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. RE 38,551
`
`
`
`_____________________________
`
`Inter Partes Review Case No. IPR2016-00204
`
`_____________________________
`
`
`
`Declaration of Dr. Lars J.S. Knutsen
`
`
`
`
`
`MYLAN - EXHIBIT 1102
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`TABLE OF CONTENTS
`
`Patent No. RE 38,551
`
`Page
`
`I.
`
`
`
`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
`
`V.
`
`
`
`STATE OF THE PRIOR ART ........................................................................... 14
`
`A.
`
`Cortes 1985 (Ex. 1015) ..................................................................... 14
`
`B.
`
`C.
`
`Le Gall (1987) (Ex. 1008) ................................................................. 15
`
`Kohn 1991 (Ex. 1012)....................................................................... 16
`
`D.
`
`The ’729 Patent (Ex. 1009) ............................................................... 18
`
`E.
`
`F.
`
`G.
`
`H.
`
`Kohn 1993 (Ex. 1017)....................................................................... 20
`
`Choi (Ex. 1010) ................................................................................ 21
`
`The ’301 Patent (1995) (Ex. 1019) .................................................... 22
`
`Silverman (1992) (Ex. 1013) ............................................................. 25
`
`VI.
`
` GROUND 1A: CLAIMS 1 AND 3-8 ARE ANTICIPATED BY LE GALL ................. 26
`
`A.
`
`B.
`
`Basis of my Opinion with Respect to Anticipation ............................ 26
`
`Claims 1 and 3-8 ............................................................................... 26
`
`VII.
`
` GROUND 1B: CLAIMS 2 AND 9-13 ARE OBVIOUS OVER LE GALL AND
`THE ’729 PATENT ........................................................................................ 29
`
`A.
`
`Basis of My Opinion with Respect to Obviousness ........................... 29
`
`-i-
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`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`B.
`
`C.
`
`D.
`
`Claims 2 and 9 Directed to Purified R-Enantiomers are Obvious ...... 31
`
`Claim 10 to a “Therapeutic Composition” is Obvious over Le
`Gall and ’729 patent .......................................................................... 32
`
`Claims 11-13 to Methods of Treatment are Obvious over Le
`Gall and the ’729 Patent .................................................................... 35
`
`VIII.
`
` GROUND 2A: CLAIMS 1-9 ARE OBVIOUS OVER CHOI AND KOHN 1991 ......... 37
`
`A.
`
`Claim 1 is Obvious ........................................................................... 37
`
`1.
`
`2.
`
`3.
`
`POSA had a reason to select compound 2d of Choi
`(compound 107d of Le Gall) as a lead compound ................... 37
`
`POSA had a reason to modify compound 2d by placing a
`“functionalized oxygen” (methoxy) two atoms removed
`from the α-carbon ................................................................... 41
`
`A POSA would have expected success in making the
`necessary modification using techniques known in the art ...... 44
`
`B.
`
`Claims 2 and 9 Directed to Purified Enantiomers are Obvious .......... 45
`
`IX.
`
` GROUND 2B: CLAIMS 10-13 ARE OBVIOUS OVER CHOI, KOHN 1991
`AND THE ’729 PATENT ................................................................................. 46
`
`A.
`
`B.
`
`Claim 10 to a “Therapeutic Composition” is Obvious ....................... 46
`
`Claims 11-13 to Methods of Treatment are Obvious ......................... 46
`
`X.
`
` GROUND 3A: CLAIMS 1-9 ARE OBVIOUS OVER KOHN 1991 AND
`SILVERMAN ................................................................................................. 47
`
`A.
`
`B.
`
`Claim 1 is Obvious ........................................................................... 47
`
`Claims 2 and 9 Directed to Purified Enantiomers are Obvious .......... 50
`
`XI.
`
` GROUND 3B: CLAIMS 10-13 ARE OBVIOUS OVER KOHN 1991,
`SILVERMAN AND THE ’729 PATENT ............................................................. 51
`
`A.
`
`Claim 10 to a “Therapeutic Composition” is Obvious ....................... 51
`
`-ii-
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`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`B.
`
`Claims 11-13 to Methods of Treatment Are Obvious ........................ 52
`
`XII.
`
` GROUND 4A: CLAIMS 1-9 ARE OBVIOUS OVER CORTES AND KOHN
`1991 ............................................................................................................ 52
`
`A.
`
`Claim 1 is Obvious ........................................................................... 53
`
`1.
`
`2.
`
`POSA had a reason to select the methyl compound of
`Cortes or Kohn 1991 as a lead compound ............................... 53
`
`POSA had a reason to modify the methyl substituent to a
`methoxymethyl ....................................................................... 54
`
`XIII.
`
` GROUND 4B: CLAIMS 10-13 ARE OBVIOUS OVER CORTES, KOHN 1991,
`AND THE ’729 PATENT ................................................................................ 56
`
`A.
`
`B.
`
`Claim 10 to a “Therapeutic Composition” is Obvious ....................... 56
`
`Claims 11-13 to Methods of Treatment are Obvious ......................... 57
`
`XIV.
`
` ABSENCE OF SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS ............. 58
`
`XV.
`
` THE DECLARATION OF DR. HEATHCOCK ...................................................... 62
`
`XVI.
`
` CONCLUSION ............................................................................................... 64
`
`
`
`
`
`-iii-
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`

`
`
`
`I, Lars Knutsen, do declare as follows:
`
`
`I.
`
`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 Mylan
`
`Pharmaceuticals Inc. 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 IPR via
`
`payments to IMS Expert Services at my standard consulting rate, which is $505 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. RE 38,551 (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 Le Gall (Ex. 1008) thesis was in
`
`dispute in the prior IPR, and that the PTAB sided with the Patent Owner on that
`
`issue. But I further understand that since that time, the Patent Owner has admitted
`
`that the Le Gall thesis does in fact constitute a “printed publication” and was
`
`publicly accessible prior to 1996.
`
`-1-
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`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`4.
`
`I am familiar with Dr. Binghe Wang and his professional
`
`qualifications. I consider him to be an expert on the subject matter at issue in this
`
`proceeding. I have reviewed the Declaration of Dr. Wang (Ex. 1002) and I agree in
`
`substance with his opinions. For convenience of the tribunal in this proceeding, I
`
`have adopted the language of the Wang Declaration with only minor variations, for
`
`example, to correct typos and provide my own background and experience instead
`
`of Dr. Wang’s.
`
`A. U.S. Patent No. RE 38,551
`
`5.
`
`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
`
`-2-
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`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`USPTO records, the ’551 patent is currently assigned to Research Corporation
`
`Technologies (“Research Corporation” or “Patentee” or “Patent Owner”).
`
`6.
`
`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;
`
` is lower alkoxy, and
`
` Q
`
`
`Q1 is methyl.
`
`
`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):
`
`-3-
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`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`
`
`R-Lacosamide
`
`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
`
`-4-
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`be intended to cover R-isomers, whether substantially pure or 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 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 present
`
`invention be substantially free from the corresponding S-isomer”. In other words,
`
`“enantiopure” means that the S-isomer is substantially not included within the
`
`-5-
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
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`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 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.
`
`
`
` MY BACKGROUND AND QUALIFICATIONS II.
`
`6. My area of expertise is the field of medicinal chemistry, and I have
`
`been an expert in this field since prior to 1996. I am presently President of
`
`Discovery Pharma Consulting LLC, building on the specialist scientific and
`
`strategic knowledge I have gained over a 30+ year career in pharmaceutical
`
`research and development. I hold an Adjunct Professorship at Drexel University
`
`College of Medicine in Philadelphia, where I have served since 2009, advising and
`
`collaborating with faculty on drug R&D strategy, teaching drug discovery, and
`
`driving entrepreneurism and new science strategy in the wider Drexel University
`
`community. My research areas include medicinal chemistry and drug discovery,
`
`with an emphasis on the design and selection of drug candidates, especially in the
`
`field of neuroscience, including the development of treatments for epilepsy, sleep
`
`disorders, cognition, and neurodegeneration.
`
`7.
`
`I obtained a Masters of Arts in Organic, Physical, and Inorganic
`
`Chemistry from the University of Oxford in 1978 and a Ph.D. in Medicinal
`
`-6-
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`Patent No. RE 38,551
`
`Chemistry while working at Glaxo Group Research in 1984. I have also served as a
`
`reviewer for journals such as the Journal of Medicinal Chemistry and Bioorganic
`
`and Medicinal Chemistry Letters, and was awarded a Top 10 Reviewer prize as a
`
`result of my efforts. Additionally, I have been a named author on many scientific
`
`papers, and I have been an inventor or co-inventor on over 20 issued U.S. patents.
`
`8. The treatment of epilepsy by a range of mechanisms has been a strong
`
`thread running through my career. On joining the CNS R&D unit at Novo Nordisk
`
`in March of 1986, I worked on the design and synthesis of the GABA uptake
`
`inhibitor, tiagabine (Gabitril®), which became a marketed drug for the treatment of
`
`partial seizures. Later, I was appointed Project Leader, and authored multiple
`
`papers on the elucidation of the structure-activity studies leading to the nomination
`
`of tiagabine as an anticonvulsant drug candidate. In fact, over a quarter of my
`
`peeR-reviewed publications are on the topic of new drugs for epilepsy.
`
`9.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately. Ex. 1103.
`
`10.
`
`In view of my professional experience and expertise outlined above
`
`and provided in my curriculum vitae, I am considered an expert in the field of
`
`medicinal chemistry.
`
`
`
` LIST OF DOCUMENTS CONSIDERED IN FORMULATING MY OPINION III.
`
`11.
`
`Ex. #
`
`In formulating my opinion, I considered the following documents:
`
`Exhibit Name
`
`-7-
`
`

`
`Patent No. RE 38,551
`
`Declaration in Support of Petition for
`Inter Partes Review
`
`1001
`
`U.S. Patent No. RE 38,551 (“the ’551 patent”)
`
`1002
`
`Declaration of Dr. Binghe 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 Le Gall, 2-Substituted-2-acetamido-N-benzylacetamides.
`Synthesis, Spectroscopic and
`Anticonvulsant Properties (Dec. 1987) (“Le Gall”)
`
`1009
`
`U.S. Patent No. 5,378,729 (“the ’729 Patent”)
`
`1010
`
`1011
`
`1012
`
`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”)
`
`Purdie et al., The Alkylation of Sugars, J.A.C.S.Vol. 83, pg. 1021
`(1903) (Purdie)
`
`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
`
`1016
`
`1017
`
`Cortes et al., Effect of Structural Modification of the Hydantoin Ring on
`Anticonvulsant Activity, J. MED. CHEM. Vol. 28, pg. 601 (1985)
`(“Cortes 1985”)
`
`Le Gall et al., Synthesis of Functionalized Non-Natural Amino Acid
`Derivatives via Amidoalkylation Transformations, INT. J. PEPTIDE
`PROTEIN RES. Vol. 32, pg. 279 (1988) (“Le Gall 1988”)
`
`Kohn et al., Synthesis and Anticonvulsant Activities of α-Heterocyclic
`α-Acetamido-N-benzylacetamide Derivatives, J. MED. CHEM. Vol. 36,
`pg. 3350 (1993)
`
`-8-
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`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)
`
`Patent No. RE 38,551
`
`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
`
`1023
`
`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 Decision-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)
`
`1032
`
`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)
`
`-9-
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`1034
`
`Löscher et al., New Avenues for Anti-Epileptic Drug Discovery and
`Development, NATURE REVIEWS: DRUG DISCOVERY Vol. 12, pg. 12
`(2013)
`
`Patent No. RE 38,551
`
`1035
`
`Cohen authorized amendment
`
`1103
`
`Curriculum Vitae of Dr. Lars J.S. Knutsen
`
`
`
` PERSON OF ORDINARY SKILL IN THE ART IV.
`
`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
`
`understand how 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.
`
`14. The following prior art references, summarized below, would have
`
`further informed a POSA’s skill and understanding of the art.
`
`-10-
`
`

`
`Declaration in Support of Petition for
`Inter Partes Review
`
`
`A. Overview of the Class of Compounds
`
`Patent No. RE 38,551
`
`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 generic
`
`name such as lacosamide often covers both isomers of a compound 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-
`
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`Declaration in Support of Petition for
`Inter Partes Review
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`Patent No. RE 38,551
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`isomers, but the individual isomers are referred to as R-thalidomide and S-
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`thalidomide.
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`18. This generally accepted naming convention makes sense because the
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`R and S isomers of compounds such as lacosamide are non-superimposable mirror
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`images and generally have the same physical and chemical properties, although
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`they may interact with biological systems differently.
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`19. Furthermore, in this declaration, in reference to the stereochemistry, I
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`generally use the R/S terminology, as opposed to the D/L terminology. Some of
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`the prior art references refer to a preference of the D-isomer. For purposes of the
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`present declaration, the D-isomer refers to the R-isomer.
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`20. Further, when faced with the disclosure of a compound that has one
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`stereocenter, a POSA would immediately recognize that the disclosure is actually
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`disclosing two compounds: both the R-isomer and the S-isomer. This fact is a
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`basic chemical fact that undergraduate chemistry students learn. In practicality,
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`there is little meaningful difference between the disclosure of a structure that does
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`not specify the particular stereochemistry of the single stereocenter and a
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`disclosure that takes the minor additional step of actually drawing both the R-
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`isomer and the S-isomer.
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`21. The table below lists compounds used herein and our nomenclature
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`for them.
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`Name
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`Structure
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`Inter Partes Review
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`Patent No. RE 38,551
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`Methyl Compound
`• Cortes AAB
`• Kohn 1990 (2a)
`• Kohn 1991 (2a)
`• Le Gall (68a)
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`Hydroxymethyl
`compound
`• Choi (2d)
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`Methoxy Compound
`• ’301 patent; D,L-2-
`acetamido-N-benzyl-
`2-methoxy-acetamide
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`Ethoxy Compound
`
`Methoxyamino
`Compound
`• Kohn 1991 (3l)
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`Methoxymethylamino
`Compound
`• Kohn 1991 (3n)
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`Amino Compound
`• Kohn 1991 (3a)
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`Declaration in Support of Petition for
`Inter Partes Review
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`Hydroxyamino
`Compound
`• Kohn 1991 (3k)
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`V.
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`STATE OF THE PRIOR ART
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`A. Cortes 1985 (Ex. 1015)
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`Patent No. RE 38,551
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`
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`22.
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`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 amino
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`acid derivatives. Ex. 1015 at 601 abstr. Cortes reported that “[a]mong the most
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`active compounds observed were the amino acid derivative N-acetyl-D, L-alanine
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`benzylamide (6d) [AAB]” (id.), depicted below:
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`
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`Methyl Compound
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`23. Based on these results, Cortes (Ex. 1015) stated that AAB was “slated
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`for additional screening.” Id. at 604. Cortes also stated “[a]dditional structure
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`proof, discussion, and experimentation and spectral data may be found in” the
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`“Ph.D. dissertation of this author,” Sergio Cortes, whose bibliographic information
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`states that he was at the “Department of Chemistry, University of Houston—
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`University Park, Houston Texas 77004.” Id. at 601 & n.1(a).
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`B.
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`Le Gall (1987) (Ex. 1008)
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`Patent No. RE 38,551
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`24.
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`I have read Le Gall. Le Gall 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 Le Gall 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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`Le Gall 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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`
`
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`Racemic Lacosamide
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`
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`
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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 Le Gall (Ex.
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`1008), compound 107e includes both the R and S-isomers. As depicted, compound
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`107e includes lacosamide. Thus, compound 107e can be referred to as “racemic
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`Declaration in Support of Petition for
`Inter Partes Review
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`Patent No. RE 38,551
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`lacosamide.” Furthermore, because lacosamide has only one stereocenter, a POSA
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`would immediately envisage both R-lacosamide and S-lacosamide when reviewing
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`the disclosure of Le Gall.
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`26. Le Gall (Ex. 1008) states an express preference for the R-
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`stereoisomer. Le Gall writes: “the D-enantiomer of 68a was thirteen times more
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`active than the L-isomer when tested orally in mice in the MES seizure test. A
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`comparable difference in activity was also noted for the two stereoisomers of 68b”
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`(id. at 42), and “more potent and less toxic than the corresponding racemates,” (id
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`at 164). Thus, a POSA would certainly read that statement to mean that the R-
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`isomers of the compounds shown in Table 35, including racemic lacosamide,
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`would be the preferred compound to use for 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 ¶ 15.
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`
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`Id. at 2445, Tbl. I.
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`Inter Partes Review
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`Patent No. RE 38,551
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`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) 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
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`mg/kg). 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 at
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`the α-carbon are methyl (-CH3) and ethoxy (-OCH2CH3), respectively (id. at 2445,
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`Tbl. I):
`
`
`Methyl Compound
`
`
`
`
`
`
`
` Ethoxy Compound
`
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`30. Reviewing the potency of the compounds, Kohn 1991 (Ex. 1012)
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`
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`makes “several important observations” about the structure-activity relationships
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`of this class of compounds including that (1) “the α-amino . . . derivative[]
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`Inter Partes Review
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`Patent No. RE 38,551
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`displayed anticonvulsant activit[y] comparable to that observed for the α-methyl
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`analogue”; (2) there are “stringent steric requirements that exist for maximal
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`anticonvulsant activity in this class of compounds”; and (3) “in the most potent
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`analogues (2d, 3l, and 3n), a functionalized oxygen atom existed two atoms
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`removed from the α-carbon atom.” Id. at 2447 (italics in original).
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`D. The ’729 Patent (Ex. 1009)
`
`31.
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`I have read the ’729 Patent. The ’729 patent claims compounds of the
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`general structure depicted below, along with the more specific formula applying
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`Kohn’s preferred substituents:
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`
`
`
`
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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 “lower
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`alkyl” (i.e., the “most preferred … methyl” (id. at 5:17-19)), and one of R2 and R3
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`Inter Partes Review
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`Patent No. RE 38,551
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`is “hydrogen” and the other “lower alkyl” (i.e., methylene) “substituted with . . . at
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`least one electron donating substituent” (i.e., “methoxy” (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 products
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`obtained thus can be mixtures of the isomers, which can be resolved.” Id. at 15:29-
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`31, 9:56-68. I agree that, to a POSA, it would have been plainly obvious that the
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`compounds described in the ’729 patent exist in stereoisomeric forms and that a
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`POSA could have resolved the isomers. The ’729 patent then describes various
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`art-recognized techniques for synthesizing and separating stereoisomers. Id. at
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`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 R-
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`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