UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`ARGENTUM PHARMACEUTICALS LLC
`Petitioner
`v.
`RESEARCH CORPORATION TECHNOLOGIES, INC.
`Patent Owner
`Patent No. RE38,551
`
`_______________
`Inter Partes Review Case No.: IPR2016-00204
`_______________
`
`Declaration of Dr. Binghe Wang
`
`
`
`
`
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`
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`MYLAN - EXHIBIT 1002
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`Declaration in Support of Petition for
`Inter Partes Review IPR2016-00204
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`TABLE OF CONTENTS
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`Patent No. RE38,551
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`
`
`I.
`
`V.
`
`Introduction ...................................................................................................... 1
`A. U.S. Patent No. RE 38,551 .................................................................... 2
`II. My Background And Qualifications ............................................................... 6
`III. List Of Documents Considered In Formulating My Opinion ......................... 7
`IV. Person Of Ordinary Skill In The Art ............................................................. 10
`A. Overview of the Class of Compounds ................................................ 11
`State Of The Prior Art ................................................................................... 14
`A.
`Cortes 1985 (Ex. 1015) ....................................................................... 14
`B.
`LeGall (1987) (Ex. 1008) .................................................................... 15
`C.
`Kohn 1991 (Ex. 1012) ......................................................................... 17
`D.
`The ’729 Patent (Ex. 1009) ................................................................. 19
`E.
`Kohn 1993 (Ex. 1017) ......................................................................... 21
`F.
`Choi (Ex. 1010) ................................................................................... 23
`G.
`The ’301 Patent (1995) (Ex. 1019) ..................................................... 24
`H.
`Silverman (1992) (Ex. 1013) ............................................................... 27
`VI. Ground 1A: Claims 1 And 3-8 Are Anticipated By LeGall .......................... 28
`A.
`Basis of my Opinion with Respect to Anticipation ............................. 28
`B.
`Claims 1 and 3-8 .................................................................................. 28
`VII. Ground 1B: Claims 2 And 9-13 Are Obvious Over LeGall And The ’729
`Patent ............................................................................................................. 31
`A.
`Basis of My Opinion with Respect to Obviousness ............................ 31
`B.
`Claims 2 and 9 Directed to Purified R-Enantiomers are Obvious ...... 33
`C.
`Claim 10 to a “Therapeutic Composition” is Obvious over LeGall and
`’729 patent ........................................................................................... 35
`Claims 11-13 to Methods of Treatment are Obvious over LeGall and
`the ’729 Patent ..................................................................................... 38
`VIII. Ground 2A: Claims 1-9 Are Obvious Over Choi And Kohn 1991 ............... 41
`
`D.
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`Declaration in Support of Petition for
`Inter Partes Review IPR2016-00204
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`2.
`
`3.
`
`A.
`
`Claim 1 is Obvious .............................................................................. 41
`1.
`POSA had a reason to select compound 2d of Choi (compound
`107d of LeGall) as a lead compound ........................................ 41
`POSA had a reason to modify compound 2d by placing a
`“functionalized oxygen” (methoxy) two atoms removed from
`the α-carbon .............................................................................. 44
`A POSA would have expected success in making the necessary
`modification using techniques known in the art ....................... 48
`Claims 2 and 9 Directed to Purified Enantiomers are Obvious .......... 49
`B.
`IX. Ground 2B: Claims 10-13 Are Obvious Over Choi, Kohn 1991 And The
`’729 Patent ..................................................................................................... 50
`A.
`Claim 10 to a “Therapeutic Composition” is Obvious ....................... 50
`B.
`Claims 11-13 to Methods of Treatment are Obvious .......................... 51
`X. Ground 3A: Claims 1-9 Are Obvious Over Kohn 1991 And Silverman ...... 52
`A.
`Claim 1 is Obvious .............................................................................. 52
`B.
`Claims 2 and 9 Directed to Purified Enantiomers are Obvious .......... 55
`XI. Ground 3B: Claims 10-13 Are Obvious Over Kohn 1991, Silverman And
`The ’729 Patent .............................................................................................. 56
`A.
`Claim 10 to a “Therapeutic Composition” is Obvious ....................... 56
`B.
`Claims 11-13 to Methods of Treatment Are Obvious ......................... 57
`XII. Ground 4A: Claims 1-9 Are Obvious Over Cortes and Kohn 1991 ............ 58
`A.
`Claim 1 is Obvious .............................................................................. 58
`1.
`POSA had a reason to select the methyl compound of Cortes or
`Kohn 1991 as a lead compound ................................................ 58
`POSA had a reason to modify the methyl substituent to a
`methoxymethyl .......................................................................... 59
`XIII. Ground 4B: Claims 10-13 Are Obvious Over Cortes, Kohn 1991, And The
`’729 Patent ..................................................................................................... 62
`A.
`Claim 10 to a “Therapeutic Composition” is Obvious ....................... 62
`B.
`Claims 11-13 to Methods of Treatment are Obvious .......................... 63
`XIV. Absence of Secondary Considerations of Non-Obviousness ........................ 63
`XV. The Declaration Of Dr. Heathcock ................................................................ 68
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`Declaration in Support of Petition for
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`XVI. Conclusion ..................................................................................................... 71
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`Patent No. RE38,551
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`Declaration in Support of Petition for
`Inter Partes Review IPR2016-00204
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`Patent No. RE38,551
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`I.
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`
`
`I, Binghe Wang, do declare as follows:
`Introduction
`1.
`
`I am over the age of eighteen (18) and otherwise competent to
`
`make this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Argentum
`
`Pharmaceuticals LLC for a inter partes review (IPR) for U.S. Patent No. RE
`
`38,551 (Ex. 1001). I am being compensated for my time in connection with this
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`IPR at my standard consulting rate, which is $500 per hour. I understand that
`
`my declaration accompanies a petition for inter partes review involving the
`
`above-mentioned U.S. Patent.
`
`3.
`
`I understand that the subject patent has been the subject of a
`
`previous IPR filed by other entities. I understand that the Patent Trial and
`
`Appeal Board denied that IPR petition for several reasons that are not
`
`implicated here. First, I understand that the former IPR petition argued that
`
`U.S. Patent No. 5,654,301 (Ex. 1020) anticipates the claims of U.S. Patent No.
`
`RE38,551 (Ex. 1001). I understand that anticipation requires an identical prior
`
`art disclosure of the claimed invention and, in the case of a prior art genus, then
`
`a POSA must be able to “immediately envisage” the claimed invention within
`
`that genus. Second, I understand that the public availability of the LeGall (Ex.
`
`1008) thesis was in dispute in the prior IPR, and that the PTAB sided with the
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`Patent No. RE38,551
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`Patent Owner on that issue. But I further understand that since that time, the
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`Patent Owner has admitted that the LeGall thesis does in fact constitute a
`
`“printed publication” and was publicly accessible prior to 1996.
`
`A. U.S. Patent No. RE 38,551
`4.
`I understand that U.S. Patent No. RE 38,551 (“the ’551 patent”)
`
`(Ex. 1001) is a reissue of U.S. Patent No. 5,773,475 (“the ’475 patent”) (Ex.
`
`1005), which issued from U.S. Patent Application No. 08/818,688 (“the ’688
`
`application”) filed on March 17, 1997, and which claims priority to U.S.
`
`Provisional Application No. 60/013,522, filed on March 15, 1996. Thus, I
`
`understand that the earliest possible priority date of a claim in the ’551 patent
`
`based on these filings alone is March 15, 1996. I understand that the priority
`
`date to which the ’551 patent is entitled may be in dispute, the Patentee may
`
`assert that the ’551 patent is entitled to the priority date of the ’522 application
`
`and the Petitioner asserts that it is entitled only to the actual filing date of March
`
`17, 1997. I have been instructed to base my opinion on the prior art that was
`
`available on March 15, 1996. However, if I were to use March 17, 1997 as the
`
`relevant date, my opinion would not be any different. I further understand that,
`
`according to the USPTO records, the ’551 patent is currently assigned to
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`Research Corporation Technologies (“Research Corporation” or “Patentee” or
`
`“Patent Owner”).
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`Declaration in Support of Petition for
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`Patent No. RE38,551
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`5.
`
`Claim 1 is the sole independent claim in the ’551 patent (Ex.
`
`1001). Claim 1 reads:
`
`1. A compound in the R configuration having the
`formula:
`
`
`
`wherein
`Ar is phenyl which is unsubstituted or substituted with at
`least one halo group;
`Q is lower alkoxy, and
`Q1 is methyl.
`
`6.
`
`Claims 2-9 are compound claims depending directly or indirectly
`
`from claim 1. Claim 8 is directed specifically to the compound known as
`
`lacosamide as referenced by its chemical name: “The compound according to
`
`claim 1 which is (R)-N-Benzyl 2-Acetamido-3-methoxypropionamide.” The
`
`structure of lacosamide is shown below (wherein Ar is unsubstituted phenyl, Q
`
`is methoxymethyl, and Q1 is methyl):
`
`
`
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`R-Lacosamide
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`Declaration in Support of Petition for
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`Patent No. RE38,551
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`Each of claims 2- 9 encompasses the above compound.
`
`7.
`
`Claim 10 recites “[a] therapeutic composition comprising an
`
`anticonvulsant effective amount of a compound according to any one of claims
`
`1-9 and a pharmaceutical carrier therefor.”
`
`8.
`
`Claims 11-13 are method claims. Claim 11 reads:
`
`A method of treating central nervous system disorders in
`an animal comprising administering to said animal in
`need thereof an anticonvulsant effective amount of a
`compound according to any one of claims 1-9.
`
`Claim 12 depends from claim 11 and specifies that the “the animal is a mammal.”
`
`Claim 13 depends from claim 12 and specifies that “the mammal is a human.”
`
`9.
`
`Regarding the scope of the compound claims, I understand that
`
`claim construction is a legal issue to be decided by the legal tribunal, here the
`
`Patent Trial and Appeal Board. I also understand that claim construction may
`
`be informed by how one of ordinary skill in the art would understand the terms
`
`used in the claims.
`
`10. From reading the claims and specification of the ’551 patent (Ex.
`
`1001), it seems clear to me that a POSA would understand the compound
`
`claims to be intended to cover R-isomers, whether substantially pure or
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`Patent No. RE38,551
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`including the S-isomers. It is also my view that a POSA would understand that
`
`the compound claims are drafted to exclude a compound or composition that is
`
`only the S-isomer. The POSA would likely conclude this for the reason that
`
`naturally occurring amino acids occupy the S configuration exclusively.
`
`Therefore, limiting claim 1 to the R-isomer would exclude compounds based on
`
`modifications of naturally occurring amino acids while encompassing the
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`synthetically created R-isomer and mixtures containing it.
`
`11. Claim 1 states that the claimed compound is the R-isomer. Under
`
`certain circumstances, this could indicate to a POSA that claim 1 is limited only
`
`to the R-isomer, i.e., it would not cover a mixture of R and S-isomers and thus
`
`would not read on a disclosure of a mixture of R and S compound. Here,
`
`however, the POSA would know that that interpretation would be incorrect
`
`because two dependent claims expressly set forth the limitation that the S-
`
`isomer is excluded, to at least some extent, thus meaning that it must be
`
`included in claim 1. Therefore, a composition containing at least some amount
`
`of the R-isomer, even if only a portion of a mixture of both enantiomers, falls
`
`within the scope of claim 1.
`
`12. Claim 2 specifies that the compound is enantiopure. The ’551
`
`patent (Ex. 1001) states that, “[i]t is… preferred that the compounds of the
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`present invention be substantially free from the corresponding S-isomer”. In
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`Declaration in Support of Petition for
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`other words, “enantiopure” means that the S-isomer is substantially not
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`Patent No. RE38,551
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`included within the scope of claim 2. If the S-isomer were not included within
`
`the scope of claim 1, then there would be no reason to specify “enantiopure” in
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`claim 2.
`
`13. Claim 9 specifies the compound according to claim 8 which
`
`contains at least 90% (w/w) R stereoisomer. I read claim 9 to specify the extent
`
`to which the R stereoisomer is enriched relative to the S stereoisomer. This is
`
`further evidence that the scope of claim 1 encompasses mixtures of both the R
`
`and S stereoisomers.
`
`II. My Background And Qualifications
`6.
`My area of expertise is the field of medicinal chemistry, and I have
`
`been an expert in this field since prior to 2002. At Georgia State University, I am
`
`presently a Regents’ Professor of Chemistry, a Georgia Research Alliance Eminent
`
`Scholar in Drug discovery, and a Georgia Cancer Coalition Distinguished Cancer
`
`Scholar. I also serve as Associate Dean for Natural and Computational Sciences in
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`the Georgia State University College of Arts and Sciences. My research areas
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`include medicinal and bioorganic chemistry with an emphasis on new drugs
`
`against cancer, infectious diseases, and inflammatory conditions as well as new
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`diagnostics for cancer, cardiovascular abnormalities, and other diseases.
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`Declaration in Support of Petition for
`Inter Partes Review IPR2016-00204
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`Patent No. RE38,551
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`7.
`
`I obtained a bachelor of science in Medicinal Chemistry from
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`Beijing Medical College in 1982 and a Ph.D. from the Department of Medicinal
`
`Chemistry at the University of Kansas in 1991.
`
`8.
`
`I also serve as Editor-in-Chief of the journal Medicinal Research
`
`Reviews and I am the founding editor of “Wiley Series in Drug Discovery and
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`Development,” which has published over 20 volumes. Medicinal Research
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`Reviews is the #2 ranked journal among the 59 medicinal chemistry journals
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`worldwide, as measured by impact factor. The journal was ranked #1 based on
`
`impact fact in 2011. Impact factor is a measure of the relative importance of a
`
`journal based on the average number of citations to recent articles.
`
`Additionally, I have been a named author on over 200 scientific papers, and I
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`have trained a large number of graduate and undergraduate students as well as
`
`postdoctoral fellows.
`
`9. My curriculum vitae is attached as an appendix to this document.
`
`10.
`
`In view of my experiences and expertise outlined above and
`
`provided in my curriculum vitae, I am an expert in the field of medicinal
`
`chemistry.
`
`III. List Of Documents Considered In Formulating My Opinion
`11.
`In formulating my opinion, I considered the following documents:
`
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`Declaration in Support of Petition for
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`Patent No. RE38,551
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`Exhibit Name
`Ex. #
`1001 U.S. Patent No. RE38,551 (“the ’551 patent”)
`1002 Declaration of Dr. Wang
`1003 Declaration of Dr. Clayton Heathcock
`1004
`Joint Statement of Uncontested Facts
`1005 U.S. Patent No. 5,773,475 (“the ’475 Patent”)
`1006 Excerpt from Application No. 08/818,688
`1007 District Court Claim Construction Opinion
`1008 Philippe LeGall, 2-Substituted-2-acetamido-N-benzylacetamides.
`Synthesis, Spectroscopic and
`Anticonvulsant Properties (Dec. 1987) (“LeGall”)
`1009 U.S. Patent No. 5,378,729 (“the ’729 Patent”)
`1010 Choi et al., Trimethylsilyl Halides: Effective Reagents for the Synthesis
`of β-Halo Amino Acid Derivatives, Tet. Lett., Vol. 36(39), pg. 7011
`(1995) (“Choi”)
`1011 Purdie et al., The Alkylation of Sugars, J.A.C.S.Vol. 83, pg. 1021
`(1903) (Purdie)
`1012 Kohn et al., Preparation and Anticonvulsant Activity of a Series of
`Functionalized α-Heteroatom-Substituted Amino Acids, J. Med. Chem.
`Vol. 34, pg. 2444 (1991) (“Kohn 1991”)
`1013 Silverman, R. B., The Organic Chemistry of Drug Design and Drug
`Action, Academic Press (1992) (“Silverman”)
`1014 Development of New Stereoisomeric Drugs, U.S. F.D.A., May 1, 1992
`1015 Cortes et al., Effect of Structural Modification of the Hydantoin Ring on
`Anticonvulsant Activity, J. Med. Chem., Vol. 28, pg. 601 (1985)
`(“Cortes 1985”)
`1016 LeGall et al., Synthesis of Functionalized Non-Natural Amino Acid
`Derivatives via Amidoalkylation Transformations, Int. J. Peptide
`Protein Res. Vol. 32, pg. 279 (1988) (“LeGall 1988”)
`1017 Kohn et al., Synthesis and Anticonvulsant Activities of α-Heterocyclic
`
`
`
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`Declaration in Support of Petition for
`Inter Partes Review IPR2016-00204
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`Patent No. RE38,551
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`1023
`
`α-Acetamido-N-benzylacetamide Derivatives, J. Med. Chem. Vol. 36,
`pg. 3350 (1993)
`1018 Kohn et al., Preparation and Anticonvulsant Activity of a Series of
`Functionalized α-Aromatic and α-Heteroaromatic Amino Acids, J. Med.
`Chem. Vol. 33, pg. 919 (1990)
`1019 U.S. Patent No. 5,654,301 (“the ’301 Patent”)
`1020 Patent Term Extension Request in U.S. Patent No. 5,654,301
`1021 FDA Guideline for Industry, November 1994
`1022 Schmidt, R., Dose-Finding Studies in Clinical Drug Development, Eur.
`J. Clin. Pharmacol, Vol. 34, pg. 15 (1988)
`Isbell, H. S., The Optical Rotation of the Various Asymmetric Carbon
`Atoms in the Hexose and Pentose Sugars, B. S. Jour. Research, Vol. 5,
`pg. 1041 (1929)
`1024 Wilson and Gisvold’s Textbook of Organic Medicinal Chemistry,
`Physicochemical Properties in Relation to Biologic Action, (Delgado J.
`N. & Remers W. A., eds. 1991) (Wilson & Gisvold)
`1025 Thornber, C. W., Isosterism and Molecular Modification in Drug
`Design, Chem. Soc. Rev., Vol. 8(4) (1979) (Thornber)
`1026 Reissue Declaration in Reissue of U.S. Patent No. 5,773,475
`1027 Subpoena directed to The University of Houston
`1028 FOIA dated September 29, 2015
`1029 Zhou et al., Decisions under Uncertainty: the Fuzzy Compromise
`Decision Support Problem, Eng. Opt. Vol. 20, pg. 21 (1992)
`1030 Mistree et al., A Decsion-Based Perspective for the Design of Methods
`for Systems Design, (1989)
`1031 Mistree et al., A Decision-based Approach to Concurrent Design,
`Concurrent Engineering: Contemporary Issues and Modern Design
`Tools, (Parsaei, H. R. & Sullivan W. G. Eds. 1993)
`Ingram W. T., Concerning Periodic Points in Mappings of Continua, J.
`Am. Math. Soc., Vol. 104(2) (1988)
`1033 Mattson, Current Challenges in the Treatment of Epilepsy, Neurology,
`Vol. 44(suppl. 5), pg. 84 (1994)
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`Patent No. RE38,551
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`1034 Löscher et al., New Avenues for Anti-Epileptic Drug Discovery and
`Development, Nature Reviews: Drug Discovery, Vol. 12, pg. 12 (2013)
`1035 Cohen authorized amendment
`
`
`IV. Person Of Ordinary Skill In The Art
`12.
`I understand that as of March 15, 1996, a hypothetical POSA
`
`would “be aware all the pertinent prior art” at the time of the alleged invention.
`
`13. The scientific field relevant to the ’551 patent (Ex. 1001) is
`
`medicinal chemistry, and a POSA would have a Ph.D. in organic or medicinal
`
`chemistry and at least a few years of experience in medicinal chemistry,
`
`including in the development of potential drug candidates. This POSA
`
`would also include a person who has a Bachelor’s or Master’s degree in
`
`organic chemistry or medicinal chemistry if such a person had more years of
`
`experience in medicinal chemistry and the development of potential drug
`
`candidates. The POSA having experience in the development of potential drug
`
`candidates would have an appreciation of the diseases or ailments that the
`
`particular drug candidates are intended to treat, but would not be a medical
`
`doctor or clinician. The POSA would know how to evaluate the physical and
`
`biological properties of chemical compounds and would be able to conduct, or
`
`otherwise have access to resources that could conduct, in vitro and in vivo
`
`evaluations of biological and toxicity properties of chemical compounds.
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`14. The following prior art references, summarized below, would have
`
`further informed a POSA’s skill and understanding of the art.
`
`A. Overview of the Class of Compounds
`15. Compounds within the class of anticonvulsants relating to the
`
`invention claimed in the ’551 patent possess the following generic structure:
`
`
`
`16. As used herein, and for ease of reference, I refer to the compounds
`
`based on the identity of the substituent on the α-carbon, i.e., the R group in the
`
`structure above. when compounds are referred to by the name of a substituent,
`
`it is to specify the nature of the R group in this structure. For example,
`
`lacosamide is the methoxymethyl compound of the structure shown above
`
`wherein R is -CH2OCH3, i.e., methoxymethyl, and shown below:
`
`
`Racemic Lacosamide (Methoxymethyl Compound)
`17. Additionally, I generally refer to lacosamide to cover both the R-
`
`and S-isomers of the lacosamide shown above. As generally used in the art, a
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`generic name such as lacosamide often covers both isomers of a compound
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`Patent No. RE38,551
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`when the compound only has two stereoisomers, and the individual isomers are
`
`specified by designating the “R” and “S” before the compound name. A
`
`common example of this is thalidomide. The generic term thalidomide covers
`
`both the R and S isomers, but the individual isomers are referred to as R-
`
`thalidomide and S-thalidomide.
`
`18. This generally accepted naming convention makes sense because
`
`the R and S isomers of compounds such as lacosamide are non-superimposable
`
`mirror images and generally have the same physical and chemical properties,
`
`although they may interact with biological systems differently.
`
`19. Furthermore, in this declaration, in reference to the
`
`stereochemistry, I generally use the R/S terminology, as opposed to the D/L
`
`terminology. Some of the prior art references refer to a preference of the D-
`
`isomer. For purposes of the present declaration, the D-isomer refers to the
`
`R-isomer.
`
`20. Further, when faced with the disclosure of a compound that has
`
`one stereocenter, a POSA would immediately recognize that the disclosure is
`
`actually disclosing two compounds: both the R-isomer and the S-isomer. This
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`fact is a basic chemical fact that undergraduate chemistry students learn. In
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`practicality, there is little meaningful difference between the disclosure of a
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`structure that does not specify the particular stereochemistry of the single
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`Patent No. RE38,551
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`stereocenter and a disclosure that takes the minor additional step of actually
`
`drawing both the R-isomer and the S-isomer.
`
`21. The table below lists compounds used herein and our nomenclature
`
`for them.
`
`Name
`
`Methyl Compound
`• Cortes AAB
`• Kohn 1990 (2a)
`• Kohn 1991 (2a)
`• LeGall (68a)
`
`
`Hydroxymethyl
`compound
`• Choi (2d)
`
`Methoxy Compound
`• ’301 patent; D,L-2-
`acetamido-N-
`benzyl-2-methoxy-
`acetamide
`
`Ethoxy Compound
`
`Structure
`
`
`
`
`
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`Methoxyamino
`Compound
`• Kohn 1991 (3l)
`
`Methoxymethylamino
`Compound
`• Kohn 1991 (3n)
`
`Amino Compound
`• Kohn 1991 (3a)
`
`Hydroxyamino
`Compound
`• Kohn 1991 (3k)
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`Patent No. RE38,551
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`V.
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`
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`State Of The Prior Art
`A. Cortes 1985 (Ex. 1015)
`22.
`I have read Cortes 1985. In 1985, Sergio Cortes co-authored an
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`article with Dr. Harold Kohn which reported the synthesis and anticonvulsant
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`activity of several different nitrogen-containing compounds, including four
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`amino acid derivatives. Ex. 1015 at 601 abstr. Cortes reported that “[a]mong
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`the most active compounds observed were the amino acid derivative N-acetyl-
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`D, L-alanine benzylamide (6d) [AAB]” (id.), depicted below:
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`Methyl Compound
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`23. Based on these results, Cortes (Ex. 1015) stated that AAB was
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`“slated for additional screening.” Id. at 604. Cortes also stated “[a]dditional
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`structure proof, discussion, and experimentation and spectral data may be found
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`in” the “Ph.D. dissertation of this author,” Sergio Cortes, whose bibliographic
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`information states that he was at the “Department of Chemistry, University of
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`Houston—University Park, Houston Texas 77004.” Id. at 601 & n.1(a).
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`B.
`24.
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`LeGall (1987) (Ex. 1008)
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`I have read LeGall. LeGall describes the synthesis and
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`anticonvulsant activity of “analogues of the potent anticonvulsant agent” referred
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`to as AAB. Ex. 1008 at 42, 132, 173 n.102. The compound AAB was described in
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`an article published by Cortes (described above). The compound AAB is referred
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`to in LeGall as compound 68a. As described below, Cortes recommended
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`conducting “additional screening” of the methyl compound 68a. Ex. 1015 at 604.
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`LeGall synthesized five “[c]ompounds 107a-e [that] were selected as polar
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`analogues of the potent anticonvulsant” AAB (compound 68a):
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`Patent No. RE38,551
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`Racemic Lacosamide
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`Ex. 1008 at 133, Tbl. 35.
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`25. Compound 107e is the methoxymethyl compound, having as the R
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`substituent a methoxymethyl (-CH2OCH3) group. As depicted in LeGall (Ex.
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`1008), compound 107e includes both the R and S-isomers. As depicted,
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`compound 107e includes lacosamide. Thus, compound 107e can be referred to
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`as “racemic lacosamide.” Furthermore, because lacosamide has only one
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`stereocenter, a POSA would immediately envisage both R-lacosamide and S-
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`lacosamide when reviewing the disclosure of LeGall.
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`26. LeGall (Ex. 1008) states an express preference for the R-
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`stereoisomer. LeGall writes: "the D-enantiomer of 68a was thirteen times
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`more active than the L-isomer when tested orally in mice in the MES seizure
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`test. A comparable difference in activity was also noted for the two
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`stereoisomers of 68b" (id. at 42), and "more potent and less toxic than the
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`Patent No. RE38,551
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`corresponding racemates," (id at 164). Thus, a POSA would certainly read that
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`statement to mean that the R-isomers of the compounds shown in Table 35,
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`including racemic lacosamide, would be the preferred compound to use for
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`anticonvulsant purposes.
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`C. Kohn 1991 (Ex. 1012)
`27.
`I have read Kohn 1991. Kohn 1991 describes the amino acid
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`derivatives AAB and the 2-furanyl derivative (2a-2d). Ex. 1012 at 2444. Kohn
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`1991 tested numerous amino acid derivatives, all of which contain both an N-
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`benzylamide moiety and an acetylated amino group, and vary only by the
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`substituent at the α-carbon (the substituent being defined as “X” in the structure
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`below). These are the same general class of compounds referred to above in
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`¶ 15.
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`Id. at 2445, Tbl. I.
`28. Of all the compounds tested, Kohn 1991 (Ex. 1012) reported that
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`“[t]he most active compounds were (R,S)-2- acetamido-N-benzyl-2-
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`(methoxyamino)acetamide (3l) and (R,S)-2-acetamido-N- benzyl-2-
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`(methoxymethylamino)acetamide (3n),” depicted below:
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`Methoxyamino Compound (3l)
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`Methoxymethylamino Compound (3n)
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`Id. at 2444, abstr.; id at 2445, Tbl. I. Among these two compounds (3l and 3n) and
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`all other compounds, the single most potent was 3l (ED50 6.2 mg/kg vs. 6.7 mg/kg).
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`Id. at 2445, Tbl. I.
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`29.
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`In compounds 2a and 3t of Kohn 1991 (Ex. 1012), the substituents
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`at the α-carbon are methyl (-CH3) and ethoxy (-OCH2CH3), respectively (id. at
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`2445, Tbl. I):
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`Methyl Compound
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`Ethoxy Compound
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`30. Reviewing the potency of the compounds, Kohn 1991 (Ex. 1012)
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`makes “several important observations” about the structure-activity
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`relationships of this class of compounds including that (1) “the α-amino . . .
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`derivative[] displayed anticonvulsant activit[y] comparable to that observed for
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`the α-methyl analogue”; (2) there are “stringent steric requirements that exist
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`for maximal anticonvulsant activity in this class of compounds”; and (3) “in the
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`most potent analogues (2d, 3l, and 3n), a functionalized oxygen atom existed
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`two atoms removed from the α-carbon atom.” Id. at 2447 (italics in original).
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`D. The ’729 Patent (Ex. 1009)
`31.
`I have read the ’729 Patent. The ’729 patent claims compounds of
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`the general structure depicted below, along with the more specific formula
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`applying Kohn’s preferred substituents:
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`Ex. 1009, col. 1:30-2:20. Kohn described the preferred substituents as follows: n is
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`1, R is “especially benzyl,” and “[t]he most preferred R1 group is methyl.” Id. at
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`5:14-19.
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`32. The above genus of the ’729 patent (Ex. 1009) covers lacosamide.
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`Lacosamide is the R-enantiomer of the claimed compound wherein R is “aryl
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`lower alkyl” (i.e., the “especially [preferred] benzyl” (id. at 5:17-18)), R1 is
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`“lower alkyl” (i.e., the “most preferred … methyl” (id. at 5:17-19)), and one of
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`R2 and R3 is “hydrogen” and the other “lower alkyl” (i.e., methylene)
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`“substituted with . . . at least one electron donating substituent” (i.e., “methoxy”
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`(id. at 4:37)).
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`33. Regarding stereospecificity, the ’729 patent (Ex. 1009) states that
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`“[t]he present compounds obviously exist in stereoisomeric forms and the
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`products obtained thus can be mixtures of the isomers, which can be resolved.”
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`Id. at 15:29-31, 9:56-68. I agree that, to a POSA, it would have been plainly
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`obvious that the compounds described in the ’729 patent exist in stereoisomeric
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`forms and that a POSA could have resolved the isomers. The ’729 patent then
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`describes various art-recognized techniques for synthesizing and separating
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`stereoisomers. Id. at 15:31-16:4.
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`34. The ’729 patent (Ex.1009) states that “[t]he D-stereoisomer is
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`preferred” (id. at 10:27). Again, this would have been a clear teaching that the
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`R-isomer is preferred for anticonvulsant activity. Here, the D-stereoisomer is
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`understood as the same as the R-isomer. The biological data provided in Table
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`I further support the preference for the R-stereoisomer. Id. at 58-61, Tbl. 1.
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`35. The ’729 patent (Ex. 1009) also states that “compounds of the
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`present invention exhibit excellent anticonvulsant activity.” Id. at 16:5-7. A
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`POSA would have understood this statement to mean that there was a
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`reasonable expectation that the compounds described therein would be excellent
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`as anticonvulsant compounds.
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`Patent No. RE38,551
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`36. The ’729 patent (Ex. 1009) also teaches that the compounds are
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`administered with a “pharmaceutically acceptable carrier,” id. at 17:53-54 and
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`that “[t]he use of such media and agents for pharmaceutical active substances is
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`well known in the art” (id. at 17:54-58). I agree with these statements. It