UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`ARGENTUM PHARMACEUTICALS LLC, MYLAN
`PHARMACEUTICALS INC., BRECKENRIDGE PHARMACEUTICAL,
`INC., and ALEMBIC PHARMACEUTICALS, LTD.,
`Petitioners,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.
`Patent Owner
`
`_______________
`
`Case IPR2016-002041
`Patent RE38,551 E
`_______________
`
`PETITIONER REPLY IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW
`
`
`
`
`
`
`
`1 Case IPR2016-01101, Case IPR2016-01242, and Case IPR2016-01245
`have been joined with this proceeding.
`
`

`
`IPR2016-00204
`Patent RE38,551
`
`TABLE OF CONTENTS
`
`
`INTRODUCTION .................................................................................................... 1
`I. The Claims Cover Anticonvulsants Potentially Useful for CNS Disorders In
`Animals, Do Not Require FDA Safety/Efficacy, and Are Not Limited to Human
`Epilepsy ..................................................................................................................... 3
`The “Reasonable Expectation of Success” is not an Expectation of
`A.
`Certain FDA Approval ......................................................................... 3
`The Method Claims Cover “CNS Disorders,” Not Only “Epilepsy” ... 4
`B.
`II. Compound 3l Was an Ideal Lead Compound .................................................... 5
`FAAs Had High Anticonvulsant Activity and Were “Drug
`A.
`Candidates” .......................................................................................... 5
`Compound 3l Had High Potency, Good Neurotoxicity, and A “Top
`Five” Protective Index .......................................................................... 6
`Patent Owner’s Various Hindsight Arguments Lack Merit ................. 9
`C.
`III. The Simplest Modification To Improve Compound 3l Was The Well-Known
`NH-to-CH2 Bioisotere Replacement ....................................................................... 10
`IV. A POSA Had a Reasonable Expectation of Success of Making and Using The
`Claimed Compounds ............................................................................................... 12
`Patent Owner Incorrectly Equates “Reasonable Expectation of
`A.
`Success” With Certainty That the Compounds Must Be Safe,
`Effective and Well-Tolerated for Treating Human Epilepsy ............. 12
`B. Modifying Compound 3l Into Lacosamide Using the “N to C”
`Bioisotere Replacement Was Expected to Yield High Anticonvulsant
`Activity and Good Neurotoxicity ....................................................... 13
`The R Enantiomer was the Known Active Isomer ............................. 14
`C.
`V. Claims 10-13 Recite Known, Obvious Limitations ......................................... 14
`VI. The Secondary Evidence Is Misdirected, Not Commensurate In Scope, And
`Does Not Overcome The Strong Obviousness ....................................................... 16
`A.
`Patent Owner Offers No Evidence of Unexpected Results ................ 17
`B.
`Vimpat Has Not Satisfied an Unmet Need for the Treatment of CNS
`Disorders, Including in Humans ......................................................... 18
`The Evidence Establishes that Keppra—Not Vimpat—Satisfied Patent
`Owner’s Alleged Unmet Need for a Subset of Human Epilepsy
`Patients ............................................................................................... 21
`The Sales Evidence Does Not Demonstrate Nonobviousness ........... 22
`
`B.
`
`C.
`
`D.
`
`
`
`ii
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`

`
`IPR2016-00204
`Patent RE38,551
`Patent Owner Does Not Present Sufficient Evidence of Skepticism
`E.
`and Failure of Others .......................................................................... 26
`The Evidence of “Copying” Confirms The ‘551 Patent’s Invalidity . 27
`F.
`VII. The Board Should Reconsider Its Construction of “Therapeutic” ................... 27
`LeGall Constitutes Prior Art and May Be Use To Rebut Patent
`VIII.
`Owner’s New Arguments ....................................................................................... 28
`CONCLUSION ....................................................................................................... 29
`
`
`
`
`
`
`
`iii
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`

`
`IPR2016-00204
`Patent RE38,551
`
`TABLE OF AUTHORITIES
`
`
`Cases
`Alcon Research v. Apotex, Inc., 687 F.3d 1362 (Fed. Cir. 2012) ........................... 25
`
`Allergan, Inc. v. Apotex Inc., 754 F.3d 952 (Fed. Cir. 2014) ........................... 16, 26
`
`Altana Pharma AG v. Teva Pharms. USA, 566 F.3d 999 (Fed. Cir. 2009) .............. 7
`
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, 752 F.3d 967 (Fed. Cir.
`2014) .............................................................................................................. 17, 22
`
`Cable Electric Prods. v. Genmark, Inc., 770 F.2d 1015 (Fed. Cir. 1985) .............. 25
`
`Dow Jones & Co. v. Ablaise Ltd., 606 F.3d 1338 (Fed. Cir. 2010) ........................ 27
`
`Galderma Labs v. Tolmar, Inc., 737 F.3d 731 (Fed. Cir. 2013) ....................... 23, 27
`
`In re Brana, 51 F.3d 1560 (Fed. Cir. 1995) .............................................................. 3
`
`In re Papesch, 315 F.2d 381 (CCPA 1963) ............................................................ 17
`
`McNeil-PPC v. Perrigo, 516 F. Supp. 2d 238 (S.D.N.Y. 2007) aff’d, 2008
`U.S. App. LEXIS 8017 (Fed. Cir. 2008) ............................................................. 23
`
`Merck & Co.. v. Teva Pharm. USA,, 395 F.3d 1364 (Fed. Cir. 2005) .............. 16, 23
`
`Nike, Inc. v. Adidas AG, 812 F.3d 1326 (Fed. Cir. 2016) ......................................... 9
`
`Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012) ....................... 6
`
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348 (Fed. Cir. 2007) ................................... 16
`
`Ritchie v. Vast Res., 563 F.3d 1334 (Fed. Cir. 2009) .............................................. 26
`
`iv
`
`
`
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`

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`IPR2016-00204
`Patent RE38,551
`
`
`INTRODUCTION
`
`Patent Owner’s Response (“POR”) makes several critically misdirected
`
`arguments. First, POR focuses exclusively on safety and efficacy for chronic
`
`epilepsy treatment in adult humans, yet the claims have no such limitation. An
`
`ordinary medicinal chemist would reasonably expect potent anticonvulsant activity
`
`when modifying Compound 3l with the bioisosteric replacement to obtain
`
`lacosamide.
`
`Second, Patent Owner does not identify the closest prior art and offers no
`
`evidence of unexpected results.
`
`Third, Patent Owner’s experts overlooked prior art and other relevant
`
`information, including the ’301 patent and levetiracetam (generic Keppra), which
`
`satisfied the alleged unmet need.
`
`Fourth, Patent Owner restricts its evidence to human epilepsy, but the
`
`claims are broader—CNS disorders—and only one claim is limited to humans.
`
`Fifth, Patent Owner’s expert Dr. Bazil admitted that the prior art drug
`
`Keppra meets the very criteria Patent Owner defined as the “unmet need.”
`
`In short, POR responds as if there is a claim directed to lacosamide for
`
`treating partial onset epilepsy in adult humans. There is no such claim in the ‘551
`
`patent (although Patent Owner may choose to narrow its claims in the pending
`
`reexamination).
`
`
`
`-1-
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`

`
`roborate
`
`or
`
`2-acetamido-2-benzyl-2-N-3-
`
`or
`
`50
`
`said animal an effective amount of
`ing to claim 67
`pyrazolylaminoacetamide
`136
`method of treating central nervous system
`IPR2016-00204
`or
`22-diacetamido-N-benzyl-acetamide
`disorders in animals comprising the administration
`Patent RE38,551
`or
`2-acetamido-N-benzyl-2-tri-
`said animal an effective amount of
`Finally, the prior art taught a clear path from Compound 3l, specifically
`fluoroacetamidoacetamide
`ing to claim 82
`123 The compound according to claim 82 which is
`137 The method of claim 132 wherein said corn
`claimed in the ‘729/‘301 patents and identified as one of the most potent FAAs:
`2-acetamido-N-benzyl-2-N-hydroxyaininoacetamide
`55 pound is administered in an amount
`or the
`isomer thereof
`or
`100 mg/kg of body weight per day
`about
`124 The compound according to claim 82 which is
`138 The method of claim 133 wherein said corn
`pound is administered in an amount
`2-acetainido-N-bezizyl-2-N-methoxyaminoacetamide
`or the
`or
`isomer thereof
`about
`100 mg/kg of body weight per day
`
`125 The compound according to claim 82 which is 60
`139 The method of claim 134 wherein said corn
`pound is administered in an amount
`2-acetamido-N-benzyl-2-N-N-methylhydroxyamino-
`Ex.1009, cl.124.
`acetarnide or the
`or
`isomer thereof
`100 mg/kg of body weight per day
`about
`126 The compound according to claim 82 which is
`140 The method of claim 135 wherein said corn
`pound is administered in an amount
`2-acetaniido-N-benzyl-2-N-NO-dimethylhydrox-
`yaminoacet amide or the
`isomer thereof
`65 about 100 mg/kg of body weight per day
`or
`141 The method of claim 136 wherein said com
`127 The compound according to claim 82 which is
`pound is administered in an amount
`or
`2-acetamido-N-benzyl-2-N-isoxazolidinoacetamide
`the
`isomer thereof
`about 100 mg/kg of body weight per day
`or
`
`
`
`Ex.1012 p.2447; Pet.44-48. Selecting the active R isomer and making the simplest
`
`bioisosteric replacement (NHàCH2) follows Dr. Kohn’s SAR and eliminates the
`
`uncommon N-O bond, yielding lacosamide with its expected anticonvulsant
`Patent No. RE38,551
`Petition For Inter Partes Review
`
`activity with an excellent protective index:
`E. Ground 3A: Claims 1-9 Are Obvious Over Kohn 1991 and
`Silverman
`
`
`Bioisosteric
`replacement
`
`
`
`Methoxyamino compound
`(Kohn 1991; 3l)
`
`
`
`
`Lacosamide
`
`1. Kohn 1991 and Silverman are prior art
`Kohn 1991 (Ex. 1012) and Silverman (Ex. 1013) are both prior art under
`
`
`
`§ 102(b) because they were published in 1991 and 1992, respectively, which is
`
`more than one year before the earliest possible priority date of the ’551 patent.
`Activity data and bioisosterism suggest the change from
`2.
`-2-
`methoxyamino to methoxymethyl (lacosamide)
`A POSA would often, but not always, be motivated to select one of the most
`
`
`
`potent compounds in the prior art as a lead compound. In this case, Kohn 1991
`
`

`
`IPR2016-00204
`Patent RE38,551
`I.
`THE CLAIMS COVER ANTICONVULSANTS POTENTIALLY USEFUL FOR CNS
`DISORDERS IN ANIMALS, DO NOT REQUIRE FDA SAFETY/EFFICACY, AND
`ARE NOT LIMITED TO HUMAN EPILEPSY
`
`Patent Owner’s evidence and arguments rely on the incorrect view that the
`
`claims are limited to an FDA-approved chronic treatment of a subset of human
`
`epilepsy. POR11 (“[A] POSA looking for a lead compound from which to develop
`
`a new, safe, and effective AED in 1996 would have modified an existing FDA-
`
`approved drug or a compound having proven clinical efficacy.”). This is fatal to
`
`Patent Owner’s reasonable-expectation-of-success argument.
`
`A. The “Reasonable Expectation of Success” is not an Expectation of
`Certain FDA Approval
`
`The POSA is a medicinal chemist, like Dr. Kohn—not a medical
`
`professional. The POSA would expect success based on animal studies, not on
`
`clinical trials necessary to establish FDA approval. Ex.1084 ¶¶8-12, 61, 44-53;
`
`Ex.2058. Patent Owner, however, frames its obviousness argument as if a POSA
`
`needed certainty of FDA approval. See In re Brana, 51 F.3d 1560, 1568 (Fed. Cir.
`
`1995) (“FDA approval, however, is not a prerequisite for finding a compound
`
`useful within the meaning of the patent laws.”).
`
`The compound claims do not require any specified level of biological
`
`activity or any minimal threshold for side effects. The “therapeutic composition”
`
`and method claims recite generic, obvious limitations from the prior art ’729 and
`
`’301 patents. Pet.29-31,48. The method claims broadly recite “CNS disorders,”
`
`
`
`-3-
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`

`
`IPR2016-00204
`Patent RE38,551
`and only claim 13 is limited to human treatment. Claim 10 is the only claim that
`
`incorporates the “chronic” claim construction.
`
`Dr. Roush’s cross-examination
`
`testimony
`
`illustrates Patent Owner’s
`
`misdirected approach. He acknowledged unfamiliarity and/or inexperience with
`
`basic medicinal chemistry concepts/tools and standard animal testing used to
`
`evaluate potential anticonvulsants. Ex.1050 pp.182-186 (discussing Ex.2058),
`
`pp.91-94; Exs.1081-1083.
`
`B.
`
`The Method Claims Cover “CNS Disorders,” Not Only
`“Epilepsy”
`
`Patent Owner’s focus on human epilepsy treatment is incorrect. The claims
`
`broadly cover “CNS disorders,” and only claim 13 is limited to humans, but not to
`
`epilepsy in adults. Ex.1084 ¶48; Ex.1087 ¶¶18-19. Patent Owner disregards the
`
`broad claim scope and limits its evidence to a single CNS. Ex.1087 ¶13. This
`
`misfocus underscores all of Patent Owner’s arguments and evidence.
`
`Patent Owner responds to the patent challenge as if the sole claim at issue
`
`were a method of using lacosamide for treating adult humans for partial onset
`
`epilepsy, because that is all lacosamide is used for. But that claim is not in the
`
`’551 patent. Patent Owner could have narrowed its claims—and could still do so
`
`in the pending reexamination.
`
`
`
`-4-
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`

`
`IPR2016-00204
`Patent RE38,551
`II. COMPOUND 3L WAS AN IDEAL LEAD COMPOUND
`The evidence confirms that Compound 3l was one of the best lead
`
`compounds and specifically identified to Eli Lilly by Dr. Kohn.
`
`A.
`
`FAAs Had High Anticonvulsant Activity and Were “Drug
`Candidates”
`
`Functionalized amino acids (“FAAs”) were identified as promising lead
`
`compounds and “drug candidates.” Ex.1084 ¶¶44-74. Kohn 1991 and the
`
`’729/’379 patents
`
`tout functionalized amino acids as having “excellent
`
`anticonvulsant activity.” Ex.1012, p.2444; Ex.1019, 18:33-36; Ex.1009, 16:5-7,
`
`1:32-33 (FAAs described as “useful in the treatment of epilepsy and other CNS
`
`disorders”). This prior art by itself suggests an FAA as a lead compound. Ex.1084
`
`¶61.
`
`Dr. Kohn boasted about the FAAs to Eli Lilly. Ex.2006 pp.1-2. Lilly and
`
`Kohn worked together on the FAAs and identified FAAs as “drug candidates.”2
`
`Ex.1084 ¶50, 86, 88, 209. Dr. Roush admitted during cross-examination that a
`
`POSA would “assume that Lilly has an interest in developing an FAA as a drug
`
`candidate.” Ex.1050, p.155.
`
`
`2 Lilly’s subsequent termination of the project (Ex.2125) is not prior art and would
`
`not have been known by a POSA.
`
`
`
`-5-
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`

`
`IPR2016-00204
`Patent RE38,551
`Contrary to Patent Owner’s arguments, POR10-11, a POSA would have
`
`selected FAAs in part because none had been approved; as Patent Owner
`
`separately argues, finding an anticonvulsant with a “different mechanism of
`
`action” was “desirable.” POR57. Moreover, no claim requires FDA approval or is
`
`limited to epilepsy treatment, supra, and the experts agree that lead compounds are
`
`commonly selected from non-FDA-approved compounds. Ex.1084 ¶42-47;
`
`Ex.2012, 134:25-135:22; Ex.2036 ¶200 (half of approved AEDs developed from
`
`non-FDA-approved compounds). Indeed, the prior art levetiracetam is a key
`
`example—a promising antiepileptic with a unique mechanism of action, disclosed
`
`and approved before Vimpat (lacosamide) as Keppra. Ex.1087 ¶¶42-46, 103-107.
`
`Patent Owner advances other purported reasons why a POSA would
`
`allegedly not select a FAA as a lead compound, but none of them suffice, as Dr.
`
`Wang explains. Ex.1084 ¶44-74. FAAs were very promising anticonvulsants, with
`
`Compound 3l being the clear frontrunner, Ex.1084 ¶87-121, and thus ideal for lead
`
`compound selection. See Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1292
`
`(Fed. Cir. 2012).
`
`B. Compound 3l Had High Potency, Good Neurotoxicity, and A “Top
`Five” Protective Index
`
`Compound 3l was one of Dr. Kohn’s two “most active” FAAs in Kohn
`
`1991. Ex.1002 ¶265. Even Patent Owner’s expert Dr. Roush recognized that
`
`“Compound 3l and 3n had demonstrated good anticonvulsant activity and
`
`
`
`-6-
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`

`
`IPR2016-00204
`Patent RE38,551
`neurotoxicity profiles; in fact Compounds 3l and 3n were the only non-aromatic
`
`FAA [compounds] with such a profile.” Ex.2036 ¶276. Good anticonvulsant
`
`activity and good neurotoxicity are excellent reasons to select a lead compound.
`
`Non-aromatic FAA compounds were also particularly attractive to a POSA.
`
`Ex.1084 ¶¶62-66, 71.
`
`Implicitly assuming only one lead compound can be used, Patent Owner
`
`argues that two additional FAA compounds were slightly more potent. POR19.
`
`Both of these compounds, however, had increased toxicity and a less favorable
`
`protective index, compared to Compound 3l. Ex.1084 ¶74-101. The existence of
`
`other promising compounds does not bar the use of the most potent compound or
`
`even “one of the more potent” compounds in the prior art as a lead compound. See
`
`Altana Pharma AG v. Teva Pharms. USA, 566 F.3d 999, 1008 (Fed. Cir. 2009).
`
`Dr. Wang explains, and Dr. Roush acknowledges, that a medicinal chemist can use
`
`multiple leads. Ex.1084 ¶84-85, 150; Ex.1050 ¶114-115.
`
`It does not matter, as Patent Owner argues, POR16, that the heteroaromatic
`
`compounds were also considered promising FAAs. A POSA can, and does, select
`
`more than a single lead. Ex.1084 ¶85, 150. In the ’301 patent, Dr. Kohn thought
`
`enough of Compound 3l to specifically disclose and claim it in the ‘729/‘301
`
`patents. Ex.1009, cl.124; Ex.1019, cl.22. Dr. Roush ignored the ’301 patent, which
`
`
`
`-7-
`
`

`
`IPR2016-00204
`Patent RE38,551
`was discussed under instituted Ground 3 and in Dr. Wang’s Declaration. Pet.46-47;
`
`Ex.1019, ¶¶44-49.
`Page 2
`February 16, 1gg0
`ll¡¡-
`ñi,.^.
`lJttclt l..1vtt.
`Dr. Kohn also identified Compound 3l (shown as L246385) to Eli Lilly
`*1f
`
`researchers as a particularly promising compound:
`
`rol
`
`7602 will
`
`RI
`
`Itiloo
`
`c Hs-c- NH-CH-C-NH-CH2 Ph
`
`R.
`
`(racemate) L 2476A2 ËÐso 8.S mg/ kg
`
`ÇÌ
`,N\NJ
`(racemate) L Z0A8S1 ËDso 10"6 mg/ kg
`Fl-
`R. - NH(OCH3) (rmmate) L A46906 ED¡o < 10 mø kg
`
`Ex.2066.
`
`
`$&Iffi .ï"1ü#i|il,_#[ffi l*å,ï-'f ,;#9,î:f ff P.î,iïîffi åîSlStinll].
`M ES activity. . The .synthetic ðhallenses Tor tÏe präñ;i¡o; oi i are-nàiñéi ì,ìu¡al nor
`insurmountable. {pti,ll"rv focus {oi rhe propoôeð iuñà¡ng pdrioã Ëlfö' "',
`preparation and cvaiuation of analogues þos'sessing a sníail Cá¿onlti¡stituted
`heteroaromatic rino. subsrituenr at th-eï:põð¡riú:- äiË finãrmacolãg¡õãlrrilürts
`obtained in this sei¡es tJãäiþð¿räd thäñ, ;l;óri ,;iiü ãårdtðñalñs enã;ilomeric
`Thus, a POSA surveying the prior art would have additional reasons to see
`forms of rhe drug cand¡dare wïil ue prépár'eããnoiväruãieo.
`
`compound 3l as lead compound. Ex.1084 ¶¶122-174.
`
`Finally, Patent Owner is mistaken when it argues that a POSA would not
`
`select a compound with a N-O bond as a lead. The role of a lead compound is as a
`
`starting point for improvement by some modification; it is not the search for a
`
`perfect compound. Ex.1084 ¶38-43, 90-94. An appropriate lead compound may
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2066 - 2/5
`be improved by some modification. A POSA would have immediately seen the N-
`
`O bond in the methoxyamino group as a target for improvement. Ex.1084 ¶70.
`
`
`
`-8-
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`

`
`IPR2016-00204
`Patent RE38,551
`C.
`Patent Owner’s Various Hindsight Arguments Lack Merit
`Patent Owner’s additional intermingled arguments fail for various reasons.
`
`First, the five years between Kohn 1991 and the filing of the ’551 patent, POR20,
`
`does not make it any less obvious to select as a lead Compound 3l—one of the
`
`most potent FAAs with a “top five” protective index. Ex.1084 ¶¶75-84; Nike, Inc.
`
`v. Adidas AG, 812 F.3d 1326, 1338 (Fed. Cir. 2016) (“[The] mere age of the
`
`references is not persuasive of the unobviousness of the combination of their
`
`teachings.” (quotation omitted)). Dr. Roush admitted it had “good anticonvulsant
`
`activity and neurotoxicity profile[].” Ex.2036 ¶276.
`
`Furthermore, the fact that the ‘729/‘301 patents expressly covered and
`
`claimed Compound 3l would confirm a POSA’s reasonable expectation of the lead
`
`compound’s utility. Ex.1084 ¶98-101; Ex.1009, cl.124; Ex.1019, cl.22. Thus,
`
`contrary to Patent Owner’s argument, a POSA would have viewed this evidence
`
`and concluded a very high likelihood that Compound 3l had an acceptable overall
`
`toxicity profile. Ex.1084 ¶98-101. This is particularly true given that the POSA
`
`already knew that Compound 3l had a very favorable protective index, and thus
`
`had high potential for treating CNS disorders. Ex.1084 ¶80. Patent Owner also
`
`argues that a lack of toxicity data and Eli Lilly’s non-public decision to cease its
`
`collaboration with Dr. Kohn would have concerned a POSA. POR22. The
`
`’301/‘729 patents, however, specifically disclosed and ultimately claimed
`
`
`
`-9-
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`

`
`IPR2016-00204
`Patent RE38,551
`Compound 3l. Ex.1084 ¶104; Ex.1009, cl.124; Ex.1019, cl.22. What Patent
`
`Owner requires—“long-term toxicity data”—is beyond what is required of a lead
`
`compound in medicinal chemistry, Ex.1084 ¶82, Ex.2058, and is beyond what the
`
`’551 patent itself discloses to support the presumed utility and enablement of the
`
`issued claims. Ex.1001, 21:27-22:22.
`
`III. THE SIMPLEST MODIFICATION TO IMPROVE COMPOUND 3L WAS THE
`WELL-KNOWN NH-TO-CH2 BIOISOTERE REPLACEMENT
`With Compound 3l in hand, a POSA would know that the methoxyamino
`
`group is uncommon and potentially unstable/toxic. Ex.1084 ¶38-43; Ex.1002
`
`¶106. Dr. Roush recognizes as much. Ex.1050 pp.287-290. This would provide
`
`sufficient motivation to modify Compound 3l. The POSA’s immediate choice
`
`would be
`
`the simplest change: The well-known NHàCH2 bioisosteric
`
`replacement. Ex.1002 ¶107; Pet.45; Ex.1084 ¶31-37, 244-246.
`
`The bioisostere approach
`
`is a well-known approach based on
`
`the
`
`physical/chemical similarities between functional groups. Ex.1084 ¶38-43. While
`
`Dr. Roush has limited experience with lead compound analysis and has instead
`
`focused on random drug screening, Ex.1050 ¶ 70-71, “[b]iososterism is a lead
`
`modification approach that has been shown to be useful to attenuate toxicity, or to
`
`modify the activity of a lead.” Ex.1013, p.14. Substitution of the -NH- group with
`
`the -CH2- group in Compound 3l would replace the unstable methoxyamino moiety
`
`
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`-10-
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`

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`IPR2016-00204
`Patent RE38,551
`with the more common methoxymethyl moiety, creating lacosamide. Ex.1002
`
`¶107.
`
`Further confirmation of the expected success of the methoxymethyl group
`
`based on the bioisostere approach resides in the ‘301 patent, which expressly
`
`claimed the methoxymethyl group:
`
`
`
`Ex.1019 cl.44; Ex.1084 ¶¶124-128.
`
`Finally, Patent Owner offers many unsupported arguments, none of which
`
`withstand scrutiny. Ex.1084 ¶¶222-245. The prior art gave clear guidance on the
`
`SAR. For example:
`
`
`
`Ex.1017 p.5; Ex.1084 ¶¶ 12, 72.
`
`None of the specific examples Dr. Roush discusses in his Declaration rebut
`
`Dr. Wang’s opinion. Ex.1084 ¶¶ 12,72. Except for one heteroaromatic compound,
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`none of the cited compounds is more potent than Compound 3l and only a few
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`have a better protective index. Ex.1084 ¶¶75-86. All the data support the specific
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`SAR teachings in the prior art.
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`IV. A POSA HAD A REASONABLE EXPECTATION OF SUCCESS OF MAKING AND
`USING THE CLAIMED COMPOUNDS
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`Patent Owner and its experts apply a stricter standard of obviousness than
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`permitted under the law by demanding certainty of success rather than a reasonable
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`expectation of success. They attempt to require certainty that the claimed
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`compounds would be a “safe, effective and well-tolerated AED [i.e., anti-epileptic
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`drug],” even though a medicinal chemist—the typical POSA—would reasonably
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`expect efficacy based on standard laboratory experiments—not FDA clinical trials.
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`Ex.1084 ¶¶8-12, 61, 44-53; Ex.2058.
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`Patent Owner offers three broad reasons to support its argument. None are
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`supported by the evidence, and the Board should reject them.
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`A.
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`Patent Owner Incorrectly Equates “Reasonable Expectation of
`Success” With Certainty That the Compounds Must Be Safe,
`Effective and Well-Tolerated for Treating Human Epilepsy
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`Patent Owner’s fundamental errors are that it interprets a POSA’s
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`“reasonable expectation of success” to mean that a POSA would know with
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`certainty that the claimed compounds would be “safe, effective, and well-
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`tolerated” for treating human epilepsy.
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`First, even under the current claim construction, the compound claims do not
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`require safety for human administration. Nor does any claim require the
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`compound to be well-tolerated. The POSA, however, would have sought
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`compounds with high potency based on the very same mouse studies Dr. Kohn
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`used in the ‘729/’301 patents. Ex.1002 ¶¶32-36.
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`Second, Patent Owner’s position assumes a POSA would expect success
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`based only on actual data for a particular compound. However, the SAR data
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`confirms that a POSA would reasonably expect the claimed compounds to exhibit
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`excellent anticonvulsant and neurotoxicity activity, based on animal testing and
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`structural analogy. Ex.1084 ¶¶8-12, 61, 44-53; Ex.2058. This would have been
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`sufficient to motivate the POSA to arrive at the claims.
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`Third, contrary to Patent Owner’s claims, Dr. Wang did not “make up data.”
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`Rather, he estimated the expected anticonvulsant potency based on known data and
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`known SAR—just as a POSA would—the estimated potency was very similar to
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`the actual potency of lacosamide. Ex.1084 ¶139-148.
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`B. Modifying Compound 3l Into Lacosamide Using the “N to C”
`Bioisotere Replacement Was Expected
`to Yield High
`Anticonvulsant Activity and Good Neurotoxicity
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`Dr. Roush chose not to consider the ’301 patent even though Petitioner cited
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`it as prior art in instituted Ground 3. Pet.46-47 (arguing reasonable expectation of
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`success because “methoxymethyl is specifically claimed at the α-carbon position in
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`the ’301 patent”), 20 (citing ’301 patent as “§ 102(e) prior art”).
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`Pet.21 (depicting claim 45 of the ‘301 patent). This waiver undercuts his opinion
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`that a POSA would not have expected success in making and using lacosamide.
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`C. The R Enantiomer was the Known Active Isomer
`The prior art is clear: The R isomer of FAAs was strongly preferred over the
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`“inactive” S isomer. Exs.1009, 1012, 1017-1019, 1016, 2053. Patent Owner’s
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`own expert Dr. Roush did not identify a single example in which the S isomer of a
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`FAA was more active than the R isomer. Ex.1050 pp.215-217. Dr. Kohn had even
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`told Eli Lilly that “only one of the two possible enantiomeric forms was active.”
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`Ex.2066. The POSA’s obvious choice was the active R isomer of an FAA,
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`including Compound 3l, and not the “inactive” S isomer.
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`V. CLAIMS 10-13 RECITE KNOWN, OBVIOUS LIMITATIONS
`Patent Owner’s arguments about the patentability of the composition and
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`method claims must be rejected. When considered from the proper perspective of
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`a POSA—namely, a medicinal chemist working in the field of CNS disorders—the
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`added limitations of claims 10-13 are merely generic limitations that were all
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`disclosed in the prior art. Once an obvious compound was expected to have good
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`anticonvulsant activity and acceptable neurotoxicity, a POSA had a reasonable
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`expectation of success that the POSA could make or use a therapeutic composition
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`for the treatment of CNS disorders in animals, including humans.
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`First, claim 10 adds two limitations that are in the prior art: “anticonvulsant
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`effective amount” and a “pharmaceutical carrier.” These limitations, as explained
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`in the Petition, are identical to limitations disclosed and claimed in the ’729 patent
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`for this same family of FAAs that covers lacosamide. Pet.29-31, 48, 58.
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`These boilerplate limitations reflect the expectation of a medicinal chemist,
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`as opposed to a clinician conducting clinical trials in order to obtain FDA
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`marketing approval treating human epilepsy patients. The medicinal chemist
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`reasonably expects anticonvulsant activity for treating CNS disorders in animals
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`once the compounds exhibited acceptable anticonvulsant activity and neurotoxicity
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`effects. Ex.2058.
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`Second, even under the Board’s current construction of “therapeutic
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`composition” as requiring chronic administration, a medicinal chemist would have
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`had a reasonable expectation of success that R-lacosamide would be useful to
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`chronic treatment of CNS disorders in animals, including epilepsy. Ex.2058
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`(confirming that “these kinds of data correlate well with the clinical use of these
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`agents and provide a basis for the evaluation of the antiepileptic potential of
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`candidate substances.
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` Such an evaluation
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`involves analysis of TD50s,
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`anticonvulsant potencies by various tests (ED50s), and PIs.”)
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`Finally, Patent Owner’s own evidence and arguments require correction of
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`the claim construction term “therapeutic composition.” See infra. When properly
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`construed, claim 10 is not limited to “chronic administration,” and the deficiency
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`in Patent Owner’s evidence is all the more apparent.
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`VI. THE SECONDARY EVIDENCE IS MISDIRECTED, NOT COMMENSURATE IN
`SCOPE, AND DOES NOT OVERCOME THE STRONG OBVIOUSNESS
`
`“[O]nce a challenger has presented a prima facie case of invalidity, the
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`patentee has the burden of going forward with rebuttal evidence. Pfizer, Inc. v.
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`Apotex, Inc., 480 F.3d 1348, 1360 (Fed. Cir. 2007). “It is the established rule that
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`objective evidence of non-obviousness must be commensurate in scope with the
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`claims which the evidence is offered to support.’” Allergan, Inc. v. Apotex Inc.,
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`754 F.3d 952, 965 (Fed. Cir. 2014) (quotation omitted). Here, Patent Owner has
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`not met its burden because, even if accepted, the evidence represents only a sliver
`
`of the claimed subject matter, and that sliver was covered by Patent Owner’s two
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`prior patents.
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`Evidence of secondary considerations is not generally attributable to a
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`subsequent patent claiming the same pharmaceutical. See Merck & Co., Inc. v.
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`Teva Pharm. USA, Inc., 395 F.3d 1364, 1377 (Fed. Cir. 2005) (holding that
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`commercial success is not determinative of non-obviousness where there is a prior
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`blocking patent).
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`A.
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`Patent Owner Offers No Evidence of Unexpected Results
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`Evidence of unexpected results must establish an unexpected difference in
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`kind between the claimed invention and the closest prior art. Bristol-Myers Squibb
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`Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014). A “mere
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`difference in degree” is insufficient. In re Papesch, 315 F.2d 381, 392 (CCPA
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`1963).
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`Patent Owner does not identify any prior art compound as the appropriate
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`comparator. POR52-54; Ex.2036 ¶305-314. Patent Owner thus offers no
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`comparison of the claimed invention to what it believes is the closest prior art
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`compound. Nor does Patent Owner compare Vimpat to the prior art levetiracetam
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`(Keppra). Patent Owner offers no evidence of unexpected results. See Bristol
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`Myers, 752 F.3d at 977.
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`Patent Owner instead submitted only conclusory statements and purported
`
`“praise” for alleged properties. POR52-53. These generic statements do not
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`constitute evidence of unexpected results. Ex.1087 ¶¶137-138; POR52-53
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`(lacosamide identified as an “AED” or “antiepileptic” without mention of surprise
`
`or unexpected properties). The lack of evidence is not surprising; lacosamide is
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`typically used only for a subset of epilepsy indications, is not usually a first choice
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`therapy for this indication, has more side effects than certain alternatives (e.g.,
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`Keppra), is not a unique or superior AED, and has not significantly reduced the
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`percentage of epilepsy patients who remain refractory to AED treatment. Ex.1087
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`¶¶47-53, 107, 130-131, 143, 148-161; Ex.1086 ¶28-30. Furthermore, the alleged
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`“praise” arises largely from individuals having a financial interest connected to
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`UCB. Ex.1048 pp.193-198; Ex.1087 ¶132.
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`Patent Owner’s expert addresses racemic lacosamide (or R,S-BAMP) (which
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`was disclosed in LeGall and which Petitioner contends is the closest prior art).
`
`Ex.2036 ¶¶305-309. But the data only show the expected—that “only one of the
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`two possible enantiomeric forms was active.” Ex.2066; Ex.1084 ¶190-205. Dr.
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`Roush’s testimony does not even apply to claims 1, 3-7, and 9 because those
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`claims are mixtures of the S and R enantiomers, and he has opined about