`
`Jan. 28, 1998 Notice of Allowability
`(excerpt from prosecution history of ’475 patent)
`
`Philippe LeGall, 2-Substituted-2-acetamido-N-
`benzylacetamides. Synthesis, Spectroscopic and
`Anticonvulsant Properties (Dec. 1987) (“LeGall thesis”)
`
`Apr. 10, 1998 Amendment Under 37 C.F.R. § 1.312
`(excerpt from prosecution history of ’475 patent)
`
`Dec. 23, 2008 Application for Extension of Patent Term
`Under 35 U.S.C. § 156
`(excerpt from prosecution history of ’301 patent)
`
`U.S. Patent No. 5,378,729 to Kohn and Watson
`(“’729 patent”)
`
`Sergio Cortes et al., Effect of Structural Modification of the
`Hydantoin Ring on Anticonvulsant Activity, 28 J. Med.
`Chem. 601 (1985) (“Cortes”)
`
`Harold Kohn et al., Preparation and Anticonvulsant Activity
`of a Series of Functionalized α-Heteroatom-Substituted
`Amino Acids, 34 J. Med. Chem. 2444 (1991) (“Kohn 1991”)
`
`U.S. Food and Drug Administration, Approved Drug
`Products With Therapeutic Equivalence Evaluations 3-202,
`ADA 101 (34th ed. 2014) (“Orange Book”)
`
`iv
`
`

`

`Exhibit
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`Description
`
`U.S. Provisional Patent Application No. 60/013,522
`(“’522 prov. app.”)
`
`Apr. 14, 2014 Plaintiffs’ Response to Defendants’ Joint Set
`of Interrogatories (UCB, Inc., et al. v. Accord Healthcare,
`Inc., et al., C.A. No. 13-1206-LPS (D. Del.))
`
`Phillipe LeGall et al., Synthesis of Functionalized Non-
`Natural Amino Acid Derivatives via Amidoalkylation
`Transformations, 32 Int’l J. Peptide Protein Res. 279 (1988)
`
`R. L. M. Synge, CCXXXIX. Experiments On Amino Acids.
`IV. The Methyl Ethers Of Some N-Acetyl-Hydroxyamino-
`Acids, 33 Biochem. J. 1931 (1939)
`
`M. Jaeger et al., Enzymatic Resolution of O-Methyl-N-
`acetyl-DL-serine. Amino Acids. XXXII., 28 Croat. Chem.
`Acta 5 (1956)
`
`Judith D. Conley & Harold Kohn, Functionalized DL-
`Amino Acid Derivatives. Potent New Agents for the
`Treatment of Epilepsy, 30 J. Med. Chem. 567 (1987)
`
`Judith D. Conley, Functionalized Amino Acid Derivatives –
`Potent New Agents for the Treatment of Epilepsy: Synthesis,
`and Spectroscopic and Pharmacological Properties (May
`1986)
`
`Harold Kohn & Judith D. Conley, New Antiepileptic Agents,
`24 Chemistry in Britain 231 (March 1988)
`
`European Patent Application No. 0 194 464
`(“’464 application”)
`
`v
`
`

`

`Exhibit
`
`1021
`
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`Description
`
`Harold Kohn et al., Marked Stereospecificity in a New Class
`of Anticonvulsants, 457 Brain Res. 371 (1988)
`
`Harold Kohn et al., Preparation and Anticonvulsant Activity
`of a Series of Functionalized α-Aromatic and α-
`Heteroaromatic Amino Acids, 33 J. Med. Chem. 919 (1990)
`
`European Patent Application No. 0 263 506
`(“’506 application”)
`
`European Patent Application No. 0 400 440
`(“’440 application”)
`
`Harold Kohn et al., Synthesis and Anticonvulsant Activities
`of α-Heterocyclic α-Acetamido-N-Benzylacetamide
`Derivatives, 36 J. Med. Chem. 3350 (1993)
`
`Harold Kohn et al., Anticonvulsant Properties of N-
`Substituted α,α-Diamino Acid Derivatives, 83 J.
`Pharmaceutical Sci. 689 (May 1994)
`
`C.W. Thornber, Isosterism and Molecular Modification in
`Drug Design, 8 Chemical Soc’y Revs. 563 (1979)
`(“Thornber 1979”)
`
`Wilson & Gisvold’s Textbook of Organic Medicinal and
`Pharmaceutical Chemistry, Ch. 2 (Delgado & Remers eds.
`1991) (“W&G 1991”)
`
`Richard B. Silverman, The Organic Chemistry of Drug
`Design and Drug Action, Ch. 2 (1992) (“Silverman 1992”)
`
`Rosa Amoroso et al., A New Route to the Synthesis of Amino
`Acids Through the Mercury Cyclization of Chiral Amidals,
`57 J. Org. Chem. 1082 (1992)
`
`vi
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`Exhibit
`
`Description
`
`S. Cerrini et al., Serine-Containing 10-Membered
`Cyclodepsipeptides, 41 Int’l J. Peptide Protein Res. 282
`(1993)
`
`Svante Axelsson et al., Versatile Synthesis of
`Stereospecifically Labelled D-Amino Acids via Labelled
`Aziridines, J. Chem. Soc. Perkin Trans. 1 (1994)
`
`Oliver Keil et al., New Hydantoinases from Thermophilic
`Microorganisms – Synthesis of Enantiomerically Pure D-
`Amino Acids, 6 Tetrahedron: Asymmetry 1257 (1995)
`
`Patrick Bardel et al., Synthesis and Anticonvulsant Activities
`of α-Acetamido-N-Benzylacetamide Derivatives Containing
`an Electron-Deficient α-Heteroaromatic Substituent, 37 J.
`Med. Chem. 4567 (1994)
`
`FDA, Guideline for Industry: Dose-Response Information to
`Support Drug Registration (Nov. 1994)
`
`R. Schmidt, Dose-Finding Studies in Clinical Drug
`Development, 34 Eur. J. Clin. Pharmacol. 15-19 (1988)
`
`1031
`
`
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`
`
`
`vii
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`Petitioners request that the Board institute an inter partes review under 35
`
`U.S.C. §§ 311-319 and 37 C.F.R. Part 42 and determine that all claims (1-13) of
`
`U.S. Patent No. RE 38,551 (“the ’551 patent”) (Ex. 1001) be canceled as
`
`unpatentable.
`
`I.
`
`INTRODUCTION
`
`The ’551 patent issued only because the Examiner made a basic chemistry
`
`mistake, which the patentee failed to correct. The ’551 patent covers a compound
`
`called “lacosamide” and its use as an “anticonvulsant” to treat epilepsy. But a key
`
`piece of prior art discussing “anticonvulsants”—U.S. Patent No. 5,654,301 (Ex.
`
`1003) (“the ’301 patent”)—already expressly disclosed and even claimed
`
`lacosamide. The Examiner overlooked that fact, finding that the ’301 patent did
`
`not “teach or suggest” lacosamide’s chemical structure. Ex. 1004 at 2. That was a
`
`mistake. Moreover, another piece of prior art about anticonvulsants—a thesis
`
`written by one of the inventor’s own students (Ex. 1005)—also expressly disclosed
`
`the lacosamide structure. But the ’551 patent inventor never told the Patent Office
`
`about that thesis.
`
`The Board should institute inter partes review, and ultimately cancel all
`
`claims of the ’551 patent, for three independent reasons:
`
`First, all claims of the ’551 patent are anticipated under 35 U.S.C. § 102(e)
`
`by the ’301 patent (Ex. 1003). The Examiner nevertheless allowed the claims to
`
`1
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`issue only after finding that the ’301 patent “never teach[es] or suggest[s]”
`
`lacosamide’s structure. Ex. 1004 at 2.
`
`That was not true: The ’301 patent expressly discloses lacosamide. That
`
`patent is directed to a basic core structure that allows for limited substitutions at
`
`various positions. For her conclusion that it did not disclose lacosamide, the
`
`Examiner concluded that the ’301 patent never disclosed the necessary “ether” at
`
`the “R2, R3” positions. On the contrary, claim 44 of the ’301 patent expressly calls
`
`for the R2 or R3 position to be a “methyl substituted” group with the substitution
`
`being a “methoxy”—a substitution that any chemist should understand describes
`
`an ether. In fact, when following the ’301 patent’s “preferred” and “most
`
`preferred” options, claim 44 leads directly only to a single compound—
`
`lacosamide.
`
`The patentee never corrected the Examiner’s basic mistake. In fact, it
`
`perpetuated the mistake, later representing to the Examiner that the ’301 patent
`
`never “discloses compounds … having the basic structure” that matches up with
`
`lacosamide. Ex. 1006 at 1-2.
`
`Notwithstanding that representation, there is now no dispute that the ’301
`
`patent discloses and claims lacosamide. Since the patent issued, the patentee has
`
`twice conceded—to both the PTO and the FDA—that the ’301 patent not only
`
`“claim[s] … lacosamide,” but also “a composition comprising lacosamide, and …
`
`2
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`methods that comprise using lacosamide for treatment of CNS (i.e. central nervous
`
`system) disorders.” Ex. 1007 at 5. Had the Examiner correctly understood the
`
`scope of the ’301 patent or had the benefit of these concessions, none of the ’551
`
`patent claims ever would have issued.
`
`Second, all claims of the ’551 patent are independently anticipated under
`
`§ 102(b) by a thesis authored by Philippe LeGall, who at the time was a graduate
`
`student of the sole inventor. Ex. 1005. The LeGall thesis, which the inventor
`
`“approved” but never disclosed to the PTO, discloses a type of chemical compound
`
`(known as a racemate) that has two parts (known as stereoisomers)—one of which
`
`is lacosamide. Id. at 135. The author describes lacosamide as being part of “a new
`
`class of anticonvulsant drugs,” i.e., drugs primarily designed to treat epilepsy. Id.
`
`at 42 (emphasis added). And, when discussing the stereoisomer associated with
`
`lacosamide, the author says it will “display … improved pharmacological
`
`properties” over both the other stereoisomer and the racemate. Id. at 42, 164-65.
`
`Isolating the lacosamide stereoisomer from the racemate was a matter of
`
`routine skill well before the earliest priority date in 1996. The patentee has already
`
`conceded that point, stating that lacosamide could be isolated “by standard
`
`techniques known in the art” as of 1996. Ex. 1001, ’551 patent col. 8:50-61
`
`(emphasis added). The LeGall thesis thus independently discloses, either expressly
`
`or inherently, each and every limitation of that patent.
`
`3
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`Third, all claims of the ’551 patent are additionally invalid under § 103(a) in
`
`view of the LeGall thesis and other prior art—including U.S. Patent No. 5,378,729
`
`(“the ’729 patent”), which shares an inventor with the ’551 patent. For example,
`
`this prior art discloses in detail how the “racemic mixture” that includes
`
`lacosamide can be “separated by recognized techniques known in the art,” thus
`
`leading a skilled artisan directly to the “[o]ptically pure” lacosamide stereoisomer
`
`claimed by the ’551 patent. Ex. 1008, ’729 patent col. 15:54-56; see id. at 15:25-
`
`16:4 (emphasis added).
`
`In sum, as shown below, there is a very strong likelihood (and, to be sure, at
`
`least a reasonable likelihood) that Petitioners will prevail in establishing that the
`
`challenged claims should be canceled. Petitioners thus ask the Board to grant inter
`
`partes review and determine that all claims of the ’551 patent are, in fact,
`
`unpatentable.
`
`II. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`A. Real Parties-In-Interest
`
`Petitioners Actavis, Inc., Actavis Laboratories FL, Inc. (f/k/a Watson
`
`Laboratories, Inc. – Florida), Actavis Pharma, Inc. (f/k/a Watson Pharma, Inc.),
`
`Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New York, LLC,
`
`Aurobindo Pharma Ltd., Aurobindo Pharma USA, Inc., Breckenridge
`
`4
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`Pharmaceutical, Inc., Vennoot Pharmaceuticals, LLC, Sandoz Inc., Sun Pharma
`
`Global FZE, and Sun Pharmaceutical Industries, Ltd., are real parties-in-interest.
`
`B. Related Matters Under 37 C.F.R. § 42.8(b)(2)
`
`The ’551 Patent is asserted in the consolidated action styled UCB, Inc., et al.
`
`v. Accord Healthcare, Inc., et al., Civil Action No. 13-1206-LPS, filed July 9,
`
`2013, in the United States District for the District of Delaware, and in UCB, Inc., et
`
`al. v. Apotex Corp. et al., Civil Action No. 14-834, filed June 27, 2014, in the
`
`United States District for the District of Delaware.
`
`C. Lead And Back-Up Counsel Under 37 C.F.R. § 42.8(b)(3)
`
`Lead Counsel
`
`Back-Up Counsel
`
`Samuel S. Park (Reg. # 59,656)
`
`Andrew R. Sommer (Reg # 53,932)
`
`WINSTON & STRAWN LLP
`
`WINSTON & STRAWN LLP
`
`35 W. Wacker Drive
`
`Chicago, IL 60601
`
`1700 K Street, NW
`
`Washington, DC 20006-3817
`
`Telephone: (312) 558-7931
`
`Telephone: (202) 282-5000
`
`Fax: (312) 558-5700
`
`Fax: (202) 282-5100
`
`Email: spark@winston.com
`
`Email: asommer@winston.com
`
`5
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`
`D.
`
`Service Information
`
`Documents may be delivered by hand to the addresses of lead and back-up
`
`counsel above. Petitioners consent to electronic service by e-mail at the above
`
`listed email addresses of Lead and Back-Up Counsel.
`
`III. PAYMENT OF FEES – 37 C.F.R. § 42.103
`
`The required fee is being paid through the Patent Review Processing
`
`System. No excess claim fees are required. The Office is authorized to charge any
`
`fee deficiency, or credit any overpayment, to Deposit Acct. No. 50-1814.
`
`IV. REQUIREMENTS FOR IPR UNDER 37 C.F.R. § 42.104
`
`A. Grounds For Standing Under 37 C.F.R. § 42.104(a)
`
`Petitioners certify that the ’551 patent is available for inter partes review
`
`and that: (1) none of the Petitioners own the ’551 patent; (2) prior to the date this
`
`Petition was filed, neither Petitioners nor any real party-in-interest filed a civil
`
`action challenging the validity of a claim in the ’551 patent; (3) this Petition has
`
`been filed less than one year after the date on which Petitioners, a real party-in-
`
`interest, or a privy of the Petitioners were served with a complaint alleging
`
`infringement of the ’551 patent; and (4) neither Petitioners, any real parties-in-
`
`interest, nor any privies of Petitioners, are estopped from challenging the claims on
`
`the grounds identified in this Petition.
`
`6
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`Identification Of Challenge Under 37 C.F.R. § 42.104(b) And
`Relief Requested
`
`B.
`
`Petitioners are requesting inter partes review, and ultimately cancellation, of
`
`claims 1-13 of the ’551 patent on the following grounds:
`
`• Ground 1: Claims 1-13 are unpatentable as anticipated under 35 U.S.C.
`
`§ 102(e) by the ’301 patent to Kohn and Watson. Ex. 1003.
`
`• Ground 2: Claims 1-13 are unpatentable as anticipated under § 102(b)
`
`by the LeGall thesis—i.e., Philippe LeGall, 2-Substituted-2-acetamido-N-
`
`benzylacetamides. Synthesis, Spectroscopic and Anticonvulsant
`
`Properties (Dec. 1987). Ex. 1005.
`
`• Ground 3: Claims 1-13 are unpatentable as obvious under § 103(a) over
`
`the LeGall thesis in view of other prior art—including, but not limited to,
`
`the ’729 patent to Kohn and Watson. Exs. 1005, 1008.
`
`C. Claim Construction Under 37 C.F.R. §§ 42.100(b), 42.104(b)(3)
`
`Pursuant to 37 C.F.R. § 42.100(b), a claim in an unexpired patent is given its
`
`broadest reasonable interpretation in light of the specification. Because the claim
`
`construction standard in an inter partes review is different than that used in
`
`litigation, Petitioners reserve the right to present different constructions of terms in
`
`litigation under claim construction standards appropriate for those cases. In re Am.
`
`Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1369 (Fed. Cir. 2004). Petitioners submit
`
`7
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. RE 38,551
`(IPR2014-01126)
`
`
`for purposes of this petition only that the terms in the claims of the ’551 patent do
`
`not have any special meanings and are presumed to take on their broadest
`
`reasonable meaning consistent with the understanding of a person of ordinary skill
`
`in the art (“POSA”) when read in light of the ’551 patent’s specification.
`
`Under this reading of the claims, as discussed in more depth below, the term
`
`“compound” as used in each of claims 1-13 of the ’551 patent includes the
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`compound known as lacosamide.
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`V.
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`SUMMARY OF THE ’551 PATENT
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`The ’551 patent issued on July 6, 2004, identifies Dr. Harold Kohn as the
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`sole inventor, and lists Research Corporation Technologies, Inc. as the assignee. It
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`is a reissue of U.S. Patent No. 5,773,475 (issued June 30, 1998), which claims
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`priority to provisional application No. 60/013,522 filed on March 15, 1996.
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`The ’551 patent has 13 claims generally directed to pharmaceutical
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`compounds for use in treating epilepsy and other CNS disorders. Claims 1-9 cover
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`chemical “compound[s]” (i.e., drug substances), claim 10 covers “therapeutic
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`composition[s]” with those compounds (i.e., drug products or formulations), and
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`claims 11-13 cover “method[s] of treating central nervous system disorders” with
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`those compounds.
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`Claim 1, the only independent claim, reads as follows:
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`1. A compound in the R configuration having the formula:
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`wherein
`Ar is phenyl which is unsubstituted or substituted
`with at least one halo group;
`Q is lower alkoxy, and
`Q1 is methyl.
`As explained in more depth in the Declaration of Clayton H. Heathcock,
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`Ph.D., the term “R configuration” (also referred to as the D configuration in the
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`context of the compounds claimed by the ’551 patent) describes the
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`stereochemistry of the compound, and is contrasted with the S configuration (or, in
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`this context, the L configuration). Ex. 1002, Heathcock Decl. ¶¶ 49-60.
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`Stereochemistry refers to the three-dimensional spatial arrangement of a
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`molecule’s atoms. Id. ¶ 49. Molecules that have the same atoms bonded together
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`in the same way, but in different spatial arrangements, are called stereoisomers. Id.
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`If the molecules contain an asymmetrical (or chiral) carbon atom, they exist as
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`non-superimposable mirror images of each other (like one’s left and right hand)
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`and are referred to as enantiomers. Id. ¶ 52-53. A mixture of equal amounts of
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`both types of enantiomers is referred to as a racemic mixture, or racemate. Id.
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`¶ 59.
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`Below is a graphic illustration of enantiomers, i.e., the compounds have the
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`same groups of atoms but arranged differently such that the molecules are non-
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`superimposable mirror images of each other:
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`Id. ¶ 53.
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`Claim 1 covers certain R enantiomers (referred to in the claims as R
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`stereoisomers) depending on the substituents that are used for Ar, Q, and Q1 below:
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`Claim 1 covers the compound lacosamide (as part of the racemate, or as an isolated
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`stereoisomer) when the Ar substituent is a benzyl group, Q is a methoxymethyl
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`group, and Q1 is a methyl group as shown in the following structure:
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`Id. ¶ 34.
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`When the claim terms are given their broadest reasonable meaning, claims
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`1-9 all cover lacosamide. Claim 8 specifically covers lacosamide as referenced by
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`its chemical name: “The compound according to claim 1 which is (R)-N-Benzyl-
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`2-Acetamido-3-methoxypropionamide.” And claims 2 and 9 cover substantially
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`pure lacosamide, i.e., the R-stereoisomer isolated from its S-stereoisomer:
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`2. The compound according to claim 1 [including lacosamide] which
`is substantially enantiopure.
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`* * *
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`9. The compound according to claim 8 [limited to lacosamide] which
`contains at least 90% (w/w) R steroisomer.
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`Claim 10, which covers therapeutic compositions—including drug products
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`with lacosamide as the active pharmaceutical ingredient—states:
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`10. A therapeutic composition comprising an anticonvulsant effective
`amount of a compound according to any one of claims 1-9 and a
`pharmaceutical carrier therefor.
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`The final claims, claims 11-13, all cover methods of treating CNS disorders
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`with lacosamide, among other compounds:
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`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.
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`12. The method according to claim 11 wherein the animal is a
`mammal.
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`13. The method according to claim 12 wherein the mammal is a
`human.
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`VI. LEVEL OF ORDINARY SKILL IN THE ART
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`As Dr. Heathcock explains in his declaration, the scientific field relevant to
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`the ’551 patent is medicinal chemistry, and that a POSA would have a Ph.D. in
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`organic or medicinal chemistry, and at least a few years of experience in medicinal
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`chemistry, including in the development of potential drug candidates. Ex. 1002,
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`Heathcock Decl. ¶ 20. A POSA would also include a person who has a Bachelor’s
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`or Master’s degree in organic chemistry or medicinal chemistry if such a person
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`had more years of experience in medicinal chemistry and the development of
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`potential drug candidates. Id.
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`VII. BACKGROUND
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`The lacosamide compound claimed by the ’551 patent was fully disclosed in
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`the prior art by the time the patentee filed its priority application in March 1996.
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`As summarized below, that compound is the product of routine modification of a
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`known lead compound in the prior art, was specifically disclosed in the LeGall
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`thesis, and was already claimed and disclosed in two prior art patents. The patent
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`issued solely because the Examiner made a basic chemistry mistake—an error
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`since recognized by the patentee itself—and because the inventor failed to disclose
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`his student’s prior art thesis to the PTO.
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`A.
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`In 1985, Dr. Kohn Co-Authors Prior Art That Discloses The
`Precursor To Lacosamide.
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`A 1985 article co-authored by inventor Dr. Kohn describes the synthesis and
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`anticonvulsant activity of several different compounds, including the lead
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`compound that led to lacosamide. Ex. 1009, Sergio Cortes et al., Effect of
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`Structural Modification of the Hydantoin Ring on Anticonvulsant Activity, 28 J.
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`Med. Chem. 601 abstr. (1985). Cortes reports that “[a]mong the most active
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`compounds observed were the amino acid derivative N-acetyl-D, L-alanine
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`benzylamide” (id.), which Cortes calls compound 6d and is also called AAB.
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`Id. at 604, Tbl. IV. Cortes discloses that, based on this research, AAB was “slated
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`for additional screening.” Id. at 604.
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`B.
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`In 1987, Dr. Kohn’s Student (LeGall) Modifies The Preferred
`Compound Of Cortes And Discloses The Chemical Structure Of
`Lacosamide.
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`The LeGall thesis represented the next step in the work with AAB. Philippe
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`LeGall was a master’s-level graduate student of Dr. Kohn, who “approved” the
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`thesis by signing it before publication in 1987. Ex. 1005 at i-ii. Mr. LeGall set out
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`to prepare “analogues of the potent anticonvulsant agent” AAB (referred to in the
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`thesis as compound 68a), thus conducting the additional screening contemplated by
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`Dr. Kohn and others as referenced in Cortes. Id. at 42, 132, 173 n.102; see also
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`Ex. 1002, Heathcock Decl. ¶¶ 82-83, 103, 112.
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`As part of this screening, Mr. LeGall synthesized five “[c]ompounds 107a-e
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`[that] were selected as polar analogues of the potent anticonvulsant” AAB
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`(compound 68a), which he represented in the following table:
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`Ex. 1005 at 133 (red box added). The R substituents represent different groups
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`that can be attached at that position on the compound.
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`Compound 107e, which has the R group methoxymethyl (CH2OCH3), is a
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`racemic mixture with the following structure:
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`Ex. 1002, Heathcock Decl. ¶ 83. A POSA would have recognized immediately
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`that 107e has both an R and an S stereoisomer, with the R stereoisomer being the
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`compound known as lacosamide. Id. ¶ 84.
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`Lacosamide is an R stereoisomer or “enantiomer.” Ex. 1002, Heathcock
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`Decl. ¶ 34. The LeGall thesis expresses a strong preference for the “D-
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`enantiomer[]” (here, another term for the R stereoisomer) of compound 68a, the
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`parent compound of 107e—describing it as “thirteen times more active” than the S
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`stereoisomer and “more potent and less toxic” than the racemic mixture when used
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`as an “antiepileptic.” Ex. 1005 at 42-43, 164.
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`C.
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`In 1991, Dr. Kohn And A Colleague Disclose Compounds That
`Include Lacosamide.
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`In 1991, a publication that included Dr. Kohn as an author disclosed a close
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`structural analogue of lacosamide as being one of the most potent anticonvulsant
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`drugs:
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`
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`Ex 1010, Harold Kohn et al., Preparation and Anticonvulsant Activity of a Series
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`of Functionalized α-Heteroatom-Substituted Amino Acids, 34 J. Med. Chem. 2444,
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`2445, 2447 (1991); Ex. 1002, Heathcock Decl. ¶¶ 128-130, 167-171.
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`On June 4, 1991, Dr. Kohn and his colleague (Dr. Darrell Watson) expanded
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`on this disclosure and applied for what ultimately became the ’729 patent, which is
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`§ 102(b) prior art because it issued on January 3, 1995. This pate