UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ACTAV1S INC ACTAVIS LABORATORIES FL INC
`ACTAVIS PHARMA INC AMNEAL PHARMACEUTICALS LLC
`AM1\EAL 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
`
`RESEARCH CORPORATION TECHNOLOGIES INC
`Patent Owner
`
`Case IPR2O14-01 126
`
`DECLARATION OF CLAYTON
`HEATHCOCK PH.D
`IN SUPPORT OF PETITION FOR INTER
`PARTES REVIEW OF U.S PATENT NO RE 38551
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O Box 1450
`Alexandria Virginia 223 131450
`Submitted Electronically via the Patent Review Processing System
`
`Breckenridge Exhibit 1003
`Breckenridge v. Research Corporation Technologies, Inc.
`
`-1-
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`ACTAV1S INC ACTAVIS LABORATORIES FL INC
`ACTAVIS PHARMA INC AMNEAL PHARMACEUTICALS LLC
`AM1\EAL 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
`
`RESEARCH CORPORATION TECHNOLOGIES INC
`Patent Owner
`
`Case IPR2O14-01 126
`
`DECLARATION OF CLAYTON
`HEATHCOCK PH.D
`IN SUPPORT OF PETITION FOR INTER
`PARTES REVIEW OF U.S PATENT NO RE 38551
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`P.O Box 1450
`Alexandria Virginia 223 131450
`Submitted Electronically via the Patent Review Processing System
`
`Breckenridge Exhibit 1003
`Breckenridge v. Research Corporation Technologies, Inc.
`
`-1-
`
`
`
`TABLE OF CONTENTS
`
`Exhibits Referenced In This Declaration
`
`iv
`
`INTRODUCTION AND QUALIFICATIONS
`
`Educational Background
`
`Career History and Relevant
`
`Industry Participation
`
`II
`
`III
`
`SCOPE OF ASSIGNMENT AND COMPENSATION
`
`LEGAL PRINCIPLES USED IN MY ANALYSIS
`
`Person of Ordinary Skill
`
`in the Art
`
`PriorArt
`
`Anticipation
`
`Obviousness
`
`IV
`
`SUMMARY OF MY OPINTONS
`
`THE 551 PATENT
`
`Overview of the 551 Patent
`
`The Alleged Invention
`
`Overview of Claims 1-13 of the 551 Patent
`
`Claim Construction of the 551 Patent
`
`VI
`
`TECEIISIICAL BACKGROUND
`
`Representation of Chemical Structures
`
`Amino Acids
`
`Stereochemistry
`
`Background on Drug Development
`
`VII CLAIMS 1-13 OF THE 551 PATENT ARE ANTICIPATED BY THE
`301 PATENT
`
`10
`
`11
`
`11
`
`11
`
`14
`
`15
`
`15
`
`19
`
`21
`
`27
`
`28
`
`-2-
`
`
`
`The 301 Patent Discloses Lacosamide
`
`.29
`
`The Preferences Disclosed by the 301 Patent Lead Directly to
`One CompoundLacosamidein Claim 44
`
`Claims 1-9 of the 551 Patent are Anticipated by the 301 Patent
`
`Claim 10 of the 551 Patent
`
`is Anticipated by the 301 Patent
`
`Claims 11-13 of the 551 Patent are Anticipated by the 301
`Patent
`
`VIII CLAIMS 1-13 OF THE 551 PATENT ARE ANTICIPATED BY THE
`LEGALL THESIS
`
`The LeGall Thesis Discloses Racemic Lacosamide as an
`Anticonvulsant Compound
`
`POSA was Enabled by the LeGall Thesis and the Prior Art to
`Enantiomer Lacosamide in Pure Form
`Isolate the
`
`Claims 1-9 of the 551 Patent are Anticipated by the LeGall
`Thesis
`
`Claim 10 of the 551 Patent
`
`is Anticipated by the LeGall Thesis
`
`Claims 11-13 of the 551 Patent are Anticipated by the LeGall
`Thesis
`
`IX CLAIMS 1-13 OF THE 551 PATENT ARE OBVIOUS
`
`The Scope and Content of the Prior Art
`
`Structure-Activity Relationships Were Well-Known For
`The Class Of Compounds Covered By The 551 Patent
`
`The Substitution of Methyl for Amino Groups was
`Commonly Performed in the Prior Art
`
`The Prior Art Taught The Preparation Of Enantiomerically
`Pure D-Serine And Its Derivatives
`
`The Differences Between the Prior Art and Claims
`
`32
`
`34
`
`36
`
`37
`
`38
`
`39
`
`42
`
`46
`
`47
`
`48
`
`49
`
`50
`
`50
`
`78
`
`80
`
`83
`
`-3-
`
`
`
`and 3-8 of the 551 Patent Would Have Been
`Claims
`Obvious in View of the LeGall Thesis and Other Prior Art
`
`of the 551 Patent Would Have Been
`and
`Claims
`Obvious in View of the LeGall Thesis and Other Prior Art
`
`Claim 10 of the 551 Patent Would Have Been Obvious in
`View of the LeGall Thesis and Other Prior Art
`
`83
`
`96
`
`99
`
`Claims 11-13 of the 551 Patent Would Have Been
`Obvious in View of the LeGall Thesis and Other Prior Art.. 102
`
`The Level of Ordinary Skill
`
`in the Art
`
`Secondary Considerations or Objective Indicia of
`Nonobviousness
`
`CONCLUSION
`
`109
`
`109
`
`109
`
`-4-
`
`
`
`EXHIBITS REFERENCED IN THIS DECLARATION
`
`Exhibit
`
`Description
`
`1001
`
`1003
`
`1004
`
`1005
`
`1006
`
`1008
`
`1009
`
`1010
`
`1012
`
`1014
`
`1015
`
`_________________
`
`U.S Patent No RE 38551 to Kohn 551 patent
`reissue of U.S Patent No 5773475 475 patent
`
`U.S Patent No 5654301 to Koirn and Watson
`the 301 patent
`
`Jan 28 1998 Notice of Allowability
`from prosecution history of 475 patent
`excerpt
`
`Philippe LeGall 2-Substituted-2-acetamido-N-
`ides Synthesis Spectroscopic and
`benylacetani
`Anticonvulsant Properties Dec 1987 LeGall thesis
`
`Apr 10 1998 AmendmentUnder37 C.F.R 1.312
`from prosecution history of 475 patent
`excerpt
`
`U.S Patent No 5378729 to Kohn and Watson
`729 patent
`
`Sergio CoPes et al Effect of Structural Modification qf the
`Med
`Hydantoin Ring on Anticonvulsant Activity 28
`Chem 601 1985 CoPes
`
`Harold Kolrn et al Preparation and Anticonvulsant Activity
`of Series of Functionalied a-Heteroatom-Substituted
`Amino Acids 34 Med Chem 2444 1991 Kohn 1991
`
`U.S Provisional Patent Application No 60/0 13522
`522 prov app
`
`Phillipe LeGall et al Synthesis of Fun ctionclied Non-
`Natural Amino Acid Derivatives via Am idoalkylation
`Peptide Protein Res 279 1988
`Transformations 32 Intl
`LeGall 1988
`
`Synge CCXXXIX Experiments on Amino Acids
`IV The Methyl Ethers of Some N-Acetyl-Hydroxyam mo
`
`-5-
`
`
`
`Exhibit
`
`Description
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`1021
`
`1022
`
`1023
`
`1024
`
`Acids 33 Biochem .1
`
`93 1939
`
`Jaeger et aT Enzymatic Resolution of 0-Methyl-N-
`acetyl-DL-serine Amino Acids XXXII 28 Croat Chem
`1956
`Acta
`
`Harold Kohn Functionalized DL-
`Judith
`Conley
`Amino Acid Derivatives Potent New Agents for the
`Treatment of Epilepsy 30 Med Chem 567 1987
`Conley 1987
`
`Conley Functionalized Amino Acid Derivatives
`Judith
`Potent New Agents for the Treatment of Epilepsy Synthesis
`and Pharmacological Properties May
`and Spectroscopic
`1986 Coriley thesis
`
`Conley New Antiepileptic Agents
`Harold Kohn
`Judith
`24 Chemistry in Britain 231 March 1988
`Kohn
`Conley 1988
`
`European Patent Application No
`464 Application
`
`194 464
`
`Harold Kohn et al Marked Stereospeqficity in New Class
`ofAnticonvulsants 457 Brain Res 371 1988
`Kohn 1988
`
`Harold Kohn et aT Preparation and Anticonvulsant Activity
`of Series of Functionalized a-Aromatic and
`Heteroaromatic Amino Acids 33 Med Chem 919 1990
`Kohn 1990
`
`European Patent Application No
`506 Application
`
`European Patent Application No
`440 Application
`
`263 506
`
`400 440
`
`-6-
`
`
`
`Exhibit
`
`1025
`
`1026
`
`1027
`
`1028
`
`1029
`
`1030
`
`1031
`
`1032
`
`1033
`
`Description
`
`Harold Kohii et al Synthesis and AniicomuI.sani Activities
`of a-Heterocyclic a-A cetam ido-N-Benzylacetamide
`Derivatives 36 Med Chem 3350 1993 Kohn 1993
`
`Harold Kohn et al Anticonvulsant Properties of N-
`a-Diamino Acid Derivatives 83
`Substituted
`Pharmaceutical Sci 689 May 1994 Kohn 1994
`
`C.W Thomber Isosterism and Molecular ModfIcation in
`Chemical Socy Revs 563 1979
`Drug Design
`Thornber 1979
`
`Wilson Gisvolds Textbook of Organic Medicinal and
`Pharmaceutical Chemistry Ch Delgado
`Remers eds
`
`1991 WG 1991
`
`Silverman The Organic Chemistry of Drug
`Richard
`Design and Drug Action Ch 1992 Silverman 1992
`
`New Route to the Synthesis ofAmino
`Rosa Amoroso et al
`Acids Through the Mercury Cyclization of Chiral Amidals
`57 Org Chem 1082 1992 Amoroso 1992
`
`Cerrilli et al Serine-Containing lO-Membered
`Peptide Protein Res 282
`Cyclodepsipeptides 41 Intl
`1993 Cerrini 1993
`
`Svante Axelsson et al Versatile Synthesis of
`Stereospecfically Labelled D-Amino Acids via Labelled
`Aziridines Chem Soc Perkin Trans
`1994 Axelsson
`1994
`
`Oliver Keil et al New Hydantoinases from Thermophilic
`Synthesis of Enantiomerically Pure
`Microorganisms
`Tetrahedron Asymmetry 1257 1995
`Amino Acids
`Keil 1995
`
`-7-
`
`
`
`Exhibit
`
`1034
`
`1035
`
`1036
`
`Description
`
`Patrick Bardel et al Synthesis and Ant/convulsant
`of a-Ace/ui
`iclo-N-Benzylacetamide Der/vat/ves Conta/n/ng
`a-Heteroaromat/c Subst/tuent 37
`an Electron-Deficient
`Med Chem 4567 1994 Bardel 1994
`
`Act/v/i/es
`
`FDA Guideline for Industry Dose-Response Inform at/on to
`Support Drug Reg/strat/on Nov 1994 FDA Dose-
`Response Guidance
`
`/n Cl/n/cal Drug
`Schmidt Dose-F/nd/ng Stud/es
`Development 34 Eur Clin Pharmacol 15-19 1988
`Schmidt 1988
`
`-8-
`
`
`
`Dr Clayton
`
`Heathcock hereby declare as follows
`
`INTRODUCTION AND QUALIFICATIONS
`
`am Emeritus Professor of the University of California at Berkeley
`
`and
`
`chemist with over 50 years of experience in organic chemistry and medicinal
`
`chemistry
`
`have been retained by Petitioners in connection with their request
`
`for
`
`inter partes review of U.S Patent No RE 38551 the 551 patent
`
`copy of
`
`the 551 patent has been designated Ex 1001
`
`have reviewed and am familiar
`
`with the 551 patent
`
`have been asked to provide my opinion regarding the validity of the
`
`claims of the 551 patent This declaration includes
`
`detailed discussion of my
`
`background
`
`and qualifications the background of the teclrnologies involved in and
`
`related to the 551 patent
`that would have been understood by
`person of ordinary
`in the art POSA at the time of the filing of the 551 patent and various
`
`skill
`
`prior art references that discloseeither 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
`
`Educational Background
`
`obtained my Bachelor of Science degree from Abilene Christian
`
`College Texas in 1958 and my Ph.D in Organic Chemistry from the University of
`
`-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
`
`did my po st-doctoral
`
`studies at Columbia University from 1963 to 1964 where
`
`was an apprentice to
`
`Professor Gilbert Stork
`
`Career History and Relevant
`
`Industry Participation
`
`Ijoined the University of California at Berkeley in 1964 as an
`
`Assistant Professor and have subsequently held
`
`number of positions at the
`
`University of California including Associate Professor 1970-75 Professor
`
`1975-2004 Vice-Chairman of the Department of Chemistiy 1972-77
`
`Chainiian of the Department of Chemistry 1986-89 and Dean of the College of
`
`Chemistry 1999-2005 and Januaiy-June 2008 From 2005 through 2008 was
`
`Chief Scientist of the Berkeley branch of the California Institute for Quantitative
`
`Biosciences QB3 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
`
`During my tenure at the University of California at Berkeley
`
`taught
`
`both graduate and undergraduate
`
`courses in organic chemistry One of the courses
`
`that
`
`taught
`
`for
`
`number of years was
`
`course for graduate students on the
`
`subject of organic synthesis
`
`-10-
`
`
`
`During my 41-year research career at the University of California
`
`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
`
`assigned research projects to them and met with them several times
`
`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
`
`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-foniiing 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
`
`was elected
`
`Fellow of the National Academy of Sciences NAS in
`
`1995
`
`have been member of the American Chemical Society for more than 50
`
`years and in 2009 was selected as an inaugural Fellow of the American
`
`Chemical Society
`
`have received
`
`number of awards for my work ill organiic
`
`chemistry including Ernest Guenther Award American Chemical Society 1986
`
`-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
`
`have consulted with
`
`number of pharniaceutical and biotechnology
`
`companies including Merck Sharp
`
`Dohme 1968-78 Abboft Laboratories
`
`1986-1997 and Plexxikon Inc 2002-2011 In my work as
`
`consultant
`
`typically met with individual medicinal chemists to review their current projects
`
`In the cases of Abboft Laboratories and Plexxikon
`
`served as member of their
`
`Scientific Advisory Boards and met regularly with top management to review and
`
`provide advice on their pharniaceutical development programs
`
`12
`
`From 1979 to 1981 was member of the National
`
`Institutes of
`
`Health Medicinal Chemistry Study Section MCHA and
`from 1981 to 1983 The MCHA reviewed research grant proposals submitted to
`
`chaired this group
`
`the NTH iii
`
`the area of medicinal chemistry arid recommended the ones that should
`
`be funded
`
`-12-
`
`
`
`13
`
`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
`
`II
`
`SCOPE OF ASSIGNMENT AND COMPENSATION
`
`15
`
`have been asked to provide my opinions regarding the validity of
`
`claims 1-13 of the 551 patent
`
`have been asked to provide
`
`detailed teclrnical
`
`overview reflecting what
`
`believe would have been known to
`
`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
`
`have been asked to focus my analysis on certain bases for invalidity
`
`e.g anticipation vs obviousness
`
`reserve the right to form opinions on other
`
`bases for the invalidity of claims 1-13 of the 551 patent at
`
`later time
`
`17
`
`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
`
`am compensated at my standard hourly rate of $1300 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
`
`-13-
`
`
`
`III
`
`LEGAL PRINCIPLES USED IN MY ANALYSIS
`
`18
`
`am not
`
`patent attorney nor have
`
`independently researched the
`
`law of patent validity Aftorneys have explained certain legal principles to me that
`
`have relied on in fonning my opinions set forth in this Declaration
`
`Person of Ordinary Skill
`
`in the Art
`
`19
`
`understand that U.S Provisional Application No 60/013522 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
`
`have used the March 15 1996 date as the relevant date for my analysis of the prior
`
`art
`
`20
`
`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 POSA in the relevant art medicinal
`
`chemistry would include
`
`person who has at least Bachelors or Masters
`
`degree but more likely Ph.D degree in organic chemistry or medicinal
`
`chemistry as well as having at least
`
`few years of experience in medicinal
`
`However if were to use March 15 1995 as the relevant date my opinion would
`not be any different
`
`-14-
`
`
`
`chemistry including in the development of potential drug candidates This person
`
`could have
`
`lower level of fornial education than Ph.D degree if such
`
`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
`
`POSA would know
`
`how to characterize potential drug candidates both structurally and with regard to
`
`their biological properties
`
`have been infoniied that from patent
`
`law
`
`perspective the POSA is
`
`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 qualified commercial
`
`testing laboratory either within or outside his/her organization or through
`
`collaboration with
`
`colleague elsewhere
`
`Prior Art
`
`21
`
`have been infornied that
`
`the law provides certain categories of
`
`inforniation known as prior art that may be used to anticipate or render obvious
`
`-15-
`
`
`
`patent claims The reference materials
`
`discuss are prior art below because they
`
`were available to those of ordinary skill
`
`in the art as of March 15 1996.2
`
`Anticipation
`
`22
`
`have been infornied that
`
`claim is not patentable when
`
`single prior
`
`art reference describes every element of the claim either expressly or inherently to
`
`person of ordinary skill
`
`in the art
`
`understand that this is referred to as
`
`anticipation
`
`have also been informed that to anticipate
`
`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
`
`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 was infonried and understand that in order to establish
`
`that an element of
`
`claim is inherent in the disclosure of 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
`
`person of ordinary skill
`
`in the art
`
`However even if were to consider the prior art as of March 15 1995 which
`understand any infoniiation published prior to that date is unequivocally prior art
`the opinions on anticipation and obviousness expressed herein would be no
`different
`
`-16-
`
`
`
`Obviousness
`
`24
`
`have been infornied that even if every element of
`
`claim is not
`
`found explicitly or implicitly in 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 whole would have been obvious at the time the
`
`invention was made to
`
`person of ordinary skill
`
`in the art That
`
`is the invention
`
`may be obvious to
`
`person having ordinary skill
`
`in the art when seen in light of
`
`one or more prior art references
`
`25
`
`have been infonned that
`
`the following four factors are considered
`
`when determining whether
`
`patent claim is obvious
`
`the scope and content of
`
`the prior art
`
`the differences between the prior art and the claim
`
`the level of
`
`ordinary skill
`
`in the art and
`
`secondary considerations tending to prove
`
`obviousness or nonobviousness These secondary considerations include
`
`long-
`
`felt need ii unexpected results iii
`
`skepticism of the invention iv teaching
`
`away from the invention
`
`commercial success vi praise by others for the
`
`invention and vii copying by other companies
`
`have also been infonned that
`
`there must be
`
`connection between these secondary factors and the scope of the
`
`invention claimed in the patent
`
`26
`
`To establish obviousness
`
`understand that
`
`it must be demonstrated
`
`that POSA would have been motivated to combine the teachings of the prior art
`
`-17-
`
`
`
`references to achieve the claimed invention and that
`
`the POSA would have had
`
`reasonable expectation of success in doing so Further
`
`understand that
`
`sufficient motivation is that the claimed and prior art compounds possess
`
`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 5654301 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-
`
`Benylacetam ides 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 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 5378729 Ex 1008 the 729 patent
`
`-18-
`
`
`
`THE 551 PATENT
`
`Overview of the 551 Patent
`
`The Alleged Invention
`
`30
`
`The 551 patent describes its alleged inivenitioll as relatmg to iOVel
`
`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
`
`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.D
`
`Overview of Claims 1-13 of the 551 Patent
`
`32
`
`Claim is the only independent claim of the 551 patent Claims 2-13
`
`are all dependent claims
`
`understand that
`
`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
`
`3Ex 1001 col 121-23
`
`41d atcol 127-28
`
`DId atcol 127-29
`
`-19-
`
`
`
`CH3
`
`acosamide
`
`34
`
`Laco samide is the R-enantiomer of
`
`-acetamido-N-benzyl-3
`
`methoxypropionamide and is the only compound claimed in claim of the 551
`
`patent Claims
`
`through
`
`are recited as follows
`
`compound in the
`
`configuration having the formula
`
`Ai LII N1I_
`
`II
`
`TI
`
`H_
`
`Qi
`
`II
`
`wherein
`
`Ar is phenyl which is unsubstituted or substituted with at
`least one halo group
`
`is lower alkoxy and
`
`is methyl
`
`The compound according to claim which is substantially
`enantiopure
`
`The compound according to claim wherein
`alkoxy containing 1-3 carbon atoms
`
`is lower
`
`The compound according to claim wherein
`
`is methoxy
`
`The compound according to claim wherein Ar is
`unsubstituted phenyl
`
`The compound according to claim wherein halo is fluoro
`
`-20-
`
`
`
`The compound according to claim wherein
`is alkoxy
`containing 1-3 carbon atoms and Ar is unsubstituted phenyl
`
`The compound according to claim which is R-N-Benzyl
`2-Acetamido-3 -methoxypropionamide
`
`The compound according to claim which contains at least
`90% w/w stereoisomer
`
`Claim thus covers certain
`
`enantiomers referred to in the claims as
`
`stereoisomers depending on the substituents that are used for Ar
`
`and Qi below
`
`Ar
`
`In particular claim covers the compound lacosamide as part of the racemate or
`
`as an isolated stereoisomer when the Ar substituent is
`
`benzyl group
`
`is
`
`methoxymethyl group and
`
`is methyl group as shown in the following
`
`structure
`
`-21-
`
`
`
`35
`
`Claim 10 of the 551 patent
`
`is directed to
`
`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
`therapeutic composition comprising an anticonvulsant
`effective amount of
`compound according to any one of claims
`1-9 and
`pharmaceutical carrier therefor
`
`36
`
`Claims 11-13 of the 551 patent are directed to method 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 method of treating central nervous system disorders in an
`in need thereof
`animal comprising administering to said animal
`an anticonvulsant effective amount of
`compound according to
`any one of claims 1-9
`
`12 The method according to claim 11 wherein the animal
`mammal
`
`is
`
`13 The method according to claim 12 wherein the mammal is
`human
`
`Claim Construction of the 551 Patent
`
`37
`
`Claim of the 551 patent claims compounds of the named chemical
`
`formula iii
`
`the
`
`configuration which refers to one of the two possible
`
`enantiomeric forms of the structure discussed in more depth later
`
`understand
`
`this claim to include mixtures of enantiomeric compounds of the claimed fonmila
`
`-22-
`
`
`
`that
`
`include any amount of the relevant enantiomer with the
`
`configuration This
`
`construction is confinned by claim which provides
`
`further limitation requiring
`
`that the compound be substantially enantiopure It
`
`is also confirmed by claim
`
`which specifies the compound of claim R-N-benzyl-2-acetamido-3
`
`methoxypropionamide contain at least 90% w/w stereoisomer
`
`38
`
`Claim provides that Ar is phenyl which is unsubstituted or
`
`substituted with at least one halo group
`
`Ai II2N1I_ -Qi
`
`IT
`
`II
`
`II
`
`Claim further specifies that the halo is fluoro Under the broadest
`
`reasonable
`
`interpretation claim could be construed to include either
`
`unsubstituted
`
`phenyl or
`
`phenyl substituted with at least one fluoro group Under that
`
`construction claim would encompass lacosamide because lacosamide has
`
`unsubstituted phenyl
`
`in the Ar position
`
`VT
`
`TECHNICAL BACKGROUND
`
`Representation of Chemical Structures
`
`39
`
`The pharniaceutical products of importance in this proceeding are
`
`organic chemical compounds In order to fully understand my opinions it
`
`is
`
`-23-
`
`
`
`necessary to have
`
`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 Cl-I4 is the simplest example of
`
`hydrocarbon molecule composed solely of hydrogen and carbon As shown in
`
`the following chemical structure carbon
`
`makes four bonds to other atoms and
`
`hydrogen
`
`makes only one
`
`H-C-H
`
`methane
`CH4
`
`41
`
`Carbon is an almost unique element in that it has the ability to form
`
`molecules by bonding to itself in the forni of chains to give molecules such as
`
`the hydrocarbon depicted below
`
`HHHHH
`H-C-C-C-C-C-H
`HHHH
`
`pentane
`C5H12
`
`highly condensed version of
`section on organic chemistry is
`This background
`portions of an introductory textbook coauthored by me
`Streitwieser Jr and
`Heathcock Introduction to Organic chemistiy 1985
`
`-24-
`
`
`
`42
`
`Although hydrogen is the most common other atomjoined to
`
`carbon in organic compounds
`
`number of other atoms can occur
`
`in organic
`
`compounds Examples are oxygen and nitrogen
`HHHHH
`HHHHH
`H-C-C-CC-C-N
`HHHHH
`HHHHH
`
`-hydroxypentane
`1-pentano
`C5H120
`
`-amnopentane
`1pentanamrne
`C5H13N
`
`As shown in these two forniulae oxygen
`
`makes two bonds to other atoms
`
`whereas nitrogen
`
`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
`
`has
`
`valence of
`
`has
`
`valence of
`
`has
`
`valence of
`
`and
`
`has
`
`valence of
`
`43
`
`The following examples illustrate
`
`shorthand that
`
`is commonly
`
`used by chemists in drawing chemical structures
`
`In this shorthand the individual
`
`carbons are not drawn but are represented by vertices in geometric depictions of
`
`chains or rings In addition the individual hydrogen atoms are not drawn and it
`
`is
`
`understood that
`
`there are enough hydrogens to give each carbon atom its valence of
`
`The hydrogens aftached to other atoms like oxygen and nitrogen are normally
`
`drawn The following examples show how chemists would normally depict the
`
`simple example compounds shown in the preceding paragraphs
`
`-25-
`
`
`
`OH
`
`H2
`
`pentane
`C5H12
`
`-hydroxypentane
`1pentanoI
`C5H120
`
`aminopentane
`-pentanamine
`C5H13N
`
`44
`
`The hydrocarbons illustrated above in J4O-41 methane and pentane
`
`are called alkanes and are said in the parlance of organic chemistry to be
`
`saturated meaning that they have as many hydrogens per carbon as they possibly
`
`can have given the valences of carbon and hydrogen Likewise
`
`-hydroxypentane
`
`and
`
`-aminopentane have as many hydrogens as they possibly can have and they
`
`are also called saturated
`
`45
`
`Carbons can also join together in rings as illustrated by the
`
`compound benzene which has
`
`six-carbon ring Derivatives of benzene in which
`
`one or more of the hydrogen atoms are replaced by another atom are called
`
`phenyl compounds Benzene and its derivatives are examples of unsaturated
`
`compounds because they have carbon-carbon double bonds and therefore do not
`
`have the maximum number of hydrogens that are possible for six-carbon
`
`compounds
`
`-26-
`
`
`
`Cc
`H-C C-H
`Ic-C
`
`H-C
`
`cc
`
`p-c
`
`benzene
`C6H6
`
`pheny group
`C6H5-
`
`benzene
`
`phenyt
`
`Amino Acids
`
`46
`
`As illustrated in J42-43
`
`compound having the grouping NH2
`
`aft ached to
`
`carbon framework is called an amine and the NIH2 grouping is
`
`called an amino group Such groups are called functional groups and they
`
`tend to dictate the chemical reactivity of
`
`compound regardless of the number of
`
`carbons in the framework to which the functional group is aftached Another
`
`commonly encountered functional group is the carboxy group -CO2H which is the
`
`typical group found in carboxylic acids An example of
`
`carboxylic acid butanoic
`
`acid is depicted below in four possible representations
`
`-27-
`
`
`
`H.H9
`
`OH
`
`OH
`
`-COOH
`
`butanoic acid
`C4H802
`
`47
`
`Many of the compounds of relevance in this proceeding are
`
`bifunctional compounds
`
`referred to as amino acids that have both an amino
`
`and
`
`carboxy functional group The chemistry of amino acids reflects the intrinsic
`
`chemical reactivity of both amines and carboxylic acids An example 2-
`
`arninopropanoic acid is illustrated below in three possible representations
`
`HH
`
`OH
`NH2
`
`OH
`
`NH2
`
`CO2H
`
`NH2
`
`2-amnopropanoic acid
`
`48
`
`Amino acids are an important group of biomolecules constituting the
`
`basic building block units from which proteins are fornied There are 20 important
`
`natural amino acids
`
`few examples are depicted below.7
`
`Streitwieser Jr and
`928 1985
`
`Heathcock Introduction to Organic chemistiy 926-
`
`-28-
`
`
`
`H2N CO2H
`
`NH2
`
`CO2H
`
`glycine
`aminoethanoic acid
`
`alanine
`2-aminopropanoic acid
`
`NH2
`
`HO kCOH
`
`NH2
`
`CO2H
`
`serine
`phenylalanine
`2amino3hydroxypropanoic acid 2amino3phenyIpropanoic acid
`
`Note that serine is
`
`trifunctional compound having an OH group in addition to
`
`the NH2 and CO2H functional groups that make it an amino acid
`
`Stereochemistry
`
`49
`
`Stereochemistry refers to the three-dimensional aspect of chemical
`
`structures and the effect this dimensionality has on physical and chemical
`
`properties of molecules Two molecules are stereoisomers of each other when they
`
`contain the same atoms bonded to the same other atoms but where the
`
`configuration of those atoms in three dimensions differs
`
`50
`
`Chemical structures are intrinsically three-dimensional although we
`
`depict
`
`them as two-dimensional objects An example is methane CH4 which has
`
`three-dimensional structure that is illustrated in the following three representations
`
`-29-
`
`
`
`51
`
`For example there is only one forni of 1-butanol but there are two
`
`fornis of 2-butanol which can only be interconverted by breaking and re-joining
`
`bond
`
`butanoi
`
`HOH
`
`HOH
`two different 2butanoIs
`
`In these structures the bold or hashed lines indicate that the OH or
`
`projects
`
`away from the general plane of the compound toward the viewer bold or away
`
`from the viewer hashed
`
`52
`
`Compounds like 1-butanol which have only one three-dimensional
`
`structure are called achiral Compounds like 2-butanol are called chiral The
`
`two stereoisomers of
`
`chiral compound like 2-butanol are called enantiomers
`
`and can be unambiguously named by
`
`special stereochemical notation called the
`
`sequence rule or RS convention R-2-butanol and S-2-butanol are depicted
`
`below
`
`-30-
`
`
`
`HOH
`
`HOH
`
`R-2-butanot
`
`S-2-butano
`
`53
`
`Enantiomers are mirror images of each other like left and right hands
`
`OH
`
`HH
`
`OH
`
`H3C\C
`
`S-2butanaI
`
`R2butano1
`
`pai
`
`54
`
`The convention used by chemists to label stereocenters as
`
`or
`
`has three steps
`
`-31-
`
`
`
`Assigning each of the four different groups attached to the
`sequence rank 1-4 using the sequence rule
`stereocenter
`
`ii
`
`iii
`
`Viewing the molecule along the bond from the stereocenter
`to
`the group with the lowest sequence nile rank usua
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