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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`v.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
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`______________________
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`CORRECTED CONTINGENT MOTION TO AMEND
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
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`with this proceeding.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`TABLE OF CONTENTS
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`Page
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`PRELIMINARY STATEMENT ..................................................................... 1
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`I.
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`II.
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`FACTS ............................................................................................................. 4
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`A.
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`B.
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`C.
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`D.
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`Proposed Amendments to Claims 1, 3 and 5 ........................................ 5
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`Disclosure of GB 0612721.1, Filed June 27, 2006 ............................... 6
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`Claims of the ’405 Patent ...................................................................... 8
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`The Instituted Grounds .......................................................................... 9
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`E.
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`The Federal Circuit Reverses the Burden of Persuasion: Aqua
`Products, Inc. ........................................................................................ 9
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`III. ARGUMENT ................................................................................................... 9
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`A.
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`B.
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`C.
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`D.
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`The Contingent Nature of the Motion ................................................... 9
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`The Proposed Substitute Claims Are Supported in the
`Application(s) ...................................................................................... 10
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`Proposed Amendments Do Not Enlarge the Scope of the Claims ...... 12
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`Proposed Amendments Respond to Petitioners’ Grounds .................. 13
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`1.
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`2.
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`3.
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`The Proposed Amendments Respond to Ground 1 ................... 14
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`The Proposed Amendments Respond to Ground 2 ................... 16
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`The Proposed Amendments Respond to Ground 3 ................... 17
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`IV. CONCLUSION .............................................................................................. 18
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`APPENDIX A: CLAIM LISTING PURSUANT TO 37 C.F.R. §42.121(B)
`PROPOSED SUBSTITUTE CLAIMS .......................................................... 19
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`CERTIFICATE OF COMPLIANCE ....................................................................... 26
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`CERTIFICATE OF SERVICE ................................................................................ 27
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`U.S. Patent No. 9,187,405
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`TABLE OF AUTHORITIES
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`Page(s)
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`Cases
`Aqua Products, Inc. v. Matal,
`872 F.3d 1290 (Fed. Cir. 2017) .................................................................. 1, 9, 13
`Corning Optical Communications RF, LLC v PPC Broadband, Inc.,
`Case No. IPR2014-00441 (P.T.A.B. Oct. 30, 2014) .......................................... 10
`In re Crish,
`393 F.3d 1253 (Fed. Cir. 2004) .......................................................................... 12
`Ex Parte Davis & Tuukkanen,
`80 U.S.P.Q. 448 (Bd. App. 1948) ....................................................................... 12
`In re Gray,
`53 F.2d 520 (C.C.P.A. 1931) .............................................................................. 12
`Mannesmann Demag Corp. v. Engineered Metal Prod. Co.,
`793 F.2d 1279 (Fed. Cir. 1986) .......................................................................... 12
`Statutes
`35 U.S.C. § 102 ........................................................................................................ 17
`35 U.S.C. § 112 ........................................................................................ 9, 11, 17, 18
`35 U.S.C. § 311(b) ................................................................................................... 17
`Regulations
`37 C.F.R. § 42.121 ........................................................................................... 1, 4, 10
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`I.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`PRELIMINARY STATEMENT
`This Corrected Contingent Motion to Amend replaces the Contingent Motion
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`to Amend filed on November 13, 2017. If any one of the original claims in U.S.
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`Patent No. 9,187,405 is deemed unpatentable by the Board, Patent Owner Novartis
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`AG moves the Board to take up this contingent motion and consider the respective
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`substitute claim(s) presented here in its stead. Novartis proposes substitute claims
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`that all include the same amendment: removing the negative limitation “absent an
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`immediately preceding loading dose regimen” and adding the phrase “consisting of”
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`along with some other language adjustments, to limit the dosage regimen to 0.5 mg
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`daily of fingolimod.
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`The burden of persuading the Board that the amended claims are unpatentable
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`rests with the Petitioner. On October 4, 2017, the Federal Circuit held that: “(1) the
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`PTO has not adopted a rule placing the burden of persuasion with respect to the
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`patentability of amended claims on the patent owner that is entitled to deference; and
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`(2) in the absence of anything that might be entitled deference, the PTO may not
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`place that burden on the patentee.” Aqua Products, Inc. v. Matal, 872 F.3d 1290,
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`1327 (Fed. Cir. 2017). Accordingly, Novartis sets out in Appendix A the
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`amendments proposed, and the support for those amendments in the original
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`application, which is identical to the application giving rise to the ’405 patent.
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`Novartis also explains below how the amendments do not enlarge the scope of the
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`original claims under 37 C.F.R. §42.121, and how these proposed amendments
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`U.S. Patent No. 9,187,405
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`respond to the instituted grounds. Novartis therefore meets its burden of production.
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`Novartis does not take on the burden of showing patentability in this paper, instead
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`holding any rebuttal argument until reply since the burden of persuasion of
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`unpatentability is now on the Petitioners as per Aqua Products, Inc.
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`The proposed amendments use the transitional phrase “consisting of” to limit
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`the dosing regimen of fingolimod to 0.5 mg daily. This amendment does not enlarge
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`the scope of the claims because “consisting of” is a closed transitional phrase
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`modifying the wherein clause of the claims. It not only excludes any fingolimod
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`loading dose, but it also excludes a fingolimod up-titration — i.e., starting at a very
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`low fingolimod dose and slowly increasing it until 0.5 mg is reached. Therefore, the
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`scope of the amended claims is not enlarged.
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`The proposed amendments are supported by the specification. Appendix A
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`sets out the support in the specification for the amendments and the claimed
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`invention. In particular, the amended claims are supported by the “Clinical Trial”
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`example reciting a daily dosage of 0.5 mg fingolimod as one embodiment. A person
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`of skill in the art would understand that this example means that 0.5 mg fingolimod
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`is administered daily with no other aspect of the dosing regimen. Therefore, the
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`proposed amended claims are fully supported in the application as filed.
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`The proposed amended claims are responsive to instituted Grounds 1, 2, and
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`3. Ground 1 relies on the Kovarik reference, a patent application directed to loading
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`dose regimens for various S1P modulators to treat a wide variety of conditions. The
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`addition of the closed language “consisting of” to the claims limits the administration
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`to a daily dose of 0.5 mg fingolimod, which excludes a loading dose. This addresses
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`the alleged obviousness raised in Ground 1 since the key teaching of Kovarik is a
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`loading dose. There is no dosing regimen disclosed in Kovarik without a loading
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`dose. A person of skill in the art would understand that a dosing regimen “consisting
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`of” a daily dose of 0.5 mg fingolimod would exclude a loading dose.
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` Ground 2 is based on three references: Kappos 2005, Budde, and Chiba. The
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`discrete dosing regimen required in the proposed amended claims would not have
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`been obvious given the teaching of Kappos 2005 to use a 1.25 mg dose, the lack of
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`multi-dosing in Budde with no MS patient data, and the mere disclosure of a very
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`broad range of fingolimod tied to no dosing regimen whatsoever in Chiba. This
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`combination of references would not have made obvious the amended claims to a
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`person of ordinary skill in the art.
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`The deletion of the negative limitation “absent an immediately preceding
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`loading dose regimen” addresses the written description allegation raised in Ground
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`3. Petitioners assert that the phrase is not adequately supported in the specification.
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`Although Novartis asserts the above phrase is fully supported by the specification,
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`and a person of ordinary skill in the art would understand that the inventors had
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`possession of the invention, the amended claims remove that phrase and thus address
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`this argument.
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`Testimony from two experts — Dr. Larry Steinman, a clinical researcher and
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`MS specialist, and Dr. William J. Jusko, a pharmacologist with expertise in
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`immunosuppressants — shows that the specification fully supports the proposed
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`amended claims. Both experts testify that the specification demonstrates to one of
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`skill that the inventors had possession of the invention as claimed.
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`For these and other reasons below, if one or more of the original claims are
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`deemed invalid by the Board, the Board should grant this motion on a claim-by-
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`claim basis, substituting one or more of the proposed, amended, substitute claims
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`presented, and allow such claims to issue.
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`II.
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`FACTS
`This motion is timely and proper. Pursuant to 37 C.F.R. §42.121(a), Novartis
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`conferred with the Board and Petitioners on August 25, 2017 and the Board
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`subsequently authorized this motion in an order at Paper 21, dated August 30, 2017.
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`On October 6, 2017, the Board issued an updated Scheduling Order (Paper 25) that
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`extended the full schedule by one month in view of the Federal Circuit’s Aqua
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`Products, Inc. opinion on October 4, 2017.
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`U.S. Patent No. 9,187,405
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`A.
`Proposed Amendments to Claims 1, 3 and 5
`Six claims issued in the ’405 patent on November 17, 2015. Proposed
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`substitute claims for each of claims 1-6 are submitted in the claim listing attached as
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`Appendix A. The Appendix lists the proposed amendments for each substitute
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`claim, as well as the claim for which each proposed claim should be substituted if
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`the original claim is found unpatentable by the Board.
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`An exemplary claim is set out below. Proposed substitute claim 7, to replace
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`original claim 1 if found unpatentable by the Board, recites:
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`Proposed Claim 7. A method for reducing or preventing or
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`alleviating relapses in Relapsing-Remitting multiple sclerosis in a
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`subject in need thereof, comprising orally administering to said subject
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`2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol, in free form or in
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`a pharmaceutically acceptable salt form,
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`wherein the subject receives a dosing regimen consisting of a
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`daily
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`dosage
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`amount
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`of
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`0.5 mg
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`of
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`2-amino-2-[2-(4-
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`octylphenyl)ethyl]propane-1,3-diol.
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`The substitute claim deletes the negative limitation “absent an immediately
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`preceding loading dose regimen.” The substitute claim also limits the dosage
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`regimen to a daily dosage amount of 0.5 mg of fingolimod by using the transitional
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`phrase “consisting of.” The dosing regimen is therefore a daily dose of 0.5 mg of
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`5
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`fingolimod, excluding for example, a fingolimod loading dose or a fingolimod up-
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`U.S. Patent No. 9,187,405
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`titration dosing regimen.
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`B. Disclosure of GB 0612721.1, Filed June 27, 2006
`The ’405 patent claims priority to a British application filed on June 27, 2006,
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`No. 0612721.1. A certified copy of this British application was filed with the
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`USPTO and can be found in Exhibit 1009 at 146-166. This original British
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`application has the same content as the specification of the ’405 patent.
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`The ’405 patent was filed as U.S. Serial No. 14/257,342, which is a divisional
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`of U.S. Serial No. 13/149,468, which is a continuation of U.S. Serial No. 12/303,765
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`filed as PCT/EP2007/005597, claiming priority to GB Application No. 0612721.1,
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`filed on June 27, 2006. Each of the above-listed applications has the same content
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`as the original British application. None of the above applications add subject matter
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`to the application filed as the British application. The disclosure of the ’405 patent
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`specification, therefore, is the same as the original British application.2
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`2 Since the disclosures of the original British application and the ’405 patent are
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`the same, for ease of reference, Novartis cites to the ’405 patent specification in
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`column and line format in this paper. Citations to the British application are
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`found in Appendix A.
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`The application describes the inventors’ discovery “that S1P receptor
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`modulators have an inhibitory effect on neo-angiogenesis associated with
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`demyelinating diseases, e.g., MS.” (Ex. 1001 at 9:13-15.) As the specification
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`explains, fingolimod or FTY720 is an “S1P receptor modulator.” (Id. at 10:22-24).
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`The specification further explains the EAE animal experiments illustrating the
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`discovery. The inventors, Hiestand and Schnell, treated some EAE rats with
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`fingolimod, while others received nothing. Hiestand and Schnell observed clinical
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`scores of treated and untreated animals. After 26 days, the untreated rats reached a
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`relapse phase. The inventors then euthanized the rats and used special polymers to
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`create negative-space casts of the rats’ vasculature. The inventors analyzed the casts
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`“using micro computer tomography,” and compared the results of the treated and
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`untreated rats. (Id. at 10:33-11:2.)
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`The inventors’ analysis showed that fingolimod—“Compound A” in the
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`specification—“significantly blocks disease-associated neo-angiogenesis when
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`administered to the animals at a dose of from 0.1 to 20 mg/kg p.o.”—i.e., orally—
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`which in turn “completely inhibits the relapse phases[.]” Moreover, Hiestand and
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`Schnell discovered that this effect could be achieved at infrequent dosing—“0.3
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`mg/kg every 2nd or 3rd day or once a week.” (Id.)
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`Based on these EAE animal studies, the specification explains how different
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`doses of S1P modulators could be useful in humans, ranging from 0.1 to 50 mg daily.
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`For oral administration, the specification identifies suitable doses from 0.1 mg to 30
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`mg daily, and fingolimod in particular “may alternatively be administered
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`intermittently, e.g. at a dose of 0.5 to 30 mg every other day or once a week.” Finally,
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`the specification explains how fingolimod can be administered with other anti-
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`angiogenic drugs as well, so-called “VEG-F receptor antagonists.” (Id. at 11:20-
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`42.)
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`The application discloses a “Clinical Trial” example where human subjects
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`with relapsing multiple sclerosis are administered fingolimod in either 0.5 mg daily
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`doses, 1.25 mg daily doses or 2.5 mg daily doses. The specification says: “20
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`patients with relapsing-remitting MS receive said compound at a daily dosage of 0.5,
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`1.25 or 2.5 mg p.o.” (Id. at 11:5-10.)
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`C. Claims of the ’405 Patent
`The USPTO allowed the present claims of the ’405 patent on November 17,
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`2015. (Ex. 1001, cover page.) There are three pairs of independent and dependent
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`claims. All require a 0.5 mg fingolimod daily dose (in free diol or salt form) as
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`RRMS therapy for a “subject in need,” absent an immediately preceding loading
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`dose regimen. The claims differ only in that claims 1 and 2 are for a subject in need
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`of “reducing or preventing or alleviating relapses” (id. at 12:49-58); claims 3 and 4
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`are for a subject in need of “treating” the disease (id. at 12:59-67); and claims 5 and
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`6 are for a subject in need of “slowing [its] progression” (id. at 13:1-9).
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`U.S. Patent No. 9,187,405
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`D. The Instituted Grounds
`The Board instituted three Grounds in this IPR: Ground 1 is based on the
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`combination of Kovarik (Ex. 1004) and Thomson (Ex. 1005) alleging obviousness;
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`Ground 2 is based on Budde (Ex. 1008), Kappos 2005 (Ex. 1007) and Chiba (Ex.
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`1006) alleging obviousness, and Ground 3 is based on Kappos 2010 (Ex. 1038)
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`alleging anticipation predicated upon a lack of written description under 35 U.S.C.
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`§ 112.
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`E.
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`The Federal Circuit Reverses the Burden of Persuasion: Aqua
`Products, Inc.
`On October 4, 2017, the Federal Circuit issued a decision in Aqua Products,
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`Inc. v. Matal, 872 F.3d 1290 (Fed. Cir. 2017) that overruled the prior law and
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`established that the burden of persuasion with respect to the patentability of amended
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`claims rests on the Petitioner. The Federal Circuit held that “(1) the PTO has not
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`adopted a rule placing the burden of persuasion with respect to the patentability of
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`amended claims on the patent owner that is entitled to deference; and (2) in the
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`absence of anything that might be entitled deference, the PTO may not place that
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`burden on the patentee.” Id. at 1327.
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`III. ARGUMENT
`A. The Contingent Nature of the Motion
`Novartis moves the Board to take up the proposed amended claims if any one
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`of the original six claims issued in the ’405 patent is finally determined by the Board
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`to be unpatentable. Novartis is not surrendering its original claims, and if they all
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`are found to be patentable, than this motion need not be considered. However, on a
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`claim-by-claim basis, Novartis requests the Board decide this motion for each
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`particular original claim that is found unpatentable. The Board has held “[t]he
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`request
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`to substitute claims
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`is always contingent.”
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` Corning Optical
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`Communications RF, LLC v PPC Broadband, Inc., Case No. IPR2014-00441, at 3
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`(P.T.A.B. Oct. 30, 2014).
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`B.
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`The Proposed Substitute Claims Are Supported in the
`Application(s)
`Pursuant to 37 C.F.R. § 42.121 (a)(3), Novartis proposes a reasonable number
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`of substitute claims. The presumption is that only one substitute claim would be
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`needed to replace each challenged claim. Here, Novartis proposes exactly that, in
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`line with the presumption. Novartis proposes one substitute claim for each original
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`claim.
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`Attached in Appendix A is a claim listing that shows the changes proposed
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`for each claim to be amended, and the support in the ’405 patent specification. The
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`’405 patent arises from a series of continuation applications, where no new matter
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`was added to the originally filed application. Therefore, the support shown in
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`Appendix A for the claims in the patent specification and for the claims in the
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`priority document, GB 0612721.1, filed June 27, 2006.
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`At 11:5-16 the patent states “20 patients with relapsing-remitting MS receive
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`said compound at a daily dosage of 0.5, 1.25 or 2.5 mg p.o.” This shows 0.5 mg is
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`a specific daily dosage regimen contemplated. As explained by Drs. Jusko and
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`Steinman, a person of ordinary skill in the art reading the specification would
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`understand that a disclosure of a dosing regimen consisting of a dosage amount of
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`0.5 mg daily of fingolimod is meant to exclude a loading dose, or an up-titration
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`dose, or any other variation other than a dosage amount of 0.5 mg daily. Exactly
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`this dosing regimen is exemplified in the Clinical Trial example in the patent. This
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`is sufficient to meet 35 U.S.C. §112. (Steinman Dec., Ex. 2022 ¶¶ 188-189; Jusko
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`Dec., Ex. 2024 ¶¶ 171-176.)
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`In particular, the patent reports results from experiments using EAE mice (a
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`rodent model of human multiple sclerosis) testing doses of fingolimod that were
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`more than half again lower than any dose shown to have clinical benefit. The
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`inventors observed “full blockage of disease-associated angiogenesis” surrounding
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`the spinal column in EAE mice receiving fingolimod, even at doses as low as 0.3
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`mg/kg once a week, which is 0.042 mg/kg daily. These mice showed complete
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`inhibition of the relapse phase of the disease. (Ex. 1001 at 10:33-11:2.)
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`The Clinical Trial example in the specification recites “20 patients with
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`relapsing-remitting MS receive said compound at a daily dosage of 0.5, 1.25 or 2.5
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`mg p.o.” This example recites the exact dosing regimen in the proposed amended
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`11
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`claims (and original claims), i.e., 0.5 mg daily of fingolimod. The specification
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`does not call for a loading dose anywhere at all. A person of skill in the art would
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`understand that no other aspect of a dosing regimen is intended when a “daily dosage
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`of 0.5” mg is recited. This regimen would be understood to be a complete
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`instruction. (Steinman Dec., Ex. 2022 ¶¶ 182-187; Jusko Dec., Ex. 2024 ¶ 174.)
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`Thus, the proposed amendments are fully supported by the patent
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`specification and the British priority application and all intervening applications,
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`since they all have the same content. No new matter is added.
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`C.
`Proposed Amendments Do Not Enlarge the Scope of the Claims
`The amendments proposed are to each of the three independent claims. The
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`claims do not enlarge the scope of the original claims as shown by the inclusion of
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`the limiting transitional phrase “consisting of.”
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`The transitional phrase “consisting of” excludes any element, step, or
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`ingredient not specified in the claim. In re Gray, 53 F.2d 520, 521 (C.C.P.A. 1931);
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`Ex Parte Davis & Tuukkanen, 80 U.S.P.Q. 448 (Bd. App. 1948) (“consisting of”
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`defined as “closing the claim to the inclusion of materials other than those recited
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`except for impurities ordinarily associated therewith”).
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`When the phrase “consisting of” appears in a clause of the body of a claim,
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`rather than immediately following the preamble, it limits only the element set forth
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`in that clause; other elements are not excluded from the claim as a whole.
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`Mannesmann Demag Corp. v. Engineered Metal Prod. Co., 793 F.2d 1279, 1282
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`(Fed. Cir. 1986); In re Crish, 393 F.3d 1253, 1257 (Fed. Cir. 2004). The dosing
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`regimen is set to “wherein the subject receives a dosing regimen consisting of a daily
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`dosage amount of 0.5 mg of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol.”
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`Thus, the claim scope is not enlarged.
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`D.
`Proposed Amendments Respond to Petitioners’ Grounds
`The proposed amendments respond to all instituted grounds.
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` The
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`amendments all use the transitional phrase “consisting of” and as such are
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`“sufficiently narrower than the challenged claim[s] to overcome the grounds of
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`unpatentability upon which the IPR was instituted.” Aqua Prod., Inc., 872 F.3d at
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`1290.3 The following sections explain briefly why the proposed amendments are
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`responsive to the instituted grounds, in view of the burden of persuasion being on
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`the Petitioner as per Aqua Products, Inc.
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`3 Novartis does not acquiesce that the specification does not support the negative
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`limitation “absent an immediately preceding loading dose” and offers the
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`arguments within this brief only under the circumstances where the Board has
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`deemed the original claims unpatentable for the reasons set out the in three
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`grounds instituted. Novartis reiterates its position that the negative limitation is
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`fully supported by the specification.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`1.
`The Proposed Amendments Respond to Ground 1
`The proposed amendments address Ground 1 because the amendments limit
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`the claims to “a dosing regimen consisting of a daily dosage amount of 0.5 mg of 2-
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`amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol.”
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` The
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`transitional phrase
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`“consisting of” particularly and distinctly claims a dosing regimen of a daily dosage
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`amount of 0.5 mg. In view of this clarifying amendment, a person of ordinary skill
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`in the art reading Kovarik in view of Thomson would not believe the claimed
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`methods would be obvious. The main point of Kovarik is to teach using a loading
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`dose. Kovarik discloses no dosing regimen without a loading dose, therefore it
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`would not make obvious the claimed invention. (Steinman Dec., Ex. 2022 ¶¶ 8, 143-
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`147, 155-177; Jusko Dec., Ex. 2024 ¶¶ 15, 130-149.)
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`In the Institution Decision, the Board apparently misapprehended Kovarik’s
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`loading dose notation. The Board said: “In one embodiment of the invention, a
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`loading dose of, e.g., 0.5 mg, 1 mg, 1.5 mg, or 2 mg fingolimod per day is
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`administered ‘during the initial period of four days. Thereafter the treatment is
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`continued with the maintenance therapy, e.g. a daily dosage of 0[.]5 mg.’ Id. at 15.”
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`(Paper 11 at 18, emphasis added.) Although the Board sets out the four doses as
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`alternatives, indicated by the word “or,” they were not alternatives. The four doses
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`were the specified doses for Days 1-4 of the loading dose period. As evidence of
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`this, Kovarik at page 15 does not show an alternative and does not use the word “or.”
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`Instead, Kovarik uses a series of slashes (/): “In a further embodiment of the
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`invention, a preferred loading regimen of a S1P receptor agonist or modulator, e.g.
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`the preferred S1P receptor modulator may be FTY720, also be e.g. 0.5mg/1
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`mg/1.5mg/2mg during the initial period of 4 day.” (Ex. 1004 at 15.) It is clear that
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`the numbers separated by the slashes are meant to refer to the dose for each of the
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`four days of the loading dose period. For example: Dose for Day 1 / Dose for Day
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`2 / Dose for Day 3 / Dose for Day 4. This meaning is clear from the words that
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`follow the notation saying: “during the initial period of 4 day[s].” This is how the
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`passage is understood by Drs. Jusko and Steinman. (Steinman Dec., Ex. 2022 ¶¶
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`164-168; Jusko Dec., Ex. 2024 ¶¶ 134-139.)
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`Based on this mis-reading, the Board suggests that four doses of 0.5 mg each
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`could be “nominally administered as a loading dose….” (Paper 11 at 18). However,
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`this would not fulfill the defined requirements of a “loading dose” as set out by
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`Kovarik. He defines a loading regimen where doses “rise” daily for four days before
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`settling back into a regular dosing pattern, preferably in “stepwise” fashion. (Ex.
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`1004 at Abstract, 13-15.) If a dose is “loading” it should rise or be larger than the
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`maintenance dose. (Steinman Dec., Ex. 2022 ¶¶ 144-145, 164-168.)
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`Furthermore, the Board’s reading of this passage is inconsistent with the rest
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`of Kovarik. As Dr. Steinman explains, the Board’s reading is at odds with the very
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`definition of a “loading dose,” which requires higher initial doses before settling into
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`lower regular doses. (Steinman Dec., Ex. 2022 ¶¶ 164-168.) Thus, Kovarik
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`U.S. Patent No. 9,187,405
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`describes a loading dose regimen in which the loading dose would be greater than
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`the daily maintenance dose and would not make obvious the strict requirement
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`claimed here: a “dosing regimen consisting of a daily dosage amount of 0.5 mg….”
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`The Thomson reference does not remedy the shortcomings of Kovarik. Thus, the
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`amendments are responsive to the allegations in Ground 1.
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`2.
`The Proposed Amendments Respond to Ground 2
`The proposed amendments respond to Ground 2, based on the combination of
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`Kappos 2005, Budde and Chiba. These three reference all describe specific dosage
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`regimens higher than the one claimed here or broad ranges of doses.
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`Kappos 2005 reports MS human clinical trial results of daily doses of 1.25 mg
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`and 5.0 mg showing equal efficacy in reducing brain lesions and reducing relapses.
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`This would teach a person of ordinary skill in the art to administer 1.25 mg for MS.
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`The discrete dosing regimen in the proposed amendments would not have been
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`obvious in view of any of these three references cited. Kappos 2005 would teach a
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`person of ordinary skill in the art away from a dosing regimen of 0.5 mg daily by
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`teaching a daily dosage of 1.25 mg — more than double that of 0.5 mg to attain
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`positive results in terms of reduction of relapses and brain lesions in human MS
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`patients. (Steinman Dec., Ex. 2022 ¶¶ 90-93, 149, 178-181; Jusko Dec., Ex. 2024
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`¶¶ 5-10, 45-48, 161-162.)
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`Budde is merely a single-dose Phase I study and as such a person of ordinary
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`skill in the art would not find a dosing regimen of multiple doses of 0.5 mg obvious
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`in view of Budde. (Steinman Dec., Ex. 2022 ¶¶ 50-54, 148, 178-181; Jusko Dec.,
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`Ex. 2024 ¶¶ 17-18, 49-52, 157-162.) Finally, Chiba only discloses a broad range of
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`doses. (Steinman Dec., Ex. 2022 ¶¶ 149, 178-181; Jusko Dec., Ex. 2024 ¶¶ 17-18,
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`163-164.) Thus, the three references either individually or combined would not
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`make obvious the discrete methods claimed here requiring “a dosing regimen
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`consisting of a daily dosage amount of 0.5 mg…” of fingolimod.
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`3.
`The Proposed Amendments Respond to Ground 3
`Ground 3 is based on the condition predicate that the original claims are not
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`described and thus do not meet the requirements of 35 U.S.C. §112.4 The proposed
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`amendments respond to Ground 3 because they delete the negative limitation “absent
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`an immediately preceding loading dose regimen.” Without this negative limitation
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`phrase in the claim, the argument set out by Apotex that that phrase and thus the
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`claims lack written description fails.
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`4 Novartis reiterates its position that Ground 3 is improper under 35 U.S.C. §
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`311(b) as it is based on a combination of 35 U.S.C. § 112 and § 102. Such a
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`combination is prohibited by the statute.
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`The proposed amendments clarify
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`that
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`the claims are directed
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`to
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`administration of “a dosage regimen consisting of a daily dosage of 0.5 mg…” of
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`fingolimod. As discussed above, the amended claims are fully supported by the
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`specification. (See Steinman Dec., Ex. 2022 ¶¶ 181-189; Jusko Dec., Ex. 2024 ¶¶
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`171-176.)
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`Since the negative limitation is deleted from the claims, the condition
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`predicate upon which Ground 3 relies — the alleged insufficient written description
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`under 35 U.S.C. § 112 of the negative limitation — no longer exists. Thus, the
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`amendments address alleged issues raised in Ground 3.
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`IV. CONCLUSION
`For the foregoing reasons, the Board should permit amendment of the claims
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`as set forth in Appendix A, and deny Grounds 1, 2 and 3 set forth in the Petition, for
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`the reasons herein and those in the Patent Owners Response, and allow the claims
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`listed in Appendix A to issue in the ’405 patent.
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`Dated: March 12, 2018
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`Respectfully submitted,
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` /Jane M. Love, Ph.D./
`Jane M. Love, Ph.D.
`Reg. No. 42,812
`Lead Counsel for Patent Owner
`Gibson, Dunn & Crutcher LLP
`200 Park Avenue
`New York, New York 10166-0193
`jlove@gibsondunn.com
`Tel: 212-351-3922
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`APPENDIX A:
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`Claim Listing Pursuant to 37 C.F.R. §42.121(b)
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`Proposed Substitute Claims
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`The proposed amendments to the original claims are shown below.
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`Underlining indicates proposed additions and a strikeout of text indicates proposed
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`deletions. If one or more of original claims 1-6 is deemed invalid by the Board,
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