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`Paper No. ____
`Filed: May 24, 2017
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`Filed on behalf of Alembic Pharmaceuticals, Ltd.
`By:
`Jeffer Ali
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`Iain A. McIntyre
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`CARLSON, CASPERS, VANDENBURGH, LINDQUIST & SCHUMAN, P.A.
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`225 South Sixth St., Suite 4200
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`Minneapolis, MN 55402
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ARGENTUM PHARMACEUTICALS LLC, MYLAN PHARMACEUTICALS
`INC., BRECKENRIDGE PHARMACEUTICAL, INC., AND ALEMBIC
`PHARMACEUTICALS, LTD.,
`Petitioners,
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`v.
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`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
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`Case No. IPR2016-002041
`Patent No. RE38,551
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`PETITIONER ALEMBIC PHARMACEUTICALS, LTD.’S
`NOTICE OF APPEAL
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`1 Case IPR2016-01101, Case IPR2016-01242, and Case IPR2016-01245 have been
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`joined with this proceeding.
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`Case IPR2016-00204
`U.S. Patent No. RE38,551 E
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`Pursuant to 37 C.F.R. § 90.2(a) and 35 U.S.C. §§ 141(c), 142, and 319,
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`Alembic Pharmaceuticals, Ltd. (“Petitioner”) respectfully gives notice that it
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`appeals to the United States Court of Appeals for the Federal Circuit from the
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`Patent Trial and Appeal Board’s Final Written Decision entered on March 22, 2017
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`(Paper 85), and from all other underlying orders, decisions, rulings, and opinions.
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`For the limited purpose of providing the Director of the United States Patent
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`and Trademark Office with the information specified in 37 C.F.R. § 90.2(a)(3)(ii),
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`the issues on appeal include the Board’s determination that Petitioners did not
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`establish that claims 1-13 of U.S. Patent No. RE38,551 are unpatentable under 35
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`U.S.C. § 103 in view of the grounds of unpatentability on which trial was instituted
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`(Paper 19) or which were asserted in the petition. The issues on appeal also include
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`any finding or determination supporting or related to these issues, as well as all
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`other issues decided adversely to Petitioners in any order, decision, ruling, or
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`opinion.
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`Simultaneous with this filing and in accordance with 37 C.F.R. § 90.2(a)(1),
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`this Notice of Appeal is being filed with the Director and served on Patent Owner
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`in accordance with 37 C.F.R. § 42.6(e). This Notice of Appeal, along with the
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`required fees, is also being filed with the Clerk’s Office for the United States Court
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`of Appeals for the Federal Circuit in accordance with Fed. Cir. R. 15(a)(1).
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`Case IPR2016-00204
`U.S. Patent No. RE38,551 E
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`Respectfully submitted,
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`s/ Jeffer Ali /
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`Jeffer Ali, Lead Counsel
`Reg. No. 46,359
`CARLSON, CASPERS, VANDENBURGH,
`LINDQUIST & SCHUMAN, P.A.
`225 South Sixth Street, Suite 4200
`Minneapolis, MN 55402
`Tel: (612) 436-9600
`Fax: (612) 436-9605
`jali@carlsoncaspers.com
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`Attorney for Petitioner Alembic
`Pharmaceuticals, Ltd.
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`3
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`Dated: May 24, 2017
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`Case IPR2016-00204
`U.S. Patent No. RE38,551 E
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`CERTIFICATES OF FILING AND SERVICE
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`I hereby certify that the foregoing PETITIONER ALEMBIC
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`PHARMACEUTICALS, LTD.’S NOTICE OF APPEAL was filed by Priority Mail
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`Express® on this 24th day of May, 2017, with the Director of the United States
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`Patent and Trademark Office, at the following address:
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`Director of the U.S. Patent and Trademark Office
`c/o Office of the General Counsel
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
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`And with the Board, at the following address:
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`Mail Stop PATENT BOARD,
`Patent Trial and Appeal board,
`United States Patent and Trademark Office
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
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`and with the Board electronically through E2E.
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`-------------------------------------------------------------------------------------
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`I hereby certify that a true and correct copy of the foregoing PETITIONER
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`ALEMBIC PHARMACEUTICALS, LTD.’S NOTICE OF APPEAL was filed
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`electronically by CM/ECF, and by Priority Mail Express® on this 24th day of May,
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`2017, with the Clerk’s Office of the United States Court of Appeals for the Federal
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`Circuit.
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`------------------------------------------------------------------------------------
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`Case IPR2016-00204
`U.S. Patent No. RE38,551 E
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`Pursuant to 37 C.F.R. § 42.6(e), I certify that I caused to be served a true and
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`correct copy of the foregoing Notice of Appeal on the Patent Owner at the
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`correspondence address of the Patent Owner as follows:
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`Andrea G. Reister (areister@cov.com)
`Jennifer L. Robbins (jrobbins@cov.com)
`Enrique D. Longton (elongton@cov.com)
`COVINGTON & BURLING LLC
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`And to counsel for Petitioners as follows:
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`IPR2016-00204
`Matthew Dowd (mjdowd@dowdpllc.com)
`DOWD PLLC
`William G. Jenks (wjenks@jenksiplaw.com)
`JENKS IP LAW
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`
`IPR2016-01101
`Steven W. Parmelee (sparmelee@wsgr.com)
`Michael T. Rosato (mrosato@wsgr.com)
`Jad A. Mills (jmills@wsgr.com)
`WILSON SONSINI GOODRICH & ROSATI
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`IPR2016-01242
`Matthew L. Fedowitz (mfedowitz@merchantgould.com)
`Daniel R. Evan (devans@merchantgould.com)
`MERCHANT & GOULD P.C.
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`Dated: May 24, 2017
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`s/ Jeffer Ali /
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`Jeffer Ali, Lead Counsel
`Reg. No. 46,359
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`5
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`Trials@uspto.gov Paper No. 85
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`571-272-7822
` Date Entered: March 22, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`_______________
`
`ARGENTUM PHARMACEUTICALS LLC,
`MYLAN PHARMACEUTICALS INC.,
`BRECKENRIDGE PHARMACEUTICAL, INC., and
`ALEMBIC PHARMACEUTICALS, LTD.,
`Petitioner,
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`v.
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`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`_____________
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`Case IPR2016-002041
`Patent RE38,551 E
`______________
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`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, FRANCISCO C. PRATS, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
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`PRATS, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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`
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`1 Case IPR2016-01101, Case IPR2016-01242, and Case IPR2016-01245
`have been joined with this proceeding.
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`IPR2016-00204
`Patent RE38,551 E
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`I.
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`INTRODUCTION
`A. Statement of the Case
`Argentum Pharmaceuticals LLC (“Argentum”) 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.”).
`Upon review of those papers and cited information, we instituted trial
`as to claims 1–13 of the ’551 patent in relation to the following two grounds
`of unpatentability (Paper 19, 23–24 (“Decision to Institute,” or “Dec.”)):
`(1) Obviousness under 35 U.S.C. § 103(a) as to claims 1–9 over
`Kohn 19912 and Silverman3; and
`(2) Obviousness under 35 U.S.C. § 103(a) as to claims 10–13 over
`Kohn 1991, Silverman, and the ’729 patent.4
`After the Decision to Institute, Mylan Pharmaceuticals, Inc.
`(“Mylan”), Breckenridge Pharmaceutical, Inc. (“Breckenridge”), and
`Alembic Pharmaceuticals, Ltd. (“Alembic”), were each joined as petitioners
`to the instant proceeding. See Case IPR2016-01101, Paper 12; Case
`IPR2016-01242, Paper 11; Case IPR2016-01245, Paper 12. Therefore, in
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`
`2 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).
`3 Richard B. Silverman, The Organic Chemistry of Drug Design and Drug
`Action, Academic Press (1992) (“Silverman”) (Ex. 1013).
`4 Kohn et al., U.S. Patent No. 5,378,729, issued on Jan. 3, 1995 (“the ’729
`patent”) (Ex. 1009).
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`the instant inter partes review, Argentum, Mylan, Breckenridge, and
`Alembic are, collectively, the “Petitioner.”
`Patent Owner filed a Response to the Petition (Paper 35; “PO Resp.”),
`and Petitioner filed a Reply to the Patent Owner Response (Paper 52, “Pet.
`Reply”).
`Patent Owner filed a paper styled as “Patent Owner’s Identification of
`Petitioners’ Arguments and Evidence Outside the Scope of a Proper Reply
`and Improper Techniques that Circumvent Word Count.” Paper 57.5
`Petitioner filed a response to that paper. Paper 63.
`Both parties filed Motions to Exclude Evidence. Paper 72 (“Pet. Mot.
`to Exclude”) and Paper 71 (“PO Mot. to Exclude”).
`Each party filed an Opposition to the other party’s Motion to Exclude
`Evidence. Paper 78 (“Pet. Opp.”); Paper 73 (“PO Opp.”). Each party filed
`also a Reply to the other party’s Opposition to the Motion to Exclude
`Evidence. Paper 81 (“Pet. Reply Opp.”); Paper 80 (“PO Reply Opp.”).
`Patent Owner filed a Motion for Observations Regarding Cross-
`Examination as to each of Petitioner’s three reply witnesses. Papers 65, 68,
`and 69. Petitioner filed responses to each of those motions. Papers 75–77.
`An oral hearing was held on January 24, 2017, and the hearing
`transcript has been entered in the record. Paper 84 (“Tr.”).6
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`5 The panel authorized this submission, and its response, by email. Ex.
`2191.
`6 Patent Owner filed Objections to Petitioner’s Demonstratives. Paper 82.
`In this Decision, we rely only on the arguments presented properly in the
`parties’ briefs and the evidence of record. Our decision does not rely on any
`information presented solely in Petitioner’s demonstrative exhibits. We,
`therefore, overrule Patent Owner’s objections.
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`We have jurisdiction under 35 U.S.C. § 6(b). This Final Written
`Decision is entered pursuant to 35 U.S.C. § 318(a).
`“In an inter partes review instituted under this chapter, the petitioner
`shall have the burden of proving a proposition of unpatentability by a
`preponderance of the evidence.” 35 U.S.C. § 316(e).
`Based on the record developed in this proceeding, we conclude that
`Petitioner has not established by a preponderance of the evidence that claims
`1–9 of the ’551 patent are unpatentable for obviousness over Kohn 1991 and
`Silverman, nor has Petitioner established by a preponderance of the evidence
`that claims 10–13 of the ’551 patent are unpatentable for obviousness over
`Kohn 1991, Silverman, and the ’729 patent.
`Petitioner’s Motion to Exclude Evidence is denied-in-part and
`dismissed-in-part as moot. Patent Owner’s Motion to Exclude Evidence is
`denied-in-part and dismissed-in-part as moot.
`B. 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 identify as related 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; PO
`Resp. 18, n.6.
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`II. PRELIMINARY MATTER—SCOPE OF PETITIONER’S REPLY
`We address initially the parties’ contentions concerning the scope of
`Petitioner’s Reply. As noted above, we authorized by email separate
`briefing on this issue. Ex. 2191.
`As provided in 37 C.F.R. § 42.23(b), a “reply may only respond to
`arguments raised in the corresponding opposition or patent owner response.”
`Thus, “a reply that raises a new issue or belatedly presents evidence will not
`be considered and may be returned. The Board will not attempt to sort
`proper from improper portions of the reply.” Office Patent Trial Practice
`Guide, 77 Fed. Reg. 48,756, 48,767 (Aug. 14, 2012).
`One indication that a new issue has been raised in a reply is where a
`petitioner submits “new evidence necessary to make out a prima facie case”
`of unpatentability of an original claim. Id.; see also Intelligent Bio-Systems,
`Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1369–70 (Fed. Cir. 2016)
`(Board did not err or abuse its discretion in declining to consider new
`contentions and evidence in reply advanced to supplement unpatentability
`rationale presented in petition).
`A. Arguments and Evidence Relating to the LeGall Thesis (Ex. 1008)
`Having reviewed the parties’ contentions (Paper 57, 1; Paper 63, 1),
`and the arguments at issue (Pet. Reply 28–29), we conclude that Petitioner’s
`Reply exceeds the proper scope of a reply in relying on the LeGall Thesis,
`even as rebuttal. As Patent Owner notes, we concluded in our Decision to
`Institute that Petitioner failed to show that the LeGall Thesis constitutes
`prior art to the claims of the ’551 patent and, therefore, declined to institute
`trial as to grounds relying on the LeGall Thesis. Dec. 8–12.
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`In its Reply, Petitioner seeks to advance additional evidence to
`supplement its original contention that the LeGall Thesis constitutes prior
`art. See Pet. Reply 28–29. Because Petitioner, thus, effectively seeks in its
`Reply to advance additional evidence to supplement its original contentions
`of unpatentability based on the LeGall Thesis, we agree with Patent Owner
`that Petitioner’s Reply exceeds the proper scope of a reply. See Office
`Patent Trial Practice Guide, 77 Fed. Reg. at 48,767; Intelligent Bio-Systems,
`821 F.3d at 1369–70.
`Accordingly, our decision herein does not consider or rely on the
`arguments on pages 27–29 of the Reply regarding the LeGall Thesis, or the
`evidence advanced in support of those arguments. We note also that,
`although Petitioner contends that its supplemental evidence regarding the
`prior art status of the LeGall thesis was unavailable until June 23, 2016 (Pet.
`Reply 28), Petitioner does not advance persuasive evidence or argument
`supporting that contention.
`B. The ’301 Patent (Ex. 1019) as Support for Rationale to
` Select Compound 3l as Lead Compound
`Having reviewed the parties’ contentions (Paper 57, 1–2; Paper 63, 1),
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`we conclude that the citations to the ’301 patent7 in the Reply do not exceed
`the proper scope of a reply. The’301 patent is relied upon in the same
`manner as relied upon in the Petition in relation to the grounds for which
`trial was instituted (see, e.g., Pet. 46–47), and as rebuttal to Patent Owner’s
`arguments about the state of the art.
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`7 Kohn et al., U.S. Patent No. 5,654,301, issued on Aug. 5, 1997 (“the ’301
`patent”) (Ex. 1019).
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`C. Unmet Need Arguments Based on Levetiracetam (Keppra®)
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`Having reviewed the parties’ contentions (Paper 57, 2; Paper 63, 2),
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`we conclude that the arguments based on levetiracetam/Keppra in the Reply
`do not exceed the proper scope of a reply, as they are proper rebuttal to
`Patent Owner’s arguments regarding long-felt but unmet need.
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`D. Techniques Allegedly Circumventing Word Count
`
`Patent Owner contends that Petitioner’s Reply circumvents the word
`count limit set forth in 37 C.F.R. § 42.24(c)(1) by 195 words, through the
`use of 4 images and the omission of a space between “Ex.” and the exhibit
`number when citing to exhibits. Paper 57, 2. Patent Owner contends that
`140 of the 195 excess words may be accorded to the exhibit citation format
`used in the Reply. Id.
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`Petitioner responds that Patent Owner cites to no Board rule in its
`contentions regarding the exhibit citation format used in the Reply, and
`contends also that the exhibit citation format in the Reply conforms with the
`Federal Circuit rule for citing to appendices. Paper 63, 2. Petitioner
`contends further that Patent Owner’s Response includes over 100 instances
`in which a space was omitted between “¶” and the paragraph number cited.
`Id. As to the use of images, Petitioner contends that “the images do not add
`text to the brief but merely act as citations to portions of exhibits in the
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`record.” Id.
`When certifying word count, a party need not go beyond the routine
`word count supplied by their word processing program. Parties should be
`careful, however, not to abuse the process. Excessive words in figures,
`drawings or images, deleting spacing between words, or using excessive
`acronyms or abbreviations for word phrases, in order to circumvent the rules
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`on word count, may lead to expungement of a party’s brief. See Google,
`Inc., v. Ji-Lee, Case No. IPR2016-00022, Paper 25 (PTAB Nov. 23, 2016).
`In the present case, the alleged discrepancies in word count in
`Petitioner’s Reply are noted. Based on the record presented, we exercise our
`discretion to not decline to limit our consideration of the Reply on this basis.
`III. PATENTABILITY
`A. The ’551 Patent (Ex. 1001)
`The ’551 patent relates to “enantiomeric compounds and
`pharmaceutical compositions useful in the treatment of epilepsy and other
`CNS [central nervous system] disorders.” Ex. 1001, 1:21–23. The ’551
`patent discloses that, although many anticonvulsant drugs were well known
`at the time of the invention, a significant number of those drugs exhibited
`liver toxicity when administered chronically. Id. at 1:45–3:6.
`Seeking to address the shortcomings of prior art anticonvulsant
`agents, 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. The disclosed compounds are derivatives
`of the amino acid serine. See id. at 5:20–8:61 (describing synthetic schemes
`using D-serine as a starting material).
`One of those serine derivatives is (R)-N-benzyl-2-acetamide-3-
`methoxypropionamide, also referred to in the ’551 patent as “BAMP.” Id. at
`11:21–13:14 (Examples 1 and 2), 24:56–58.
`(R)-N-benzyl-2-acetamide-3-methoxypropionamide is also known as
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`“lacosamide.” See Pet. 6; PO Resp. 6.
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`Claim 1 of the ’551 patent, the sole independent claim under review,
`reads as follows:
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`1. A compound in the R configuration having the formula:
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`wherein Ar is phenyl which is unsubstituted or substituted
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`with at least one halo group;
`Q is lower alkoxy, and
`Q1 is methyl.
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`Id. at 38:8–23. Claims 2–9 are compound claims that depend directly or
`indirectly from claim 1. Id. at 38:24–40.
`Claim 8 of the ’551 patent is specifically directed to lacosamide, and
`recites “[t]he compound according to claim 1 which is (R)-N-benzyl 2-
`acetamide-3-methoxypropionamide.” Id. at 38:37–38.
`Claim 10 of the ’551 patent recites “[a] therapeutic composition
`comprising an anticonvulsant effective amount of a compound according to
`any one of claims 1–9 and a pharmaceutical carrier therefor.” Id. at 38:41–
`43.
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`Claims 11–13 are directed to therapeutic methods. Id. at 38:44–51.
`Claim 11 recites “[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.” Id. at 38:44–47.
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`Claim 12 recites “[t]he method according to claim 11 wherein the
`animal is a mammal,” and claim 13 recites “[t]he method according to claim
`12 wherein the mammal is a human.” Id. at 38:48–51.
`B. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are given
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`their broadest reasonable construction in light of the specification of the
`patent in which they appear. 37 C.F.R. § 42.100(b); Cuozzo Speed Techs.,
`LLC v. Lee, 136 S. Ct. 2131, 2142 (2016) (affirming applicability of
`broadest reasonable construction standard to inter partes review
`proceedings). Under that standard, claim terms are generally given their
`ordinary and customary meaning, as understood by one of ordinary skill in
`the art in the context of the entire disclosure. In re Translogic Tech., Inc.,
`504 F.3d 1249, 1257 (Fed. Cir. 2007).
`In our Decision to Institute, based on the parties’ initial submissions,
`we set out preliminary constructions for the terms “compound in the R
`configuration” in claim 1, and “therapeutic composition” in claim 10. Dec.
`5–8. As evidenced by the discussion below, however, the construction of
`neither of those terms, nor any other claim term, is critical to our final
`disposition of the issues developed during trial. Accordingly, we conclude
`that, for the purposes of this decision, no claim term requires express
`construction. See Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
`803 (Fed. Cir. 1999) (only those claim terms in controversy need to be
`construed, and only to the extent necessary to resolve the controversy).
`C. Obviousness—Claims 1–9
`Petitioner contends that the compounds recited in claims 1–9 would
`have been obvious over Kohn 1991 and Silverman, and relies on a
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`declaration by Dr. Binghe Wang (Ex. 1002 (“Wang Decl.”)), in support of
`that contention. Pet. 44–48.
`Patent Owner contends to the contrary, and in support of its
`contentions relies on declarations by William R. Roush, Ph.D. (Ex. 2036
`(“Roush Decl.”)), Carl W. Bazil, M.D., Ph.D. (Ex. 2038 (“Bazil Decl.”)),
`and Christopher A. Vellturo, Ph.D. (Ex. 2132 (“Vellturo Decl.)). PO Resp.
`1–45, 51–61.
`In its Reply to Patent Owner’s Response, Petitioner relies on a second
`declaration by Dr. Binghe Wang (Ex. 1084 (“Wang Reply Decl.”)), as well
`as declarations by DeForest McDuff, Ph.D. (Ex. 1086 (“McDuff Decl.”)),
`and Kathryn A. Davis M.D., MSTR (Ex. 1087 (“Davis Decl.”)). Pet. Reply
`1–14, 16–28.
` As the Supreme Court has stated, when evaluating claims for
`obviousness, “the scope and content of the prior art are to be determined;
`differences between the prior art and the claims at issue are to be
`ascertained; and the level of ordinary skill in the pertinent art resolved.”
`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (quoting Graham v.
`John Deere Co., 383 U.S. 1, 17–18 (1966)). Secondary considerations, if
`present, also must be considered. Id.
`
`1. Level of Ordinary Skill in the Art
`Petitioner contends that the relevant art is medicinal chemistry. Pet
`12. As to the level of ordinary skill in that art as of March 15, 1996 (the
`earliest possible priority date of the ’551 patent), Petitioner contends as
`follows:
`[A] POSA [person of ordinary skill in the art] would have a Ph.D.
`in organic or medicinal chemistry and at least a few years of
`experience in medicinal chemistry, including in the development
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`of potential drug candidates. Ex. 1002, ¶ 13 [Wang Decl.]. The
`POSA would also include a person having a Bachelor’s or
`Master’s degree (organic chemistry or medicinal chemistry) if
`such a person had more years of experience in medicinal
`chemistry and the development of potential drug candidates. Id.
`With experience in drug development, the POSA would have an
`appreciation of the diseases and ailments a particular drug
`candidate is intended to treat, but would not necessarily be a
`medical doctor or clinician. The POSA would know how to
`evaluate the physical and biological properties of chemical
`compounds and would be able to conduct, or otherwise have
`access to resources that could conduct, in vitro and in vivo
`evaluations of biological and toxicity properties of chemical
`compounds. Id.
`
`
`Pet. 12. Patent Owner does not controvert Petitioner’s characterization of
`the relevant art, or the level of ordinary skill in that art, nor does Patent
`Owner advance a specific assertion of its own as to the level of ordinary
`skill. See, generally, PO Resp.
`Accordingly, when evaluating the parties’ contentions regarding the
`scope and content of the prior art, and the differences between the prior art
`and the challenged claims, we take into consideration Petitioner’s assertions
`regarding the level of ordinary skill. We also consider that the cited
`references provide evidence as to the level of ordinary skill in the art. See
`Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001).
`2. Kohn 1991 (Ex. 1012)
`Kohn 1991, a publication coauthored by Harold Kohn, the sole
`inventor of the ’551 patent, discloses that previous prior art studies had
`“reported the excellent anticonvulsant activity of certain functionalized
`amino acid derivatives [FAAs].” Ex. 1012, 2444. In the study disclosed in
`Kohn 1991, the authors present the “synthesis and anticonvulsant properties
`
`
`
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`of a novel series of α-heteroatom-substituted amino acid derivatives (26
`examples).” Id.
`Kohn 1991 sets out the following general formula for the FAAs it
`tested (id. at 2445 (Table 1)):
`
`
`Kohn 1991 explains that the moiety at the “X” position is termed “the
`α-substituent.” Id. at 2444.
`Table 1 of Kohn 1991 lists the moiety substituted at the “X” position
`for each of the 26 compounds studied, numbered “3a” through “3z.” Id. at
`2445. The compounds were evaluated for anticonvulsant activity in mice
`using the maximal electroshock seizure test (MES), and a median effective
`dose (ED50) for that test was determined for each compound. Id. at 2444–
`45. As in our Decision to Institute, we note that the lower the MES ED50,
`the more potent the compound. See Dec. 13, n.8.
`Table 1 also discloses the MES ED50 for several compounds
`previously tested and synthesized by the same group of investigators
`(compounds 2a through 2d), as well as several known antiepileptic drugs
`(AEDs), including phenytoin, phenobarbital, and valproate. Ex. 1012, 2445.
`Kohn 1991 discloses that the “most active compounds were (R,S)-2-
`acetamido-N-benzyl-2-(methoxyamino)acetamide (3l) and (R,S)-2-
`acetamido-N-benzyl-2-(methoxymethylamino)acetamide (3n). After ip
`[intraperitoneal] administration, the MES ED values for 3l (6.2 mg/kg) and
`3n (6.7 mg/kg) compared favorably with phenytoin (9.50 mg/kg).” Ex.
`1012, 2444 (abstract).
`
`
`
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`
`Kohn 1991 concludes:
`The pharmacological data obtained in this investigation provided
`additional information concerning the structure activity profile
`of functionalized amino acid anticonvulsants. The biological
`activities for 3 reinforced our notions that stringent steric and
`electronic requirements exist for maximal anticonvulsant activity
`in this class of compounds. The potencies of 3l and 3n in the
`MES test were comparable to those of phenytoin and 2d.
`Additional studies in progress are aimed at investigating the
`generality of this class of compounds, as well as their mode of
`action.
`
`Id. at 2447.
`
`3. 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, title page; see also id. at 4. 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.
`
`Id. at 19 (citations omitted). Table 2.2 on the same page of Silverman
`presents “Classical Isosteres,” including:
`
`Id.
`
`
`
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`
`4. Analysis—Lead Compound Inquiry
`Petitioner presents a summary of its initial obviousness contentions in
`the following diagram:
`
`
`
`Pet. 44.
`Petitioner contends that an ordinary artisan would have selected
`compound 3l from Kohn 1991 as a lead compound, based on its potency. Id.
`As seen in its diagram, Petitioner contends that, having selected compound
`3l as a lead, the ordinary artisan then would have used the technique of
`bioisosterism taught in Silverman and replaced the -NH- group of the
`methoxyamino substituent with a -CH2- group, thereby yielding the
`methoxymethyl substituent seen in the lacosamide molecule, and producing
`a racemic mixture of lacosamide. Id. at 45.
`Petitioner contends that, from the resulting racemic mixture of
`lacosamide, an ordinary artisan would have had good reason, based at least
`on Kohn 1991 itself, to isolate the R-isomer of lacosamide. Id. at 47.
`Although Petitioner does not state so expressly, based on the above
`contentions, we understand Petitioner as contending that each of claims 1–9
`encompasses R-lacosamide.8
`
`8 Patent Owner infers that claim 6 does not cover lacosamide. See PO Resp.
`23, n.9 (contending Petitioner’s showing is insufficient as to claim 6); see
`
`
`
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`
`As explained by our reviewing court, “[t]o establish obviousness in
`cases involving new chemical compounds, [the proponent of the
`compounds’ obviousness] must identify some reason that would have led a
`chemist to modify a known compound.” Bristol-Myers Squibb Co. v. Teva
`Pharmaceuticals USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014).
`“Generally, an obviousness inquiry concerning such ‘known
`compounds’ focuses on the identity of a ‘lead compound.’” Id. (quoting
`Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353, 1359 (Fed. Cir.
`2008)). “A lead compound is a compound in the prior art that would be ‘a
`natural choice for further development efforts.’” Id. (quoting Altana
`Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir.
`2009). “The motivation to modify that lead compound can come from any
`number of sources and need not necessarily be explicit in the art.” Id.
`Consistent with the flexible principles of obviousness enunciated in
`KSR v. Teleflex, to demonstrate that a claimed compound would have been
`obvious, “a showing that the prior art would have suggested making the
`specific molecular modifications necessary to achieve the claimed invention
`[i]s also required.” Takeda Chemical Industries, Ltd. v. Alphapharm Pty.,
`
`
`also id. at 51, n.15 (not including claim 6 among claims asserted as covering
`lacosamide). We conclude, however, that claim 6 covers lacosamide.
`Claim 1, from which claim 6 depends, recites as to the relevant moiety
`that “Ar is phenyl which is unsubstituted or substituted with at least one halo
`group.” Ex. 1001, 38:19–20. Claim 6 recites, in its entirety, “[t]he
`compound according to claim 1 wherein halo is fluoro.” Id. at 38:32–33.
`Thus, claim 6 does not limit the “Ar” moiety of claim 1 to a substituted
`moiety, and, therefore, encompasses a compound having the unsubstituted
`phenyl group of lacosamide.
`
`
`
`
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`Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007) (internal quotations omitted,
`emphasis added).
`In the present case, even assuming arguendo that an ordinary artisan
`would have selected compound 3l of Kohn 1991 as a lead compound for
`further development, Petitioner does not persuade us that the prior art of
`record would have suggested making the specific modification to compound
`3l required to yield lacosamide.
`Petitioner identifies two reasons for modifying the methoxyamino
`moiety of compound 3l: “First, the methoxyamino moiety is not a common
`moiety used in the compounds the result in commercial pharmaceuticals.
`Ex. 1002, ¶ 106 [Wang Decl.]. Second, the methoxyamino moiety may
`present synthetic and stability issues.” Pet. 45 (citing Ex. 1002 ¶ 106).
`As to the specific modification to the methoxyamino group of
`compound 3l required to arrive at lacosamide, Petitioner contends that
`bioisosteric replacement of the -NH- group of compound 3l’s methoxyamino
`substituent with a -CH2- group converts the methoxyamino substituent into
`a methoxymethyl group, which “is a more common and acceptable moiety
`for pharmaceu
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