Case217-2088
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`Document: 91
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`Page:1
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`aflniteb gates QEnurt of Qppealg
`
`fur the erheral (Eirtuit
`
`MYLAN PHARMACEUTICALS INC.,
`BRECKENRIDGE PHARMACEUTICAL, INC.,
`ALEMBIC PHARMACEUTICALS LTD.,
`Appellants
`
`V.
`
`RESEARCH CORPORATION TECHNOLOGIES,
`INC.,
`Appellee
`
`2017-2088, 2017-2089, 2017-2091
`
`Appeals from the United States Patent and Trade-
`mark Office, Patent Trial and Appeal Board in Nos.
`IPR2016-00204,
`IPR2016-01101,
`IPR2016-01242,
`IPR2016-01245.
`
`Decided: February 1, 2019
`
`STEVEN WILLIAM PARMELEE, Wilson, Sonsini, Goodrich
`& Rosati, PC, Seattle, WA, argued for all appellants.
`Appellant Mylan Pharmaceuticals Inc. also represented
`by MICHAEL T. ROSATO,
`JAD ALLEN MILLS; ADEN M.
`ALLEN, NICOLE W. STAFFORD, Austin, TX.
`
`MATTHEW L. FEDOWITZ, Buchanan Ingersoll & Rooney
`PC, Alexandria, VA, for appellant Breckenridge Pharma-
`
`

`

`Casez17—2088
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`Document: 91
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`Page:2
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`2
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`MYLAN PHARMACEUTICALS INC. V. RESEARCH CORPORATION
`TECqulNC
`
`ceutical, Inc.
`
`TODD S. WERNER, Carlson, Caspers, Vandenburgh,
`Lindquist & Schuman, PA, Minneapolis, MN, for appel-
`lant Alembic Pharmaceuticals Ltd. Also represented by
`SARAH STENSLAND, Patterson Thuente Pedersen,- PA,
`Minneapolis, MN.
`
`JACK B. BLUMENFELD, Morris, Nichols, Arsht & Tun-
`nell LLP, Wilmington, DE, argued for appellee. Also
`represented by ALEXA HANSEN, Covington & Burling LLP,
`San Francisco, CA; JENNIFER L. ROBBINS, New York, NY;
`BETH S. BRINKMANN, PRISCILLA GRACE DODSON, EVAN
`SMITH KRYGOWSKI, GEORGE FRANK PAPPAS, Washington,
`DC.
`
`Before LOURIE, BRYSON, and WALLACH, Circuit Judges.
`
`LOURIE, Circuit Judge.
`
`Mylan Pharmaceuticals Inc. (“Mylan”), Breckenridge
`Pharmaceutical,
`Inc.
`(“Breckenridge”),
`and Alembic
`Pharmaceuticals, Ltd.
`(“Alembic”)
`(collectively, “Appel-
`lants”) appeal from the final written decision of the US.
`Patent and Trademark Office Patent Trial and Appeal
`Board (“the Board”) in an inter partes review concluding
`that claims 1—13 of US. Reissue? Patent 38,551 (“the ’551
`patent”) are not unpatentable.
`See Argentum Pharm.
`LLC U. Research Corp. Techs., IPR 2016-00204, 2017 WL ,
`1096590, at *1—2 (P.T.A.B. Mar. 22, 2017) (“Decision”).
`For the reasons detailed below, we affirm.
`
`BACKGROUND
`
`Epilepsy is a neurological disorder that affects about
`one percent of the human population. It is characterized
`by two or more unprovoked seizures occurring more than
`24 hours apart. Epilepsy can be associated with condi-
`tions affecting the structure of the brain, but, for the vast
`
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`MYLAN PHARMACEUTICALS INC. V. RESEARCH CORPORATION
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`TECHS., INC.
`
`majority of affected individuals, no specific cause-can be
`identified. While there is no known cure for epilepsy,
`treatment can include both drug therapy and surgery, and
`most patients are treated via long-term administration of
`anticonvulsant drugs to prevent seizures. The nature and
`severity of seizures varies considerably across the patient
`population, and treatment is typically tailored for each
`specific patient.
`
`Research Corporation Technologies, Inc. (“RCT”) owns
`the ’551 patent, which discloses and claims enantiomeric
`compounds and pharmaceutical compositions useful in the
`treatment of epilepsy and other central nervous system
`(“CNS”) disorders. Claim 1 recites:
`
`1. A compound in the R configuration having the
`formula:
`
`H
`
`H
`
`Ar_CH2NH(|:|—(I: —N —|C|—Q1
`O
`(IZHZ
`O
`
`Q
`
`wherein
`
`Ar is phenyl which is unsubstituted or
`substituted with at least one halo group;
`
`Q is lower alkoxy, and
`
`Q1 is methyl.
`
`1’551 patent col. 3811. 8—23.
`
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`MYLAN PHARMACEUTICALS INC. V. RESEARCH CORPORATION
`TECHS., INC.
`
`At issue here are claims 8—13.1 Claim 8 depends from
`claim 1 and recites‘‘[t]he compound according to claim 1
`which
`is
`(R)-N-benzyl-2-acetamido-3-
`methoxypropionamide,” referred to in the patent as
`“BAMP” and referred to herein as lacosamide:
`
`L“N
`.0, w;
`
`N
`
`3
`
`I C
`
`H3
`
`Claim 9 claims lacosamide in 90 percent or greater
`purity, claim 10, therapeutic compositions comprising the
`claimed compounds, and claims 11—13, use of the com-
`pounds for treating central nervous system disorders. Id.
`col. 38 11. 39—51. Because arguments have not been made
`concerning the separate claims, we will consider them
`together, as did the Board.
`
`Before the Board, Appellants challenged claims 1—
`1
`13, but, since this appeal was taken, claims 1—7 have been
`voluntarily cancelled in a separate, ex parte reexamina-
`tion proceeding. See Citation of Supplemental Authority,
`Mylan Pharm. Inc.
`12. Research Corp. Techs, No. 2017-
`2088 (Fed. Cir. Apr. 23, 2018), ECF No. 73. Because there
`is no case or controversy regarding the finally cancelled
`claims, we rule only on the still-existing claims 8—13. See
`Fresenius USA, Inc. v. Baxter Int’l, Inc., 721 F.3d 1330,
`1347 (Fed. Cir. 2013) (litigation became moot because of
`the cancellation of claims).
`
`

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`MYLAN PHARMACEUTICALS INC. V. RESEARCH CORPORATION
`TECHS., INC.
`
`1
`
`5
`
`On November 23, 2015, Argentum Pharmaceuticals
`LLC (“Argentum”) petitioned for
`inter partes review
`(“IPR”) of the ’551 patent.
`In its petition, Argentum
`challenged claims 1—13 on eight grounds. The Board only
`instituted on two grounds involving three references:
`(1) obviousness of claims 1—9 over Kohn 19912 and Sil-
`verman3 and (2) obviousness of claims 10—13 over Kohn
`1991, Silverman, and U.S. Patent 5,378,729 (“the ’729
`patent”).4 The instituted grounds appear in the petition
`as ground 3A and ground 3B.
`
`In its argument, Argentum advanced a lead com-
`pound analysis.
`It relied on Kohn 1991 for disclosure of
`compound 31, its proffered lead compound. Kohn 1991,
`authored by the named inventor of the ’551 patent, Dr.
`Harold Kohn, discloses a series of functionalized amino
`acids (“FAAs”) with anticonvulsant activity. Dr. Kohn
`observed that FAA racemates with N-benzylamide moie-
`ties and acetylated amino groups provided potent protec-
`tion against seizures in mice. For his research presented
`in the
`1991 paper, Dr. Kohn began with (R,S)-2-
`acetamidorN-benzyl-2-methylacetamide as a lead com-
`pound and replaced the a-methyl group, denoted in the
`structure below as “X,” with functionalized nitrogen,
`oxygen, and sulfur substituents:
`
`2 Harold Kohn et al., Preparation and Anticonuul-
`sant Activity of a Series of Functionalized a-Heteroatom-
`Substituted Amino Acids, 34 J. Medicinal Chemistry
`2444 (1991); J.A. 2404—12.
`3 Richard B. Silverman, The Organic Chemistry of
`Drug Design and Drug Action (1st ed. 1992); J.A. 2413—
`61.
`
`The application that led to the ’551 patent was
`4
`filed before March 16, 2013, and the pre-Leahy—Smith
`America Invents Act, Pub L. No. 112-29, 125 Stat. 284
`(2011), version of § 103 applies.
`
`

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`MYLAN PHARMACEUTICALS INC. V. RESEARCH CORPORATION
`TECHS., INC.
`
`if
`’1‘
`3
`cnac NH —cu —cu HCHzPh
`
`Dr. Kohn then evaluated the potency of the compounds in
`mice, reporting for each the effective dosage for 50 percent
`of the tested population (“ED5o”).
`
`Based on the reported EDso values, Dr. Kohn conclud-
`ed that “in the most potent analogues (2d, 31, and 3n), a
`functionalized oxygen atom existed two atoms removed
`from the o-carbon atom.” J .A. 2407. The most efficacious
`
`compound (i.e., the compound with the lowest ED50) was
`compound 31.
`In compound 31, NH(OCH3) is at the a-
`carbon position. J .A. 2405. Its structure is as follows:
`
`Elwiiim
`
`To supply a motivation to modify compound 31, Argen-
`tum relied on Silverman, a book chapter on drug discov-
`ery, design, and development.
`Silverman describes
`bioisosterism as a “lead modification approach. . .useful
`to attenuate toxicity or to modify .
`.
`. activity. ” J .A. 2430.
`He specifically defines bioisosteres as “substituents or
`groups that have chemical or physical similarities, and
`which produce broadly similar biological properties.” Id.
`As
`relevant here, Silverman explains that “classical
`
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`
`isosteres” are groups with the same number of valence
`electrons but potentially different atoms: Under the
`subheading “[b]ivalent atoms and groups,” he lists the
`following compounds as classical isosteres: —CH2—, —NH—,
`—O—, —S—, and —Se—. Id.
`
`As a third reference, relevant only to the second insti-
`tuted ground of review, Argentum cited the ”729 patent,
`another patent issued to Dr. Kohn and assigned to RCT.
`The ’7 29 patent is directed to a genus of FAAs with activi-
`ty “useful in the treatment of epilepsy and other CNS
`disorders.” ’729 patent, Abstract. Specifically, a method
`of treating CNS disorders in animals with a racemate of
`N-benzyl Z-acetamido-3-methoxypropionamide (“racemic
`lacosamide”) is recited in claim 132 of the ’729 patent.
`
`Based on Argentum’s petition, the Board instituted
`review on (1) obviousness of claims 1—9 over Kohn 1991
`and Silverman and (2) obviousness of claims 10—13 over
`Kohn 1991, Silverman, and the ’729 patent. As for the
`first ground, the Board was “persuaded that [Argentum]
`sufficiently articulate[d] reasoning, with adequate ration-
`al underpinnings, as to why an ordinary artisan would
`have chosen derivative 31 from Kohn 1991 as a lead
`
`compound for the purposes of making compositions exhib-
`iting anticonvulsant activity.” J .A. 367. The Board noted
`that Kohn 1991 identified compound 31 as “the most
`potent derivative,” and, based on the record at the time, it
`was not persuaded that “potential synthetic or stability
`issues” would have counseled against its selection as a
`lead compound.
`J.A. 367—68. The Board was also per-
`suaded 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 31 from
`Kohn 1991 with a methylene group,” “in an effort
`to
`attenuate toxicity, modify activity, or positively affect the
`metabolism of a compound.” J .A. 368. That change would
`lead to lacosamide.
`
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`As for the second ground, the Board concluded that
`Argentum had adequately supported its contention that
`an ordinary artisan would have had reason to expect “that
`compounds falling within claim 132 of the ’729 patent—
`such as racemic lacosamide and R-lacosamide—would be
`
`useful for treating CNS disorders, and would have a
`reasonable expectation of success in using them for this
`purpose.” J.A. 372.
`
`Three days after the Board instituted Argentum’s pe-
`tition, Mylan, Breckenridge, and Alembic each filed their
`own petitions for review with concurrent motions for
`joinder. Each party had been sued for infringement of the
`’551 patent in 2013., more than a year before the petitions
`were filed.5 On October 24, 2016, the Board instituted on
`each petition and joined each proceeding with the Argen-
`tum IPR.
`In its decision permitting joinder, the Board
`noted that Mylan, Breckenridge, and Alembic “agree[d] to
`be limited to an ‘understudy’ role, and limited to evidence
`and arguments presented in the Argentum Petition in
`relation to instituted Grounds 3A—3B.” J .A. 1463.
`
`Five months later, the Board issued its final written
`decision, concluding that each challenged claim had not
`been shown to be unpatentable. Regarding ground one,
`Petitioners identified two reasons
`for modifying the
`methoxyamino moiety of compound 31 in Kohn 1991:
`(1) that the methoxyamino moiety was not a common
`moiety in compounds that result in commercial pharma-
`
`Inc., No. 1:13-cv-
`v. Mylan Pharm.
`Inc.
`UCB,
`5
`01214-LPS (D. Del. Jul. 10, 2013); UCB, Inc. U. Alembic
`Pharm. Ltd., No. 1:13-cv-01207-LPS (D. Del. Jul. 10,
`2013); UCB, Inc. U. Breckenridge Pharm., Inc., No. 1:13-
`cv-01211-LPS (D. Del. Jul. 10, 2013). We resolved the
`appeal of these cases in UCB, Inc. v. Accord Healthcare,
`Inc., 890 F.3d 1313 (Fed. Cir. 2018), cert. denied, No. 18-
`441, 2018 WL 4899559 (US. Nov. 19, 2018).
`
`

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`ceutical compounds and (2) that the methoxyamino moie-
`ty may present synthetic and stability problems. Accord—
`ing to Petitioners, a person of skill in the art would have
`been motivated to substitute the —NH— group in 31 for a ——
`CH2— group because it is a more common and acceptable
`moiety for pharmaceutically active compounds. Further,
`because Kohn 1991 disclosed a ten-fold higher activity for
`31, which has an R group of —NH(OCH3), over a compound
`with an R group of —NH2, a person of skill in the art
`would have been motivated to substitute the —CH3 group
`with —CH2()CH3.
`
`Contrary to its Views in the institution decision, the
`Board disagreed with Petitioners.
`It “assum[ed] arguen-
`do, that an ordinary artisan would have selected com-
`pound 31 of Kohn 1991 as a lead compound” but found
`that converting the methoxyamino group would have been
`viewed as undesirable because the compounds in Kohn
`1991 without a methoxyamino or nitrogen-containing
`moiety at the a-carbon had reduced activity. Decision,
`2017 WL 1096590, at *8—9.
`
`The Board also credited evidence suggesting that an
`ordinary artisan would have understood the methoxy-
`amino moiety to confer significant activity to the com-
`pound and that substitution of nitrogen for carbon would
`have led to a significantly different conformation and
`biological activity.
`Id. at *10—11. While the Board
`“acknowledge[d] Silverman’s teaching .
`.
`. that bioisoster-
`ism has been shown to be useful to attenuate toxicity in
`lead compounds,” it found a lack of “specific evidence
`suggesting an ordinary artisan would have understood
`that modifying the methoxyamino group of Kohn 1991’s
`compound 31 would have reduced that compound’s toxici-
`ty.” Id. at *12.
`
`Although the Board did proceed to evaluate objective
`indicia of nonobviousness, it nonetheless concluded that
`even without objective evidence of nonobviousness Peti-
`
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`their burden to establish by a
`tioners failed to meet
`preponderance of the evidence that challenged claims 1—9
`would have been obvious. Id. at *13.
`
`Proceeding to the second ground relating to the de-
`pendent claims, the Board declined to consider Petition-
`ers’ arguments because they incorporated by reference a
`separate ground, Ground 1B, on which the Board did not
`institute review. Specifically, in Ground 1B, Petitioners
`advanced arguments based on a LeGall thesis, a reference
`not at issue in the proceeding as instituted. The Board
`found that the second ground was “based on a conclusory
`assertion referencing a distinct ground of unpatentability
`discussing a different combination of references.”
`J.A.
`129. Moreover, because it concluded that independent
`claim 1 would not have been obvious over Kohn 1991 and
`
`Silverman, the Board reasoned that it could not conclude
`that the more limited dependent claims 10—13, the only
`claims at issue in the second ground, would have been
`obvious.
`
`Of the four petitioners, Mylan, Breckenridge and
`Alembic appealed. RCT challenges whether Appellants
`have standing to challenge the Board’s decision. We have
`jurisdiction
`for
`this
`appeal
`under
`28 U.S.C.
`§1295(a)(4)(A) and 35 U.S.C. §141(c). We review the
`Board’s legal determinations de novo, In re Elsner, 381
`F.3d 1125, 1127 (Fed. Cir. 2004), and its fact findings for
`substantial evidence, In re Gartside, 203 F.3d 1305, 1316
`(Fed. Cir. 2000). A finding is supported by substantial
`evidence if a reasonable mind might accept the evidence
`as sufficient to support the finding. Consol. Edison Co. U.
`NLRB, 305 US. 197, 229 (1938).
`
`DISCUSSION
`
`1. STANDING
`
`As a threshold matter, we first address whether Ap-
`pellants have standing to make this appeal. RCT does not
`
`

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`
`assert that Appellants lack Article III standing. Appel-
`lee’s Br. 20. However, RCT submits that each Appellant
`lacks standing because it does not fall within the zone of
`interests of 35 U.S.C. § 319. According to RCT, Appel-
`lants fall outside that zone because RCT brought an
`infringement action against each Appellant more than a
`year before it filed its IPR petition, and each Appellant’s
`petition was therefore time-barred.
`
`In its institution and joinder decision, the Board exer-
`cised its discretion to join each Appellant as a party to
`Argentum’s IPR as permitted by 35 U.S.C. § 315(c). J.A.
`670 (“[T]he later Petitioners are joined as parties .
`.
`. .”).
`RCT does not challenge the propriety of the Board’s
`joinder decision. However, RCT argues that the “statuto-
`ry scheme here .
`.
`. does not authorize Appellants to seek
`federal court review of the Board’s [final written] deci-
`sion.” Appellee’s Br. 18. Its argument is that the initial
`Petitioner, Argentum, would have lacked Article III
`standing to appeal the Board’s decision, because “its IPR
`was limited to an agency matter.”
`Id. at 18—19. The
`parties appear to agree‘that Argentum, who is not a party
`to this appeal,
`lacks standing.
`See Appellants’ Br. 71;
`Appellee’s Br. 20.
`
`For their part, Appellants maintain that they have an
`express, statutory right to appeal under 35 U.S.C. § 319
`because they were joined as petitioners to Argentum’s
`IPR. Appellants’ Br. 70—71. We agree.
`
`We presume that a statutory cause of action extends
`only to litigants that “fall within the zone of interests
`protected by the law invoked.” Lexmark Int’l, Inc. v.
`Static Control Components, Inc., 572 U.S. 118, 129 (2014)
`(quoting Allen 0. Wright, 468 U.S. 737, 751 (1984)). The
`zone of interests limitation “always applies and is never
`negated.” Id. To determine Whether an appellant falls
`within the zone of interests, we apply traditional princi-
`ples of statutory interpretation, asking not “whether in
`
`

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`judgment Congress should have authorized [the
`our
`appeal], but whether Congress in fact did so.” Id. at 128.
`
`We begin our analysis on this point with the text of
`the statute. Section 315(c) provides for joinder as follows:
`
`If the Director institutes an inter partes review,
`the Director, in his or her discretion, may join as a
`party to that inter partes review any person who
`properly files a petition under section 311 that the
`Director, after receiving a preliminary response
`under section 313 or the expiration of the time for
`filing such a response, determines warrants the
`institution of an inter partes review under section
`314.
`
`Section 315 thus contemplates the
`(emphasis added).
`joining of petitioners as “parties.”
`Section 319 then
`provides that “ [a] party dissatisfied with the final written
`decision” of the Board “may appeal the decision pursuant
`to sections .141 through 144. Any party to the inter partes
`review shall have the right to be a party to the appeal.”
`(emphasis added).
`
`“It is a ‘fundamental canon of statutory construction
`that the words of a statute must be read in their context
`
`and with a View to their place in the overall statutory
`scheme.” Nielson U. Shinselci, 607 F.3d 802, 807 (Fed.
`Cir. 2010) (quoting Davis v. Michigan Dep’t of Treasury,
`489 US. 803, 809 (1989)). Joined parties, as provided in
`§315, may appeal pursuant to § 319. Accepting RCT’s
`argument would require us to read the word “party”
`differently between § 315 and § 319, an argument for
`which RCT provides no support.
`
`,
`
`RCT also argues that, because Appellants’ role before
`the Board was limited by agreement and prohibited
`presentation of evidence independent of Argentum, Appel-
`lants’ participation should not be “transformed into a
`right to federal court review.” Appellee’s Br. 19—20. But
`
`

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`§ 315 provides the Board with discretion in joinder, and
`that discretion allows for the Board to place requirements
`and limitations on joined parties. RCT points to no sup-
`port for the proposition that a party subject to such re-
`strictions in its IPR should be considered to have less
`
`standing to appeal than a party under § 319. RCT argues
`that allowing Appellants’ appeal “would constitute an
`end-run around the statutory time-limit for instituting
`IPR proceedings,” id. at 19, but cites no provision in the
`text or legislative history supporting its reading.
`
`Accordingly, we conclude that Appellants fall within
`the zone of interests of § 319 and are not barred from
`appellate review. We therefore proceed to the merits.
`
`H . MERITS
`
`On the merits, Appellants challenge the Board’s non-
`obviousness conclusion. Regarding claims 1—9, Appel-
`lants
`assert
`a
`lead compound analysis,
`proposing
`compound 31 in Kohn 1991 as the lead.
`In its final writ-
`ten decision, the Board did not resolve whether compound
`31 was an appropriate lead compound.
`Instead, it accept-
`ed compound 31 as the lead and concluded that Petitioners
`did not meet their burden to establish a motivation to
`
`modify that compound. Because we agree with the Board
`that Appellants failed to meet their burden to establish a
`motivation to modify, we likewise need not resolve wheth-
`er compound 81 would have been a suitable lead com-
`pound. Accordingly, for our analysis below, we assume, as
`the Board did, that compound 31 was an appropriate lead
`compound.
`
`Obviousness is a question of law based on underlying
`factual findings. In re Baxter Int’l, Inc. 678 F.3d 1357,
`1361 (Fed. Cir. 2012).
`
`Appellants first argue that an ordinary artisan would
`have recognized the methoxyamino group in compound 31
`to be uncommon and to have potential synthetic and
`
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`stability problems. According to Appellants, a person of
`skill in the art would then have been motivated to modify
`compound 31 by replacing the amine of its methoxyamino
`group with a methylene link to yield a more stable, syn-
`thetically accessible, pharmaceutically common
`and
`acceptable moiety.
`
`In proposing this modification, Appellants rely on the
`principles of bioisosterism as
`recited in Silverman.
`Appellants submit that, of the “classical bioisosteres” in
`Silverman, only methylene would result in a more phar-
`maceutically common and acceptable compound and
`resolve the potential stability and synthesis concerns
`presented by the methoxyamino moiety. Appellants’ Br.
`23. Appellants maintain that Silverman would have
`motivated a person of skill in the art to replace thelamine
`in the methoxyamino group with a methylene link and
`have a reasonable expectation of success having done so.
`
`Appellants submit that their proposed modification
`was consistent with Kohn 1991, which detailed “‘stringent
`steric and electronic requirements that exist for maximal
`anticonvulsant activity in this class of compounds,’ includ-
`ing the size of the group on the a-carbon.” Id. at 24 (quot-
`ing Kohn 1991, J .A. 2407). According to Appellants, their
`proposed replacement retained a small moiety at the a-
`carbon, which would have satisfied steric rcquircmcnts
`and would have left the N-benzylamide moiety and acety-
`lated amino group unchanged. Appellants also argue
`that, consistent with Kohn 1991, their proposed modifica-
`tion retained a functionalized oxygen atom two atoms
`removed from the d-carbon atom, which Kohn 1991 dis-
`closed as associated with excellent potency.
`
`Appellants further contend that their proposed modi-
`fication to compound 31 would have been expected to have
`excellent potency. Specifically, Appellants point to Kohn
`1991’s teaching that a terminal methoxy group added to
`compound 3a resulted in compound 31, which was ten
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`Document: 91
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`15
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`times more potent than compound 3a. Before the Board,
`Appellants’ expert, Dr. Wang, testified that a person of
`skill in the art would have reasonably expected a similar
`ten-fold increase in activity from adding a terminal meth-
`oxy group to the methyl compound 2a, yielding a racemic
`mixture of lacosamide with a predicted EDso value of 7.6
`mg/kg. According to Dr. Wang, this EDso value would
`have been comparable or better than commercially avail-
`able reference compounds,
`including phenytoin, pheno-
`barbital, and valproate.
`
`Notably, Appellants’ predicted potency for “racemic
`lacosamide” was less impressive than that of compound
`31. Appellants address that fact by' stating that a person
`of skill in the art would have sacrificed some potency to
`achieve the superior stability of racemic lacosamide over
`compound 31. Appellants maintain that a person of skill
`in the art would have had reason to modify 31 to address
`stability, synthetic simplicity, and pharmaceutical famili-
`arity and acceptability, even if doing so would result in
`lower potency.
`
`As a final point, Appellants argue that a person of
`skill in the art would have had reason to isolate the R
`
`enantiomer from its “racemic lacosamide” mixture be-
`
`cause Kohn 1991 teaches that the “anticonvulsant activity
`resided primarily with the R stereoisomcr.” Appellants’
`Br. 32 (quoting Kohn 1991, J.A. 2404).
`
`RCT counters that, while the record supports the idea
`that N—O bonds generally can be labile, the record lacks
`evidence that the N—O bond in compound 31 specifically is
`labile and would have motivated modification. According
`to RCT, such an argument would have been contrary to
`the teaching of Kohn 1991, which remarked that its
`disclosed compounds, including 81, were stable. RCT also
`suggests that the record is devoid of evidence that the
`potential stability issues with the N—O bond would have
`outweighed other considerations,
`including potency and
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`Document: 91
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`Page: 16
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`Instead, RCT contends that the record
`neurotoxicity.
`supports that a person of skill in the art would consider
`all of a compound’s properties together, as the Board did
`in its analysis.
`
`RCT also argues that Appellants did not provide any
`evidence that “only methylene would result in a more
`pharmaceutically common and acceptable compound and
`'resolve the potential stability and synthesis concerns
`presented by the methoxyamino moiety.” Appellee’s Br.
`23. RCT submits that the EDso values for the methox-
`
`ymethyl compound, racemic lacosamide, would not have
`been known, and Dr. Wang’s prediction of an EDso was
`based only on impermissible hindsight. Similarly, Appel-
`lants’ position before the Board was that a person of skill
`in the art would replace the NH group with CH2, but RCT
`suggests that the FAA literature consistently showed that
`removing the amino in the a-carbon amino substituents
`reduced potency.
`
`We agree with RCT that the Board’s findings are sup-
`ported by substantial evidence. Even if a person of skill
`in the art would have been motivated to modify compound
`31, the record evidence suggests that compounds without a
`methoxyamino 0r nitrogen-containing group at
`the (:1-
`carbon had reduced activity. For example, compound 3a
`in Kohn 1991, with an amino group at the a-carbon,
`reported an ED50 of 65.1 mg/kg, whereas compound 2a,
`with a methyl group at that position, was less potent with
`an ED5o of 76.5 mg/kg. J .A. 2405. Likewise, compounds
`3a, 3b, and 30, with ED5o values of 65.1 mg/kg, 44.5
`mg/kg, and 42.4 mg/kg, each have a nitrogen-containing
`moiety at the a-carbon.
`Id. These compounds were more
`potent than their oxygen-containing analogs, compounds
`3r, 3s, and 3t, with ED50 values of 80.1 mg/kg, 98.3 mg/kg,
`and 62.0 mg/kg, respectively. Id.
`
`The evidence also suggests that replacing the meth-
`oxyamino in compound 31 would have yielded a different
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`Document: 91
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`conformation. Such a conformational change may have
`affected interaction with receptors and altered biological
`activity.
`J.A. 11113—14. Kohn 1991 itself explains that
`“stringent steric and electronic requirements exist for
`maximal anticonvulsant activity,” J.A. 2404, which would
`counsel against modifying compound 31 in a way that
`would change its conformation significantly.
`
`Appellants fault the Board for crediting the testimony
`of Dr. Roush, RCT’s
`expert,
`regarding the three-
`dimensional structures of compound 31 and racemic
`lacosamide. The Board, however, provided a sufficient
`rationale for relying on Dr. Roush’s testimony that the
`three-dimensional structures of compound 31 and racemic
`lacosamide would be “very different.” Decision, 2017 WL
`1096590, at *10. Specifically, the Board compared Dr.
`Roush’s testimony to that of Dr. Heathcock, who agreed
`that a molecule’s shape and potency may differ upon
`substitution of carbon for nitrogen.
`Id. at *10—11. The
`Board was well within its discretion to credit Dr. Roush’s
`
`testimony. See Yorkey v. Diab, 601 F.3d 1279, 1284 (Fed.
`Cir. 2010) (“[T]he Board was well within its discretion to
`give more credibility to [one expert’s]
`testimony over
`[another expert’s testimony] unless no reasonable trier of
`fact could have done $0.”).
`
`The Board also was entitled to rcjcct bioisosterism as
`a basis for a motivation to modify compound 31. While
`Silverman does disclose that that bioisosterism may be
`useful to attenuate toxicity in a lead compound, the record
`does not indicate why bioisosterism would have been used
`to modify compound 31 in particular, which already had a
`high potency and low toxicity, and why methylene was a
`natural isostere of methoxyamino.
`
`In light of the reductions in potency and the signifi-
`cant conformational changes that would have been ex-
`pected, the Board’s finding that a person of skill in the art
`would not have been motivated to modify the methoxy-
`
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`Document191
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`MYLAN PHARMACEUTICALS INC.‘V. RESEARCH CORPORATION
`TECHS., INC.
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`amino group in compound 31 was supported by substan-
`tial evidence.
`
`Because we agree with the Board that Appellants
`failed to establish a motivation to modify compound 31, we
`need not reach Appellants’ arguments regarding objective
`indicia. Likewise, because we find that Appellants did not
`meet their burden to show that claims 1—9 would have
`
`been obvious over Kohn 1991 and Silverman, we conclude
`that the Board did not err in concluding that Appellants
`failed to meet their obviousness burden regarding claims
`10—13, which depend therefrom. Dependent claims, with
`added limitations, are generally not obvious when their
`parent claims are not. W.L. Gore & Assocs., Inc. U. Gar-
`lock, Inc., 721 F.2d 1540, 1555 (Fed. Cir. 1983).
`
`Aside from these factual issues, Appellants challenge
`aspects of the Board’s legal analysis, contending that the
`Board improperly required them to prove that the pro-
`posed modification would increase or maintain potency
`and that the Board negated their proposed motivation
`argument without making a finding that the prior art
`taught away from the proposed modification. None of
`these arguments has merit. Appellants’ arguments are
`merely an attack on factual findings under the guise of a
`challenge to the Board’s legal analysis. As discussed
`above, the Board appropriately considered all the facts
`before making a final obviousness determination.
`
`Having considered the record below, we conclude that
`the Board’s obviousness conclusion was supported by
`substantial evidence.
`
`Finally, at oral argument, Appellants requested in the
`alternative that the court remand this case in light of
`SAS Institute, Inc. v. Iancu, 138 S. Ct. 1348 (2018). Oral
`Arg. at 27:05—27:17, http://Oralarguments.cafc.uscourts.go
`v/default.aspx?fl=2017-2088.mp3. We decline to do so.
`
`

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`Document: 91
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`Page: 19
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`Filed: 02/01/2019
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`We have held that a party’s request for SAS relief can
`be waived. PGS Geophysical AS v. Iancu, 891 F.3d 1354,
`1362—63 (Fed. Cir. 2018). In cases where a litigant lodges
`a prompt request for SAS-based relief, however, this court
`has found waiver inapplicable and remanded to the Board
`to consider noninstituted grounds. See, e.g., Adidas AG 1).
`Nike, Inc, 894 F.3d 1256, 1258 (Fed. Cir. 2018); Polaris
`Indus. Inc. 0. Arctic Cat, Inc., 724 F. App’x 948, 950 (Fed.
`Cir. 2018) (per curiam); South-Tek Sys., LLC v. Engi-
`neered Corrosion Sols, LLC, No