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
`
`
`
`DECLARATION OF CLAYTON H. HEATHCOCK, PH.D.
`IN SUPPORT OF 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
`
`IPR2014-01126- Exhibit 1002 p. 1
`
`

`
`
`
`TABLE OF CONTENTS
`
`Exhibits Referenced In This Declaration .................................................................. iv
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS ............................................... 1
`
`A.
`
`B.
`
`Educational Background ....................................................................... 1
`
`Career History and Relevant Industry Participation ............................. 2
`
`II.
`
`SCOPE OF ASSIGNMENT AND COMPENSATION .................................. 5
`
`III. LEGAL PRINCIPLES USED IN MY ANALYSIS ........................................ 6
`
`A.
`
`B.
`
`C.
`
`Person of Ordinary Skill in the Art ....................................................... 6
`
`Prior Art ................................................................................................. 7
`
`Anticipation ........................................................................................... 8
`
`D. Obviousness ........................................................................................... 9
`
`IV. SUMMARY OF MY OPINIONS ................................................................. 10
`
`V.
`
`THE ’551 PATENT ....................................................................................... 11
`
`A. Overview of the ’551 Patent – The Alleged Invention ....................... 11
`
`B.
`
`C.
`
`Overview of Claims 1-13 of the ’551 Patent ...................................... 11
`
`Claim Construction of the ’551 Patent ................................................ 14
`
`VI. TECHNICAL BACKGROUND ................................................................... 15
`
`A.
`
`B.
`
`C.
`
`D.
`
`Representation of Chemical Structures ............................................... 15
`
`Amino Acids ........................................................................................ 19
`
`Stereochemistry ................................................................................... 21
`
`Background on Drug Development .................................................... 27
`
`VII. CLAIMS 1-13 OF THE ’551 PATENT ARE ANTICIPATED BY THE
`’301 PATENT ................................................................................................ 28
`
`i
`
`IPR2014-01126- Exhibit 1002 p. 2
`
`

`
`
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`The ’301 Patent Discloses Lacosamide ............................................... 29
`
`The Preferences Disclosed by the ’301 Patent Lead Directly to
`One Compound—Lacosamide—in Claim 44 ..................................... 32
`
`Claims 1-9 of the ’551 Patent are Anticipated by the ’301 Patent ...... 34
`
`Claim 10 of the ’551 Patent is Anticipated by the ’301 Patent ........... 36
`
`Claims 11-13 of the ’551 Patent are Anticipated by the ’301
`Patent ................................................................................................... 37
`
`VIII. CLAIMS 1-13 OF THE ’551 PATENT ARE ANTICIPATED BY THE
`LEGALL THESIS ......................................................................................... 38
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`The LeGall Thesis Discloses Racemic Lacosamide as an
`Anticonvulsant Compound .................................................................. 39
`
`A POSA was Enabled by the LeGall Thesis and the Prior Art to
`Isolate the R Enantiomer, Lacosamide, in Pure Form ........................ 42
`
`Claims 1-9 of the ’551 Patent are Anticipated by the LeGall
`Thesis ................................................................................................... 46
`
`Claim 10 of the ’551 Patent is Anticipated by the LeGall Thesis ...... 47
`
`Claims 11-13 of the ’551 Patent are Anticipated by the LeGall
`Thesis ................................................................................................... 48
`
`IX. CLAIMS 1-13 OF THE ’551 PATENT ARE OBVIOUS ............................ 49
`
`A.
`
`The Scope and Content of the Prior Art .............................................. 50
`
`1.
`
`2.
`
`3.
`
`Structure-Activity Relationships Were Well-Known For
`The Class Of Compounds Covered By The ’551 Patent .......... 50
`
`The Substitution of Methyl for Amino Groups was
`Commonly Performed in the Prior Art ..................................... 78
`
`The Prior Art Taught The Preparation Of Enantiomerically
`Pure D-Serine And Its Derivatives ........................................... 80
`
`B.
`
`The Differences Between the Prior Art and Claims ........................... 83
`
`ii
`
`IPR2014-01126- Exhibit 1002 p. 3
`
`

`
`
`
`1.
`
`2.
`
`3.
`
`4.
`
`Claims 1 and 3-8 of the ’551 Patent Would Have Been
`Obvious in View of the LeGall Thesis and Other Prior Art ..... 83
`
`Claims 2 and 9 of the ’551 Patent Would Have Been
`Obvious in View of the LeGall Thesis and Other Prior Art ..... 96
`
`Claim 10 of the ’551 Patent Would Have Been Obvious in
`View of the LeGall Thesis and Other Prior Art ........................ 99
`
`Claims 11-13 of the ’551 Patent Would Have Been
`Obvious in View of the LeGall Thesis and Other Prior Art ... 102
`
`C.
`
`D.
`
`The Level of Ordinary Skill in the Art .............................................. 109
`
`Secondary Considerations or Objective Indicia of
`Nonobviousness ................................................................................. 109
`
`X.
`
`CONCLUSION ............................................................................................ 109
`
`iii
`
`IPR2014-01126- Exhibit 1002 p. 4
`
`

`
`
`
`Exhibit
`
`1001
`
`1003
`
`1004
`
`1005
`
`1006
`
`1008
`
`1009
`
`1010
`
`1012
`
`1014
`
`1015
`
`EXHIBITS REFERENCED IN THIS DECLARATION
`
`Description
`
`U.S. Patent No. RE 38,551 to Kohn (“’551 patent”)
`(reissue of U.S. Patent No. 5,773,475 (“’475 patent”))
`
`U.S. Patent No. 5,654,301 to Kohn and Watson
`(the “’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)
`
`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. Provisional Patent Application No. 60/013,522
`(“’522 prov. app.”)
`
`Phillipe LeGall et al., Synthesis of Functionalized Non-
`Natural Amino Acid Derivatives via Amidoalkylation
`Transformations, 32 Int’l J. Peptide Protein Res. 279 (1988)
`(“LeGall 1988”)
`
`R. L. M. Synge, CCXXXIX. Experiments On Amino Acids.
`IV. The Methyl Ethers Of Some N-Acetyl-Hydroxyamino-
`
`iv
`
`IPR2014-01126- Exhibit 1002 p. 5
`
`

`
`
`
`Exhibit
`
`Description
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`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)
`(“Conley 1987”)
`
`Judith D. Conley, Functionalized Amino Acid Derivatives –
`Potent New Agents for the Treatment of Epilepsy: Synthesis,
`and Spectroscopic and Pharmacological Properties (May
`1986) (“Conley thesis”)
`
`Harold Kohn & Judith D. Conley, New Antiepileptic Agents,
`24 Chemistry in Britain 231 (March 1988)
`(“Kohn & Conley 1988”)
`
`European Patent Application No. 0 194 464
`(“’464 Application”)
`
`Harold Kohn et al., Marked Stereospecificity in a New Class
`of Anticonvulsants, 457 Brain Res. 371 (1988)
`(“Kohn 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)
`(“Kohn 1990”)
`
`European Patent Application No. 0 263 506
`(“’506 Application”)
`
`European Patent Application No. 0 400 440
`(“’440 Application”)
`
`v
`
`IPR2014-01126- Exhibit 1002 p. 6
`
`

`
`
`
`Exhibit
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`Description
`
`Harold Kohn et al., Synthesis and Anticonvulsant Activities
`of α-Heterocyclic α-Acetamido-N-Benzylacetamide
`Derivatives, 36 J. Med. Chem. 3350 (1993) (“Kohn 1993”)
`
`Harold Kohn et al., Anticonvulsant Properties of N-
`Substituted α,α-Diamino Acid Derivatives, 83 J.
`Pharmaceutical Sci. 689 (May 1994) (“Kohn 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) (“Amoroso 1992”)
`
`S. Cerrini et al., Serine-Containing 10-Membered
`Cyclodepsipeptides, 41 Int’l J. Peptide Protein Res. 282
`(1993) (“Cerrini 1993”)
`
`Svante Axelsson et al., Versatile Synthesis of
`Stereospecifically Labelled D-Amino Acids via Labelled
`Aziridines, J. Chem. Soc. Perkin Trans. 1 (1994) (“Axelsson
`1994”)
`
`Oliver Keil et al., New Hydantoinases from Thermophilic
`Microorganisms – Synthesis of Enantiomerically Pure D-
`Amino Acids, 6 Tetrahedron: Asymmetry 1257 (1995)
`(“Keil 1995”)
`
`vi
`
`IPR2014-01126- Exhibit 1002 p. 7
`
`

`
`
`
`Exhibit
`
`1034
`
`1035
`
`1036
`
`Description
`
`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) (“Bardel 1994”)
`
`FDA, Guideline for Industry: Dose-Response Information to
`Support Drug Registration (Nov. 1994) (“FDA Dose-
`Response Guidance”)
`
`R. Schmidt, Dose-Finding Studies in Clinical Drug
`Development, 34 Eur. J. Clin. Pharmacol. 15-19 (1988)
`(“Schmidt 1988”)
`
`vii
`
`IPR2014-01126- Exhibit 1002 p. 8
`
`

`
`
`
`1.
`
`I, Dr. Clayton H. Heathcock, hereby declare as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`
`2.
`
`I am Emeritus Professor of the University of California at Berkeley
`
`and a chemist with over 50 years of experience in organic chemistry and medicinal
`
`chemistry.
`
`3.
`
`I have been retained by Petitioners in connection with their request for
`
`inter partes review of U.S. Patent No. RE 38,551 (“the ’551 patent”). A copy of
`
`the ’551 patent has been designated Ex. 1001. I have reviewed and am familiar
`
`with the ’551 patent.
`
`4.
`
`I have been asked to provide my opinion regarding the validity of the
`
`claims of the ’551 patent. This declaration includes a detailed discussion of my
`
`background and qualifications, the background of the technologies involved in and
`
`related to the ’551 patent that would have been understood by a person of ordinary
`
`skill in the art (“POSA”) at the time of the filing of the ’551 patent, and various
`
`prior art references that disclose—either alone or in combination with each other—
`
`all of the relevant features of ’551 patent claims 1-13. The bases and reasons for
`
`my opinions are set forth in this declaration.
`
`A. Educational Background
`I obtained my Bachelor of Science degree from Abilene Christian
`5.
`
`College, Texas in 1958 and my Ph.D. in Organic Chemistry from the University of
`
`
`
`IPR2014-01126- Exhibit 1002 p. 9
`
`

`
`
`
`Colorado in 1963. The subject of my Ph.D. thesis was the synthesis of steroids
`
`that were modified by the incorporation of heterocyclic rings, mainly three-
`
`membered, nitrogen-containing structures called aziridines. I did my post-doctoral
`
`studies at Columbia University from 1963 to 1964, where I was an apprentice to
`
`Professor Gilbert Stork.
`
`B. Career History and Relevant Industry Participation
`I joined the University of California at Berkeley in 1964 as an
`6.
`
`Assistant Professor and have subsequently held a number of positions at the
`
`University of California, including: Associate Professor (1970-75); Professor
`
`(1975-2004); Vice-Chairman of the Department of Chemistry (1972-77);
`
`Chairman of the Department of Chemistry (1986-89); and Dean of the College of
`
`Chemistry (1999-2005 and January-June 2008). From 2005 through 2008, I was
`
`Chief Scientist of the Berkeley branch of the California Institute for Quantitative
`
`Biosciences (QB3), a research institute that was created to bring together the
`
`quantitative sciences at UC Berkeley and UC Santa Cruz and the clinical sciences
`
`at UC San Francisco to address and solve significant problems in human health.
`
`7.
`
`During my tenure at the University of California at Berkeley, I taught
`
`both graduate and undergraduate courses in organic chemistry. One of the courses
`
`that I taught for a number of years was a course for graduate students on the
`
`subject of organic synthesis.
`
`2
`
`IPR2014-01126- Exhibit 1002 p. 10
`
`

`
`
`
`8.
`
`During my 41-year research career at the University of California, I
`
`trained more than 80 doctoral students and approximately 50 post-doctoral fellows.
`
`My relationship with these students and post-doctoral fellows was that of mentor-
`
`apprentice. I assigned research projects to them and met with them several times a
`
`week to discuss the results of their laboratory experiments and to decide on the
`
`next steps to take in the research. The majority of the students who did their
`
`research training in my laboratory are now employed as medicinal or process
`
`chemists in pharmaceutical and biotech companies, or have retired after occupying
`
`such positions during their careers.
`
`9.
`
`During my active research career, my research subjects included the
`
`development of new synthesis strategies, biomimetic (nature-imitating) synthesis,
`
`natural products chemistry, and studies of the stereochemistry of carbon-carbon
`
`bond-forming reactions. My research projects were funded mainly by the National
`
`Institutes of Health and the National Science Foundation, but some were funded
`
`with direct grants from pharmaceutical companies.
`
`10.
`
`I was elected a Fellow of the National Academy of Sciences (NAS) in
`
`1995. I have been a member of the American Chemical Society for more than 50
`
`years, and in 2009, I was selected as an inaugural Fellow of the American
`
`Chemical Society. I have received a number of awards for my work in organic
`
`chemistry including: Ernest Guenther Award, American Chemical Society (1986);
`
`3
`
`IPR2014-01126- Exhibit 1002 p. 11
`
`

`
`
`
`Award for Creative Work in Synthetic Organic Chemistry, American Chemical
`
`Society (1990); A.C. Cope Scholar, American Chemical Society (1990); Prelog
`
`Medal, ETH (Eidgenossische Technische Hochschule (Swiss Federal Institute of
`
`Technology) (1991); American Academy of Arts and Sciences (1991); Pfizer
`
`Award in Synthetic Organic Chemistry (1993); Centenary Medal, Royal Society of
`
`Chemistry (1996); H.C. Brown Award, American Chemical Society (2002); and
`
`Paul Gassman Award for Distinguished Service, American Chemical Society
`
`(2004).
`
`11.
`
`I have consulted with a number of pharmaceutical and biotechnology
`
`companies including: Merck, Sharp & Dohme (1968-78); Abbott Laboratories
`
`(1986-1997); and Plexxikon, Inc. (2002-2011). In my work as a consultant, I
`
`typically met with individual medicinal chemists to review their current projects.
`
`In the cases of Abbott Laboratories and Plexxikon, I served as a member of their
`
`Scientific Advisory Boards and met regularly with top management to review and
`
`provide advice on their pharmaceutical development programs.
`
`12. From 1979 to 1981, I was a member of the National Institutes of
`
`Health Medicinal Chemistry Study Section A (MCHA), and I chaired this group
`
`from 1981 to 1983. The MCHA reviewed research grant proposals submitted to
`
`the NIH in the area of medicinal chemistry and recommended the ones that should
`
`be funded.
`
`4
`
`IPR2014-01126- Exhibit 1002 p. 12
`
`

`
`
`
`13.
`
`I have published more than 275 scientific papers and patents relating
`
`to organic synthesis and medicinal chemistry.
`
`14. Additional information regarding my background, qualifications,
`
`publications, and presentations is provided in my CV, which is included in
`
`Appendix A.
`
`II.
`
`SCOPE OF ASSIGNMENT AND COMPENSATION
`
`15.
`
`I have been asked to provide my opinions regarding the validity of
`
`claims 1-13 of the ’551 patent. I have been asked to provide a detailed technical
`
`overview reflecting what I believe would have been known to a person of ordinary
`
`skill in the art at the time that the earliest priority application for the ’551 patent
`
`was filed in March 1996.
`
`16.
`
`I have been asked to focus my analysis on certain bases for invalidity
`
`(e.g., anticipation vs. obviousness). I reserve the right to form opinions on other
`
`bases for the invalidity of claims 1-13 of the ’551 patent at a later time.
`
`17.
`
`I am being compensated at my standard hourly consulting rate of $650
`
`per hour for the time spent for the research, study, and writing required for this
`
`declaration. I am compensated at my standard hourly rate of $1,300 per hour for
`
`time spent giving testimony at deposition. My compensation is in no way
`
`contingent on the substance of my opinions or the outcome of this matter.
`
`5
`
`IPR2014-01126- Exhibit 1002 p. 13
`
`

`
`
`
`III. LEGAL PRINCIPLES USED IN MY ANALYSIS
`I am not a patent attorney, nor have I independently researched the
`18.
`
`law of patent validity. Attorneys have explained certain legal principles to me that
`
`I have relied on in forming my opinions set forth in this Declaration.
`
`A.
`19.
`
`Person of Ordinary Skill in the Art
`
`I understand that U.S. Provisional Application No. 60/013,522, which
`
`the ’551 patent claims priority to, was filed on March 15, 1996. Ex. 1012. For the
`
`purposes of my analysis, and in the absence of any information to the contrary, I
`
`have used the March 15, 1996 date as the relevant date for my analysis of the prior
`
`art.1
`
`20.
`
`I understand that assessment of the validity of the claims of the ’551
`
`patent must be undertaken from the perspective of what would have been known
`
`and understood by someone of ordinary skill in the art as of the earliest priority
`
`date of the ’551 patent. Based on my knowledge and expertise and the prior art
`
`cited in the ’551 patent, it is my opinion that a POSA in the relevant art (medicinal
`
`chemistry) would include a person who has at least a Bachelor’s or Master’s
`
`degree, but more likely a Ph.D. degree in organic chemistry or medicinal
`
`chemistry, as well as having at least a few years of experience in medicinal
`
`
`1 However, if I were to use March 15, 1995, as the relevant date, my opinion would
`not be any different.
`
`6
`
`IPR2014-01126- Exhibit 1002 p. 14
`
`

`
`
`
`chemistry, including in the development of potential drug candidates. This person
`
`could have a lower level of formal education than a Ph.D. degree if such a person
`
`had more years of experience in medicinal chemistry and the development of
`
`potential drug candidates. This person would regularly peruse the literature of
`
`organic and medicinal chemistry and would know how to carry out library research
`
`using Chemical Abstracts and other library resources to find out more information
`
`about areas being researched. Included in the literature that would be regularly
`
`perused would be the patent literature in areas of interest. A POSA would know
`
`how to characterize potential drug candidates, both structurally and with regard to
`
`their biological properties. I have been informed that, from a patent law
`
`perspective, the POSA is a hypothetical person who is presumed to have
`
`knowledge of all of the relevant art at the relevant time. In addition, the POSA
`
`would know how to evaluate potential drugs for their in vitro and in vivo activity,
`
`and although he/she might not actually be set up to carry out those biological
`
`assays, he/she would know how to obtain such results from a qualified commercial
`
`testing laboratory, either within or outside his/her organization, or through a
`
`collaboration with a colleague elsewhere.
`
`B.
`21.
`
`Prior Art
`
`I have been informed that the law provides certain categories of
`
`information (known as prior art) that may be used to anticipate or render obvious
`
`7
`
`IPR2014-01126- Exhibit 1002 p. 15
`
`

`
`
`
`patent claims. The reference materials I discuss are prior art below because they
`
`were available to those of ordinary skill in the art as of March 15, 1996.2
`
`C. Anticipation
`I have been informed that a claim is not patentable when a single prior
`22.
`
`art reference describes every element of the claim, either expressly or inherently to
`
`a person of ordinary skill in the art. I understand that this is referred to as
`
`“anticipation.” I have also been informed that, to anticipate a patent claim, the
`
`prior art reference need not use the same words as the claim, but it must describe
`
`the requirements of the claim with sufficient clarity that a person of skill in the art
`
`would be able to make and use the claimed invention based on the single prior art
`
`reference.
`
`23.
`
`In addition, I was informed and understand that, in order to establish
`
`that an element of a claim is “inherent” in the disclosure of a prior art reference, it
`
`must be clear to one skilled in the art that the missing element is an inevitable part
`
`of what is explicitly described in the prior art, and that it would be recognized as
`
`necessarily present by a person of ordinary skill in the art.
`
`
`2 However, even if I were to consider the prior art as of March 15, 1995, which I
`understand any information published prior to that date is unequivocally prior art,
`the opinions on anticipation and obviousness expressed herein would be no
`different.
`
`8
`
`IPR2014-01126- Exhibit 1002 p. 16
`
`

`
`
`
`D. Obviousness
`I have been informed that, even if every element of a claim is not
`24.
`
`found explicitly or implicitly in a single prior art reference, the claim may still be
`
`unpatentable if the differences between the claimed elements and the prior art are
`
`such that the subject matter as a whole would have been obvious at the time the
`
`invention was made to a person of ordinary skill in the art. That is, the invention
`
`may be obvious to a person having ordinary skill in the art when seen in light of
`
`one or more prior art references.
`
`25.
`
`I have been informed that the following four factors are considered
`
`when determining whether a patent claim is obvious: (1) the scope and content of
`
`the prior art; (2) the differences between the prior art and the claim; (3) the level of
`
`ordinary skill in the art; and (4) secondary considerations tending to prove
`
`obviousness or nonobviousness. These secondary considerations include: (i) long-
`
`felt need, (ii) unexpected results, (iii) skepticism of the invention, (iv) teaching
`
`away from the invention, (v) commercial success, (vi) praise by others for the
`
`invention, and (vii) copying by other companies. I have also been informed that
`
`there must be a connection between these secondary factors and the scope of the
`
`invention claimed in the patent.
`
`26. To establish obviousness, I understand that it must be demonstrated
`
`that a POSA would have been motivated to combine the teachings of the prior art
`
`9
`
`IPR2014-01126- Exhibit 1002 p. 17
`
`

`
`
`
`references to achieve the claimed invention, and that the POSA would have had a
`
`reasonable expectation of success in doing so. Further, I understand that a
`
`sufficient motivation is that the claimed and prior art compounds possess a
`
`sufficiently close relationship to create an expectation, in light of the totality of the
`
`prior art, that the new compound will have similar properties to the old.
`
`IV. SUMMARY OF MY OPINIONS
`27. As set forth more fully herein, it is my opinion that claims 1-13 of the
`
`’551 patent are anticipated by U.S. Patent No. 5,654,301 (Ex. 1003) (“the ’301
`
`patent”).
`
`28. As set forth more fully herein, it is my opinion that claims 1-13 of the
`
`’551 patent are anticipated by Philippe LeGall, 2-Substituted-2-Acetamido-N-
`
`Benzylacetamides. Synthesis, Spectroscopic and Anticonvulsant Properties
`
`(December 1987) (Ex. 1005) (“the LeGall thesis”).
`
`29. As set forth more fully herein, it is my opinion that claims 1-13 of the
`
`’551 patent would have been obvious to a POSA before March 15, 1996, based on
`
`the disclosures in the LeGall thesis (e.g., compound 107e) in view of other prior
`
`art, including U.S. Patent No. 5,378,729 (Ex. 1008) (“the ’729 patent”).
`
`10
`
`IPR2014-01126- Exhibit 1002 p. 18
`
`

`
`
`
`V. THE ’551 PATENT
`A. Overview of the ’551 Patent – The Alleged Invention
` The ’551 patent describes its alleged invention as relating “to novel
`30.
`
`enantiomeric compounds and pharmaceutical compositions useful in the treatment
`
`of epilepsy and other CNS disorders.”3
`
`31. The compounds described in the ’551 patent are a class of drugs
`
`referred to as “anticonvulsant drugs,” compounds, or agents.4 Anticonvulsant
`
`drugs are used to “control and prevent[] seizures associated with epilepsy or
`
`related central nervous system disorders.”5
`
`B. Overview of Claims 1-13 of the ’551 Patent
`32. Claim 1 is the only independent claim of the ’551 patent. Claims 2-13
`
`are all dependent claims. I understand that a dependent claim incorporates all of
`
`the elements of the claims on which the dependent claim depends.
`
`33. Claims 1-9 of the ’551 patent are claims directed to chemical
`
`compounds that can be construed to cover the chemical compound lacosamide,
`
`which has the following chemical structure:
`
`
`3 Ex. 1001, col. 1:21-23.
`4 Id. at col. 1:27-28.
`5 Id. at col. 1:27-29.
`
`11
`
`IPR2014-01126- Exhibit 1002 p. 19
`
`

`
`
`
`
`
`
`
`34. Lacosamide is the R-enantiomer of 2-acetamido-N-benzyl-3-
`
`methoxypropionamide and is the only compound claimed in claim 8 of the ’551
`
`patent. Claims 1 through 9 are recited as follows:
`
`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.
`2. The compound according to claim 1 which is substantially
`enantiopure.
`3. The compound according to claim 1 wherein Q is lower
`alkoxy containing 1-3 carbon atoms.
`4. The compound according to claim 3 wherein Q is methoxy.
`5. The compound according to claim 1 wherein Ar is
`unsubstituted phenyl.
`6. The compound according to claim 1 wherein halo is fluoro.
`
`12
`
`IPR2014-01126- Exhibit 1002 p. 20
`
`

`
`
`
`7. The compound according to claim 1 wherein Q is alkoxy
`containing 1-3 carbon atoms and Ar is unsubstituted phenyl.
`8. The compound according to claim 1 which is (R)-N-Benzyl
`2-Acetamido-3-methoxypropionamide.
`9. The compound according to claim 8 which contains at least
`90% (w/w) R stereoisomer.
`
`Claim 1 thus covers certain R enantiomers (referred to in the claims as R
`
`stereoisomers) depending on the substituents that are used for Ar, Q, and Q1 below:
`
`
`
`In particular, claim 1 covers the compound lacosamide (as part of the racemate, or
`
`as an isolated stereoisomer) when the Ar substituent is a benzyl group, Q is a
`
`methoxymethyl group, and Q1 is a methyl group as shown in the following
`
`
`
`13
`
`structure:
`
`
`
`IPR2014-01126- Exhibit 1002 p. 21
`
`

`
`
`
`
`
`35. Claim 10 of the ’551 patent is directed to “[a] therapeutic composition
`
`comprising an anticonvulsant effective amount” of the compounds recited in
`
`claims 1-9, including lacosamide. Claim 10 of the ’551 patent recites:
`
`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.
`
`36. Claims 11-13 of the ’551 patent are directed to “method[s] of treating
`
`central nervous system disorders in an animal comprising administering … an
`
`anticonvulsant effective amount” of the compounds recited in claims 1-9, including
`
`lacosamide. Claims 11-13 of the ’551 patent recite:
`
`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.
`12. The method according to claim 11 wherein the animal is a
`mammal.
`13. The method according to claim 12 wherein the mammal is a
`human.
`
`C. Claim Construction of the ’551 Patent
`37. Claim 1 of the ’551 patent claims compounds of the named chemical
`
`formula “in the R configuration,” which refers to one of the two possible
`
`enantiomeric forms of the structure (discussed in more depth later). I understand
`
`this claim to include mixtures of enantiomeric compounds of the claimed formula
`
`14
`
`IPR2014-01126- Exhibit 1002 p. 22
`
`

`
`
`
`that include any amount of the relevant enantiomer with the R configuration. This
`
`construction is confirmed by claim 2, which provides a further limitation requiring
`
`that the compound be “substantially enantiopure.” It is also confirmed by claim 9,
`
`which specifies the compound of claim 8, (R)-N-benzyl-2-acetamido-3-
`
`methoxypropionamide, contain at least 90% (w/w) R stereoisomer.
`
`38. Claim 1 provides that “Ar is phenyl which is unsubstituted or
`
`substituted with at least one halo group”:
`
`
`
`Claim 6 further specifies that the “halo is fluoro.” Under the broadest reasonable
`
`interpretation, claim 6 could be construed to include either (1) unsubstituted
`
`phenyl; or (2) phenyl substituted with at least one fluoro group. Under that
`
`construction, claim 6 would encompass lacosamide because lacosamide has
`
`unsubstituted phenyl in the Ar position.
`
`VI.
`
` TECHNICAL BACKGROUND
`A. Representation of Chemical Structures
`39. The pharmaceutical products of importance in this proceeding are
`
`organic chemical compounds. In order to fully understand my opinions, it is
`
`15
`
`IPR2014-01126- Exhibit 1002 p. 23
`
`

`
`
`
`necessary to have a rudimentary understanding of some of the basic tenets of
`
`organic chemistry.6
`
`40. Organic chemistry is the chemistry of compounds of carbon. Each
`
`carbon atom forms four bonds to other atoms and the most common other atom in
`
`organic compounds is hydrogen. Methane, CH4, is the simplest example of a
`
`“hydrocarbon,” a molecule composed solely of hydrogen and carbon. As shown in
`
`the following chemical structure, carbon (C) makes four bonds to other atoms and
`
`hydrogen (H) makes only one.
`
`
`
`41. Carbon is an almost unique element in that it has the ability to form
`
`molecules by bonding to itself in the form of “chains” to give molecules such as
`
`the hydrocarbon depicted below:
`
`
`6 This background section on organic chemistry is a highly condensed version of
`portions of an introductory textbook coauthored by me: A. Streitwieser, Jr. and C.
`H. Heathcock, Introduction to Organic Chemistry (1985).
`
`
`
`16
`
`IPR2014-01126- Exhibit 1002 p. 24
`
`

`
`
`
`42. Although hydrogen is the most common “other atom” joined to
`
`carbon in organic compounds, a number of other atoms can occur in organic
`
`compounds. Examples are oxygen and nitrogen.
`
`
`
`As shown in these two formulae, oxygen (O) makes two bonds to other atoms
`
`whereas nitrogen (N) makes three bonds to other atoms. The number of bonds to
`
`other atoms is called the “valence” of the atom. Thus, as shown in the examples so
`
`far, H has a valen