`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`____________
`
`Case IPR2016-00204
`Patent RE38,551 E
`____________
`
`Trials@uspto.gov
`571-272-7822
`
`
`
`
`
`
`
`Paper 19
`Date: May 23, 2016
`
`
`
`Before FRANCISCO C. PRATS, JACQUELINE WRIGHT BONILLA, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`BONILLA, Administrative Patent Judge.
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
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`I.
`
`INTRODUCTION
`Argentum Pharmaceuticals LLC (“Petitioner”) filed a Petition
`requesting an inter partes review of claims 1–13 of U.S. Patent No.
`RE38,551 E (Ex. 1001, “the ’551 patent”). Paper 2 (“Pet.”). Research
`Corporation Technologies, Inc. (“Patent Owner”) filed a Preliminary
`Response. Paper 9 (“Prelim. Resp.”). Under 35 U.S.C. § 314(a), an inter
`partes review may not be instituted unless it is determined that there is “a
`reasonable likelihood that the petitioner would prevail with respect to at least
`1 of the claims challenged in the petition.”
`Based on the information presented in the Petition and Preliminary
`Response, we are persuaded that there is a reasonable likelihood Petitioner
`would prevail with respect to the claims challenged in the Petition. We
`institute inter partes review of claims 1–13 of the ’551 patent.
`A. Related Proceedings
`Patent Owner identifies multiple lawsuits it has filed against different
`defendants in relation to the ’551 patent in several U.S. district courts. Paper
`6, 2–3. Most of those cases have been consolidated with UCB, Inc. v.
`Accord Healthcare Inc., 1:13-cv-01206 (D. Del.). Id.; Pet. 1.
`The parties also discuss IPR2014-01126, where a panel previously
`denied an inter partes review based on a petition filed by a different
`petitioner, challenging the same claims of the same patent at issue here.
`Actavis, Inc., v. Research Corporation Technologies, Inc., Case No.
`IPR2014-01126, Paper 22 (PTAB Jan. 9, 2015). Pet. 1; Prelim. Resp. 2.
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`B. Proposed Grounds of Unpatentability
`Petitioner advances eight grounds of unpatentability under 35 U.S.C.
`§ 102(b) or § 103(a) in relation to claims 1–13 of the ’551 patent (Pet. 2):
`
` References
`
`The LeGall thesis1
`
`Statutory
`Basis
`§ 102(b)
`
`Challenged
`Claims
`1, 3–8
`
`The LeGall thesis and the ’729 patent2
`
`§ 103(a)
`
`2, 9–13
`
`Choi3 and Kohn 19914
`
`§ 103(a)
`
`1–9
`
`Choi, Kohn 1991, and the ’729 patent
`
`§ 103(a)
`
`10–13
`
`Kohn 1991 and Silverman5
`
`§ 103(a)
`
`1–9
`
`Kohn 1991, Silverman, and the ’729 patent § 103(a)
`
`10–13
`
`
`1 Philippe LeGall, 2-Substituted-2-acetamido-N-benzylacetamides.
`Synthesis, Spectroscopic and Anticonvulsant Properties (Dec. 1987) (“the
`LeGall thesis”) (Ex. 1008).
`2 Kohn et al., U.S. Patent No. 5,378,729, issued on Jan. 3, 1995 (“the ’729
`patent”) (Ex. 1009).
`3 Choi et al., Trimethylsilyl Halides: Effective Reagents for the Synthesis of
`β-Halo Amino Acid Derivatives, 36(39) TETRAHEDRON. LETT. 7011–14
`(1995) (“Choi”) (Ex. 1010).
`4 Kohn et al., Preparation and Anticonvulsant Activity of a Series of
`Functionalized α-Heteroatom-Substituted Amino Acids, 34 J. MED. CHEM.
`2444–52 (1991) (“Kohn 1991”) (Ex. 1012).
`5 Silverman, The Organic Chemistry of Drug Design and DrugAction,
`Academic Press (1992) (“Silverman”) (Ex. 1013).
`3
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` References
`
`Cortes6 and Kohn 1991
`
`Statutory
`Basis
`§ 103(a)
`
`Challenged
`Claims
`1–9
`
`Cortes, Kohn 1991, and ’729 patent
`
`§ 103(a)
`
`10–13
`
`In addition, Petitioner supports its challenges in the Petition with a
`Declaration by Dr. Binghe Wang (“Wang Decl.”) (Ex. 1002). Pet. 4–5.
`C. The ’551 Patent
`The ’551 patent relates to enantiomeric compounds and
`pharmaceutical compositions useful in the treatment of epilepsy and other
`central nervous system (“CNS”) disorders. Ex. 1001, 1:21–23. According
`to the ’551 patent, at the time of the invention many anticonvulsant drugs
`were well known, but they exhibited liver toxicity over chronic
`administration. Id. at 1:45–47, 2:62–3:6. The ’551 patent discloses “a group
`of compounds that is generally potent, exhibit minimal neurological toxicity,
`has a high protective index and is relatively non-toxic to the body organs,
`including the liver upon multiple dosing.” Id. at 3:56–60. One of those
`compounds is lacosamide, (R)-N-benzyl 2-acetamide 3-methoxy-
`propionamide. Id. at claim 8.
`D. Claims
`Among the challenged claims, claim 1 is the sole independent claim.
`It reads:
`
`
`6 Cortes et al., Effect of Structural Modification of the Hydantoin Ring on
`Anticonvulsant Activity, 28 J. MED. CHEM. 601–06 (1985) (“Cortes”) (Ex.
`1015).
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`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.
`Claims 2–9 are compound claims that depend directly or indirectly
`from claim 1. Claim 8 is directed specifically to lacosamide. Claim 10 is
`directed to a therapeutic composition:
`10. A therapeutic composition comprising an anticonvulsant
`effective amount of a compound according to any one of claims
`1–9 and a pharmaceutical carrier therefor.
`Claims 11–13 are method claims. Claim 11 reads:
`11. A method of treating central nervous system disorders in an
`animal comprising administering to said animal in need thereof
`an anticonvulsant effective amount of a compound according to
`any one of claims 1–9.
`
`II. ANALYSIS
`A. Claim Construction
`For inter partes review, claim terms in an unexpired patent are given
`their broadest reasonable interpretation in light of the patent specification.
`37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268,
`1278–79 (Fed. Cir. 2015), cert. granted, sub nom. Cuozzo Speed Techs. LLC
`v. Lee, 136 S.Ct. 890 (2016) (No. 15-446). Claim terms are given their
`ordinary and customary meaning, as would be understood by one of ordinary
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`skill in the art in the context of the entire disclosure. In re Translogic Tech.,
`Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definition for a
`claim term must be set forth in the specification with reasonable clarity,
`deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir.
`1994).
`Both parties provide proposed constructions of certain terms in the
`challenged claims. Pet. 7–11; Prelim. Resp. 10–16. Specifically, the parties
`dispute the meaning of a “compound in the R configuration” in claim 1, and
`“therapeutic composition” in claim 10. Pet. 7–11; Prelim. Resp. 10–16. For
`the purpose of institution, we construe those terms, but determine that
`construction of other terms is not necessary to our analysis on whether to
`institute. Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803
`(Fed. Cir. 1999) (only claim terms in controversy need to be construed, and
`only to the extent necessary to resolve the controversy).
`1. A “compound in the R configuration” (claim 1)
`According to Petitioner, the term “a compound in the R
`configuration” in claim 1 excludes “pure S-isomer, which would have no
`R-isomer,” but otherwise encompasses anything that includes an R-isomer,
`such as a racemic mixture (having both R- and S-isomers) or an isomerically
`enriched compound. Pet. 10. Petitioner contends that dependent claim 2,
`which recites “substantially enantiopure,” and dependent claim 9, which
`recites “contains at least 90% (w/w) R stereoisomer,” confirm this
`construction. Id. at 10–11 (citing Ex. 1002 ¶¶ 9–13).
`Patent Owner, on the other hand, contends that the specification of the
`’551 patent indicates “a compound in the R configuration” refers to “a
`compound containing greater than 50% R enantiomer,” and therefore
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`excludes a racemic mixture (a 50/50 mix) or an isomerically enriched
`compound having greater than 50% S-isomer. Prelim. Resp. 10–13.
`Neither party points us to where the ’551 patent specification defines
`the term expressly. As Patent Owner notes, however, the specification states
`in a relevant part that “the R stereoisomer at the asymmetric carbon at the
`asterisk is significantly more efficacious than the corresponding S
`enantiomer or a racemic mixture thereof.” Ex. 1001, 5:1–4; see also id. at
`23:28–33 (stating that “the R enantiomers of the present invention have quite
`potent anticonvulsant activity,” and “the R stereoisomer is unexpectedly
`more potent than the corresponding S stereiosomer and the racemic
`mixture”); Prelim. Resp. 10. We agree with Patent Owner that this
`description in the specification indicates that “a compound in the R
`configuration” in claim 1 does not refer to a racemic mixture, but rather a
`compound containing more than 50% of the R stereoisomer, including, for
`example, a compound that is “substantially enantiopure” (claim 2) or
`“contains at least 90% (w/w) R stereoisomer” (claim 9).
`2. A “therapeutic composition” (claim 10)
`In a related district court litigation involving Patent Owner and the
`patent at issue here, a district court judge construed “therapeutic
`composition” in the preamble of claim 10 as a claim limitation, and to mean
`“suitable for use as a treatment regimen over an extended period of time
`(chronic administration)” Ex. 1007, 5, 8; Prelim. Resp. 16 n.6.
`Patent Owner argues that the specification supports that same
`interpretation here. Prelim. Resp. 13–16 (citing Ex. 1001, 2:62–3:61, 8:62–
`9:26, 10:29–52, 21:13–24, 24:30–29:29, 37:5–51). Petitioner counters that
`the district court construction is not the “broadest reasonable interpretation
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`(‘BRI’).” Pet. 7–10. Petitioner argues that the “preamble, ‘a therapeutic
`composition,’ does not ‘give life, meaning, and vitality’ to the claim, but
`merely describes an intended purpose,” and the body of claim 10 “sets forth
`all limitations of the claimed invention.” Id. at 8 (quoting Rowe v. Dror, 112
`F.3d 473, 478 (Fed. Cir. 1997)). Thus, according to Petitioner, “BRI cannot
`be limited to only a composition that is administered ‘over an extended
`period of time’ and for ‘chronic administration.’” Id. at 9.
`As noted by Patent Owner, although not binding us, claim
`construction by a district court in a relevant case is instructive and
`persuasive here. Prelim. Resp. 16 n.6 (citing Ex. 1007). In this instance, we
`determine the district court’s claim construction under Phillips v. AWH
`Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) also presents the broadest
`reasonable interpretation in light of the specification. The district court
`opinion discusses in detail why the preamble in claim 10 is limiting, and
`how the specification supports its construction. Ex. 1007, 5–10. Petitioner
`does not persuade us that the “BRI” standard of claim interpretation dictates
`a different result in view of the record before us (Pet. 7–10). Thus, we adopt
`the district court’s claim construction (Ex. 1007, 5), and interpret
`“therapeutic composition” in claim 10 to be limiting, and to mean “suitable
`for use as a treatment regimen over an extended period of time (chronic
`administration).”
`B. The LeGall Thesis as “Printed Publication” Prior Art Under 35
`U.S.C. §102
`35 U.S.C. § 311(b) states that a “petitioner in an inter partes review
`may request to cancel . . . claims of a patent only on a ground that could be
`raised under section 102 or 103 and only on the basis of prior art consisting
`of patents or printed publications.” Before considering Petitioner’s two
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`grounds based on the LeGall thesis, we must address whether that thesis
`constitutes prior art under 35 U.S.C. § 102—a legal question based on
`underlying factual determinations.7 Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561, 1568 (Fed. Cir. 1987); Kyocera Wireless Corp. v. Int’l Trade
`Comm’n, 545 F.3d 1340, 1350 (Fed. Cir. 2008).
`The Federal Circuit has held that “public accessibility” is the
`touchstone in determining whether a reference is a “printed publication”
`under § 102. In re Hall, 781 F.2d 897, 898–99 (Fed. Cir. 1986). “A
`reference is publicly accessible ‘upon a satisfactory showing that such
`document has been disseminated or otherwise made available to the extent
`that persons interested and ordinarily skilled in the subject matter or art
`exercising reasonable diligence, can locate it . . . .”’ Kyocera, 545 F.3d at
`1350 (quoting SRI Int’l, Inc. v. Internet Sec. Sys. Inc., 511 F.3d 1186, 1194
`(Fed. Cir. 2008)); In re Lister, 583 F.3d 1307, 1315 (Fed. Cir. 2009).
`A party seeking to introduce a reference “should produce sufficient
`proof of its dissemination or that it has otherwise been available and
`accessible to persons concerned with the art to which the document relates
`and thus most likely to avail themselves of its contents.” In re Wyer, 655
`F.2d 221, 227 (CCPA 1981) (quoting Philips Elec. & Pharm. Indus. Corp. v.
`Thermal & Elecs. Indus., Inc., 450 F.2d 1164, 1171 (3d Cir. 1971)). As
`
`
`7 We decline to deny the two grounds relying on the LeGall thesis under 35
`U.S.C. § 325(d) based on the premise that the current Petition constitutes a
`“second bite at the apple.” Prelim. Resp. 17. Petitioner here differs from the
`petitioner in IPR2014-01126, and the petition in the earlier case raises
`different arguments. Actavis, Inc., v. Research Corporation Technologies,
`Inc., Case No. IPR2014-01126, Paper 22, slip op. at 10–13 (PTAB Jan. 9,
`2015)
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`explained by the Federal Circuit, a “determination of whether a reference is
`a ‘printed publication’ under 35 U.S.C. § 102(b) involves a case-by-case
`inquiry into the facts and circumstances surrounding the reference’s
`disclosure to members of the public.” In re Klopfenstein, 380 F.3d 1345,
`1350 (Fed. Cir. 2004).
`Petitioner asserts that the LeGall thesis (Ex. 1008) constitutes prior art
`under 35 U.S.C. § 102(b) because: (1) “Patent Owner has now admitted that
`LeGall qualifies as prior art”; (2) the University of Houston (where the
`thesis is located) has denied Petitioner’s request for information regarding
`public access to the thesis; and (3) evidence indicates “that the University of
`Houston’s theses were generally accessible to the public” in the relevant
`time frame. Pet. 21–23 (citing Ex. 1004 ¶ 87; Ex. 1028, 5, 11, 15–16; Ex.
`1029, 42–43 nn.8, 11, 20; Ex. 1029, 1135 nn.21, 28; Ex. 1030, 157–158; Ex.
`1031, 649 n.9).
`As an initial matter, Petitioner relies on a “Joint Statement of
`Uncontested Facts” submitted in a district court case involving Patent Owner
`and defendants other than Petitioner. Pet 22 (Ex. 1004 ¶ 87). There, among
`other things, the Joint Statement states that “for purposes of this litigation,
`the LeGall thesis was publicly accessible more than one year before the
`earliest priority date for the ’551 patent and constitutes a ‘printed
`publication’ within the meaning of 35 U.S.C § 102(b).” 1004 ¶ 87
`(emphasis added). We are unpersuaded that this “Joint Statement” provides
`a sufficient “threshold showing” of public accessibility. Apple, Inc. v. DSS
`Tech. Mgmt., Inc., Case IPR2015-00369, Paper 14, slip op. at 5 (PTAB Aug.
`12, 2015) (requiring a “threshold showing” of public availability in order to
`institute trial); Hughes Network Systems, LLC v. California Institute of
`
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`Technology, IPR2015-00059, Paper 34, slip op. at 4 (PTAB Dec. 30, 2015).
`During the district court litigation, Patent Owner may have agreed to
`stipulate to certain facts to streamline matters at trial there, for example, or
`had other reasons to stipulate on the issue in a case involving different
`parties in a different forum, regardless of whether the thesis was, in fact,
`publicly accessible or not. Prelim. Resp. 20–21.
`We likewise are not persuaded that the University of Houston’s
`refusal to provide information in response to Petitioner’s request is a
`sufficient threshold showing. The record before us does not explain
`adequately the University’s rationale for declining Petitioner’s request for
`information, and we do not agree that the University’s action “gives rise to a
`rebuttable presumption that the information both exists and establishes a
`reasonable likelihood that LeGall is prior art,” as proposed by Petitioner.
`Pet. 22–23. The request relates to two different theses (Ex. 1028, 2), and a
`statement that “releasing the dates when each thesis was checked out of the
`University library would cause the University competitive harm” (id. at 5) is
`insufficient to create a presumption as to when or if the LeGall thesis was
`ever publicly accessible.
`Patent Owner also persuades us that articles cited by Petitioner that
`reference “theses of other students in other departments at the University of
`Houston” likewise fail to provide threshold evidence that the LeGall thesis
`was publicly accessible in the relevant time frame. Prelim. Resp. 21–22. As
`noted by Patent Owner (id. at 22), “in each of Petitioner’s examples, just like
`Dr. Kohn’s articles citing the LeGall Thesis, the article was authored by the
`student who wrote the thesis or by the student’s thesis advisor,” thereby
`indicating the authors had personal knowledge regarding the cited thesis
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`work, even if others did not have public access to any of those theses per se.
`Absent in the evidence cited by Petitioner is information related to
`whether the LeGall thesis itself was publicly accessible in the relevant time
`frame, how one might have obtained a copy of the thesis, or whether the
`thesis was reasonably accessible through generally available means.
`Without more here, contentions and evidence cited by Petitioner do not rise
`to the level of “threshold evidence” that justifies going forward with a trial
`on any ground that relies on the LeGall thesis as “printed publication” prior
`art.
`C. Asserted Anticipation by the LeGall Thesis and Obviousness over
`the LeGall Thesis and the ’729 patent
`Petitioner contends that the LeGall thesis anticipates challenged
`claims 1 and 3–8, and that challenged claims 2 and 9–13 are rendered
`obvious over the LeGall thesis and the ’729 patent (Ex. 1009). Pet. 21–34.
`Both grounds rely on teachings in the LeGall thesis. Id. As discussed
`above, we are not persuaded that Petitioner has made a threshold showing
`that the LeGall thesis was sufficiently publicly accessible to qualify as a
`“printed publication” under § 102(b). Thus, Petitioner has not demonstrated
`that there is a reasonable likelihood that it would prevail in showing that
`challenged claims of the ’551 patent are unpatentable based on the two
`asserted grounds that rely on the LeGall thesis.
`D. Asserted Obviousness of Claims 1–9 over Kohn 1991 and
`Silverman
`Petitioner contends that claims 1–9 of the ’551 patent would have
`been obvious over Kohn 1991 (Ex. 1012) and Silverman (Ex. 1013). Pet.
`44–48. Patent Owner disagrees. Prelim. Resp. 46–50. Petitioner contends,
`and Patent Owner does not dispute, that Kohn 1991 and Silverman both
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`qualify as 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. Pet. 44; Prelim. Resp. 46–50, 58; Ex. 1001.
`1. Kohn 1991 (Ex. 1012)
`Kohn 1991 discloses the preparation and anti-convulsive activity of
`“functionalized α-heteroatom-substituted amino acids.” Ex. 1012, 2444.
`Kohn states that “comparison of the two individual enantiomers of 2a, b, d
`revealed that in each case the anticonvulsant activity resided primarily in the
`R stereoisomer.” Id. at 2444, 1st col. Table 1 in Kohn 1991 presents
`physical and pharmacological data, including ED50,8 for those compounds,
`as well as derivatives 3a–3z, prepared as racemates. Id. at 2444, 2nd col.,
`2445, Table 1. Table 1 lists the “X” group for different derivatives having
`the following formula:
`
`
`Id. The formula depicted above is similar to the formula recited in claim 1
`of the ’551 patent.
`Kohn 1991 teaches that “[i]mportantly, in the most potent analogues
`(2d, 3l, and 3n), a functionalized oxygen atom existed two atoms removed
`from the α-carbon atom.” Id. at 2447, 1st col. As depicted in Table 1,
`
`8 ED50 refers to an “effective dose, for 50% of people receiving the drug.”
`Effective dose (pharmacology), Wikipedia, The Free Encyclopedia,
`https://en.wikipedia.org/wiki/Effective_dose_ (pharmacology) (last visited
`May 18, 2016); see also Bourne, Drug Receptors & Pharmacodynamics, in
`BASIC & CLINICAL PHARMACOLOGY 29 (Katzung, Apple & Lange 7th ed.
`1998) (stating that “the median effective dose (ED50)” is “the dose at which
`50% of the individuals exhibit the specified quantal effect”). A lower ED50
`indicates a compound is more effective than one with a higher ED50.
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`derivative 2d (where X is “2-furanyl”) has an ED50 of 10.3 mg/kg, derivative
`3l (where X is NH(OCH3)) has an ED50 of 6.2 mg/kg, and derivative 3n
`(where X is N(CH3)OCH3) has an ED50 of 6.7 mg/kg. Id. at 2445, Table 1.
`Table 1 indicates that other derivatives have a higher ED50. Id. For
`example, derivative 3a (where X is NH2) has an ED50 of 65.1 mg/kg, and
`derivative 2a (where X is CH3) has an ED50 of 76.5 mg/kg. Id.
`2. Silverman (Ex. 1013)
`Silverman presents a chapter entitled “Drug Discovery, Design, and
`Development” in a book entitled “The Organic Chemistry of Drug Design
`and Drug Action.” Ex. 1013, 1–3.9 In a section discussing “Bioisosterism,”
`Silverman teaches that:
`Bioisosteres are substituents or groups that have chemical or
`physical similarities and which produce broadly similar
`biological properties. Bioisosterism is a lead modification
`approach that has been shown to be useful to attenuate toxicity
`or to modify the activity of a lead, and it may have a significant
`role in the alteration of metabolism of a lead. There are classical
`isosteres and nonclassical isosteres.
`
`Ex. 1013, 18 (citations omitted). Table 2.2 on the same page of Silverman
`presents “Classical Isosteres,” including:
`
`
`
` Id.
`
`3. Analysis
`Petitioner presents the following diagram in relation to derivative 3l
`disclosed in Kohn 1991:
`
`9 We cite page numbers added to Exhibit 1013, rather than page numbers in
`the reference itself.
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`Pet. 44; see also id. at 4, 14–15. This diagram depicts the chemical structure
`of a “methoxyamino compound” (3l) disclosed in Kohn 1991, as compared
`to lacosamide, a relevant compound encompassed by challenged claim 1 and
`specifically recited in dependent claim 8.
`Petitioner contends that an ordinary artisan would have had reason to
`choose derivative 3l (i.e., the “methoxyamino compound”) from Kohn 1991
`as a lead compound because the reference teaches that derivative 3l, which
`has an ED50 of 6.2 mg/kg, is the most potent compound tested. Pet. 44
`(citing Ex. 1012, Table 1; Ex. 1002 ¶ 105), 37. According to Petitioner,
`“[t]his compound would have been of immediate interest to a [person of
`ordinary skill in the art, ‘POSA’] based on its activity and would have been
`selected for optimization.” Id. (citing Ex. 1002 ¶ 105).
`Petitioner further contends that “[h]aving recognized the desire to
`modify the methoxyamino moiety, a POSA would utilize the well-known
`concept of bioisosterism and bioisosteric replacements.” Id. at 45 (citing Ex.
`1002 ¶ 107). Citing Silverman, Petitioner also argues that in the relevant
`time frame, an ordinary artisan would have known that “a methylene group
`(-CH2-) is a bioisosteric replacement for a secondary amino group (-NH-).”
`Id. (citing Ex. 1013, 18; Ex. 1002 ¶ 107). Petitioner also refers to ED50 data
`in Kohn 1991 to support the contention that an ordinary artisan would have
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`known “the equivalence between the amino and the methylene group off the
`α-carbon.” Id. at 45–46.
`In addition, Petitioner argues “the predicted activity based on the prior
`art data and the use of bioisosteres provides a strong reason for a POSA to
`modify the methoxyamino compound (3l) to make racemic lacosamide.” Id.
`at 46. Petitioner also contends that an ordinary artisan would have had a
`reasonable expectation of success in making racemic lacosamide, and in
`making or isolating the R-isomer using known techniques in the art. Id. at
`46–47 (citing Ex. 1002 ¶ 109; Ex. 1012, 2444; Ex. 1009, 15:31–16:4).
`Patent Owner responds that Petitioner fails to demonstrate sufficiently
`that an ordinary artisan would have selected derivative 3l from Kohn 1991
`as a lead compound. Prelim. Resp. 46. Patent Owner contends that
`Petitioner and experts admit that “the methoxyamino moiety may present
`synthetic and stability issues,” and “might be susceptible to acid catalyzed
`dehydration.” Id. (citing Pet. 45; Ex. 1002 ¶ 106; Ex. 2012, 137:10–138:5).
`We are persuaded that Petitioner sufficiently articulates reasoning,
`with adequate rational underpinnings, as to why an ordinary artisan would
`have chosen derivative 3l from Kohn 1991 as a lead compound for the
`purposes of making compositions exhibiting anticonvulsant activity. See In
`re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) (stating that determination of
`unpatentability on the ground of obviousness must include “articulated
`reasoning with some rational underpinning to support the legal conclusion of
`obviousness”).
`As Petitioner points out (Pet. 44), Kohn 1991 identifies derivative 3l
`as the most potent derivative, among many tested, in terms of a “median
`effective dose ED values required to prevent seizures” in a maximal
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`electroshock seizures (“MES”) test in mice. Ex. 1012, 2444, 1st col., 2445,
`Table 1, 2447, 1st col. Based on the record before us, the potential synthetic
`or stability issues cited by Patent Owner do not persuade us that an ordinary
`artisan would have failed to consider derivative 3l as a lead compound for
`study. See Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed.
`Cir. 2012) (“In determining whether a chemist would have selected a prior
`art compound as a lead, the analysis is guided by evidence of the
`compound’s pertinent properties,” including “positive attributes such as
`activity and potency” and “adverse effects such as toxicity.”).
`In addition, we are persuaded that Petitioner adequately shows at this
`stage that an ordinary artisan reading Silverman would have had reason to
`substitute the amino group (-NH-) in the X moiety of NH(OCH3) in
`derivative 3l from Kohn 1991 with a methylene group (-CH2-), thereby
`producing a compound having the formula recited in challenged claims 1
`and 8. As stated in Silverman, bioisosterism “is a lead modification
`approach that has been shown to be useful to attenuate toxicity or to modify
`the activity of a lead, and it may have a significant role in the alteration of
`metabolism of a lead.” Ex. 1013, 18. In this context, Silverman teaches that
`-CH2- is a “classical isostere” of -NH-. Id. at 18, Table 2.2. Petitioner
`reasonably contends that those teachings in Silverman suggest substituting
`one bioisostere for the other in a lead compound modification (e.g., in the X
`moiety in derivative 3l from Kohn 1991), in an effort to attenuate toxicity,
`modify activity, or positively affect the metabolism of a compound.
`We acknowledge Patent Owner’s contentions that one would have
`known that such a substitution “affects the size, shape, solubility, pKa, and
`hydrogen bonding of the molecule,” citing district court testimony by Dr.
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`Heathcock and Silverman. Prelim. Resp. 47 (citing Ex. 2012, 190:18–
`191:13; Ex. 1013, 18–22). Silverman itself states, however:
`It is actually quite surprising that bioisosterism should be such
`successful approach to lead modification. Perusal of Table 2.2,
`and especially of Table 2.3 [listing nonclassical bioisosteres],
`makes it clear that in making bioisosteric replacement, one or
`more of the following parameters will change: size shape
`electronic distribution, lipid solubility, water solubility pKa,
`chemical reactivity, and hydrogen bonding.
`
`Ex. 1013, 20. Silverman then lists other effects that modifications can have
`in relation to structure, receptor interactions, pharmacokinetics, and
`metabolism, and states “[i]t is because of these subtle changes that
`bioisosterism is effective.” Id. (emphasis added).
`Patent Owner also relies on testimony by Dr. Heathcock and Kohn
`1991 to support its contention that, in some relevant compounds, replacing a
`nitrogen with a carbon results in a reduction in anticonvulsant activity. Id. at
`47–48 (citing Ex. 2012, 188:23–189:17; Ex. 1012, 2445). A review of Table
`1 in Kohn 1991 in relevant part, however, indicates that substituting a
`nitrogen (X = NH2) with a carbon (X = CH3) in different but related
`compounds has what appears to be a relatively small impact on ED50 (65.1
`mg/kg vs. 76.5 mg/kg, respectively). Ex. 1012, 2445, Table 1 (also
`indicating that a number of other related derivatives have ED50 of ~100 or
`greater). In addition, Silverman teaches that bioisosterism, using classical
`isosteres such as -CH2- and -NH-, can attenuate toxicity of a lead compound,
`which reasonably provides an additional, but different, reason to do the
`modification. Ex. 1013, 18, 20. We also are not persuaded by Patent
`Owner’s contention that other Kohn references “explicitly disclose[] that
`heteroaromatic compounds – not aliphatic compounds like compound 3l or
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`lacosamide – were ‘the most promising compounds.’” Prelim. Resp. 49
`(citing Ex. 1017, 3350; Ex. 1018, 919). Although the cited Kohn references
`may indicate that certain heteroaromatic compounds are promising, we are
`not persuaded, based on arguments and information before us at this time,
`that those references undermine teachings in Kohn 1991 that suggest that
`derivative 3l is also promising as a lead compound. “[T]he lead compound
`analysis must, in keeping with KSR, not rigidly focus on the selection of a
`single, best lead compound.” Daiichi Sankyo v. Matrix Labs., 619 F.3d
`1346, 1354 (Fed. Cir. 2010).
`We also are persuaded that Petitioner sufficiently contends, in view of
`teachings in Kohn 1991, for example, that an ordinary artisan would have
`been motivated to make or isolate the R-isomer of a modified derivative 3l
`using known techniques, with a reasonable expectation of success. Id. at
`46–47 (citing Ex. 1002 ¶ 109; Ex. 1012, 2444; Ex. 1009, 15:31–16:4). For
`example, Petitioner points to Kohn 1991 as teaching, in relation to a relevant
`class of compounds, that “in each case the anticonvulsant activity resided
`primarily in the R stereoisomer.” Id. at 47 (citing Ex. 1012, 2444).
`Having considered the information and arguments presented in the
`Petition and Preliminary Response, we are persuaded that Petitioner has
`established a reasonable likelihood of prevailing in its challenge of claims 1–
`9 as obvious over Kohn 1991 and Silverman.
`E. Asserted Obviousness of Claims 10–13 over Kohn 1991,
`Silverman, and the ’729 Patent
`Petitioner contends that claims 10–13 of the ’551 patent would have
`been obvious over Kohn 1991, Silverman, and the ’729 patent (Ex. 1009).
`Pet. 44–48, 25–34. Patent Owner disagrees. Prelim. Resp. 46–50.
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`1. The ’729 Patent (Ex. 1009)
`The ’729 patent describes “compounds and pharmaceutical
`compositions having central nervous system (CNS) activity which are useful
`in the treatment of epilepsy and other CNS disorders.” Ex. 1009, 1:30–33.
`In this context, the ’729 patent discloses compounds
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