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`Paper No. ___
`Filed: March 16, 2018
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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 INDUSTIRES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`
`v.
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`NOVARTIS A.G.,
`Patent Owner.
`_____________________________
`
`IPR2017-008541
`Patent No. 9,187,405
`_____________________________
`
`PETITIONER’S OPPOSITION TO PATENT OWNER’S
`CORRECTED MOTION TO AMEND UNDER 37 C.F.R. §42.121
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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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`TABLE OF CONTENTS
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`Page
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`OVERVIEW OF WHY THE MOTION SHOULD BE
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`I.
`DENIED. ..................................................................................................... 1
`CLAIM CONSTRUCTION ......................................................................... 3
`II.
`A.
`“a subject in need” ............................................................................. 3
`B.
`PO’s Construction: “at a daily dosage of 0.5” mg” ............................ 6
`III. THE PROPOSED AMENDMENTS ARE BROADENING. ....................... 9
`IV. THE PROPOSED AMENDED CLAIMS ARE
`ANTICIPATED. ........................................................................................ 11
`THE PROPOSED AMENDED CLAIMS ARE OBVIOUS. ...................... 17
`V.
`A.
`Ground 1. ......................................................................................... 17
`B.
`Ground 2. ......................................................................................... 21
`C.
`Release. ........................................................................................... 24
`VI. CONCLUSION ......................................................................................... 25
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`The Proposed Amended Claims Are Not Responsive To
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`The Proposed Amended Claims Are Not Responsive To
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`The Proposed Amended Claims Are Obvious Over
`Grounds 1 or 2 In Further View of Chavez or Press
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`I.
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`OVERVIEW OF WHY THE MOTION SHOULD BE DENIED.
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`Petitioner opposes Novartis’s Corrected Contingent Motion to Amend
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`(Paper 61 “Mot.”). Novartis fails to satisfy the threshold requirements for amended
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`claims. 35 U.S.C. §316(d)(3) (“An amendment under this subsection may not
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`enlarge the scope of the claims of the patent or introduce new matter.”); 37 C.F.R.
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`§42.121(a)(2)(i)-(ii), (b)(2); 37 C.F.R. §42.20(c); Aqua Products, Inc. v. Matal,
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`872 F.3d 1290, 1305-06 (Fed. Cir. 2017) (en banc) (“For these reasons, we believe
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`that the only reasonable reading of the burden imposed on the movant in §316(d) is
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`that the patent owner must satisfy the Board that the statutory criteria in
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`§316(d)(1)(a)-(b) and §316(d)(3) are met and that any reasonable procedural
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`obligations imposed by the Director are satisfied before the amendment is entered
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`into the IPR. Only once the proposed amended claims are entered into the IPR does
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`the question of burdens of proof or persuasion on propositions of unpatentability
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`come into play.”).
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`In its February 16, 2018 Opposition to Novartis’s original Motion to Amend
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`(Paper 28), Petitioner argued Novartis had impermissibly broadened the scope of
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`the claims by changing the claimed compound. Paper 51 at 1-2. On March 3,
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`2018, Novartis approached Petitioner about correcting the claimed compound to
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`what was in the original claims. EX3009 at 3. The Board authorized Novartis to
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`make the change to maintain clarity of the record and to conserve Board resources,
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`and authorized Petitioner to file an Opposition to the corrected motion within two
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`weeks of Novartis’s filing. Paper 60 at 2.2 Petitioner agreed to file its Opposition
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`today at the request of Novartis’s attorneys.
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`Notwithstanding Novartis’s correction, the proposed amended claims still
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`impermissibly broaden the claims by removing the negative limitation “absent an
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`immediately preceding loading dose regimen.” Mot. 5. Novartis argues it has not
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`broadened the claims because it replaced the negative limitation with “consisting
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`of” language that applies to “a dosing regimen” comprised by the method. Mot. 2.
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`However, the “consisting of” language does not prohibit the method from
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`comprising another dosing regimen preceding the 0.5 mg dose (e.g., wherein the
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`preceding regimen is a loading dose regimen). This impermissible claim
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`broadening requires denial of the Motion.
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`The Motion should also be denied because the proposed amended claims are
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`anticipated by the prior art. For example, the proposed amended claims recite the
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`same method that was disclosed in the prior art Chavez (EX2031) and Press
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`Release (EX2072) references. The proposed claims are therefore anticipated and
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`unpatentable. Pre-AIA 35 U.S.C. §102(b).
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`2 Paper 60 refers to the filing date of Paper 51 as February 22, 2018, but E2E
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`correctly reflects the actual filing date of February 16, 2018.
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`The proposed substitute claims are obvious over the prior art of record. Pre-
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`AIA 35 U.S.C. §103. The proposed amended claims do not address Ground 1 or
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`Ground 2 of the Petition. Novartis’s arguments directed to Grounds 1 and 2 merely
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`repeat the same arguments Novartis made regarding the original claims. Those
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`arguments fail for the same reasons here. 37 C.F.R. §42.121(a)(2)(i). The proposed
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`amended claims also are obvious over either Ground 1 or Ground 2 in further view
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`of Chavez or Press Release.
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`Each of these reasons independently suffices for denying Novartis’s Motion.
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`II. CLAIM CONSTRUCTION
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`The Board interprets unexpired claims in an IPR using the “broadest
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`reasonable construction in light of the specification of the patent in which [they]
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`appear[].” 37 C.F.R. §42.100(b); Cuozzo Speed Technologies, LLC v. Lee, 136 S.
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`Ct. 2131, 2133-36 (2016). Proposed amended claims must satisfy the written
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`description, enablement, and definiteness requirements of 35 U.S.C. §112 and 37
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`C.F.R. §42.121(b).
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`A.
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`“a subject in need”
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`The Board previously construed the preambles of independent claims 1, 3,
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`and 5, which respectively recite a method for “reducing or preventing or alleviating
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`relapses in Relapsing-Remitting multiple sclerosis in a subject in need thereof,” for
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`“treating Relapsing-Remitting multiple sclerosis in a subject in need thereof,” and
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`for “slowing progression of Relapsing-Remitting multiple sclerosis in a subject in
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`need thereof.” EX1001, 12:49-13:10. The Board noted that the “‘subject in need
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`thereof’ is then reflected in the body of each claim as it recites the step of orally
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`administering fingolimod ‘to said subject.’” Paper 11 at 10-11. The Board
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`concluded that the preambles limited the body of the claim to the extent that “the
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`words in the preambles inform the scope of ‘said subject’ in the body of each
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`claim.” Id. at 12.
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`The Board noted that the independent claims differ from one another in the
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`breadth of the “need” of the subject being administered fingolimod. Id. In claims 1
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`and 5, for example, the subject being administered the fingolimod is respectively in
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`need of “reducing or preventing or alleviating relapses” or “slowing progression”
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`of RR-MS. Id. at 11-12. In accord with the plain meaning of the term “treating,”
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`claim 3 is “broader” than, and subsumes, the narrower language in the preambles
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`of claims 1 and 5. Id. at 12. Novartis has conceded that original claims 1-6 “differ
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`only in that claims 1 and 2 are for a subject in need of ‘reducing or preventing or
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`alleviating relapses’ ([EX1001] at 12:49-58); claims 3 and 4 are for a subject in
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`need of ‘treating’ the disease (id. at 12:59-67); and claims 5 and 6 are for a subject
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`in need of ‘slowing [its] progression’ (id. at 13:1-9).” Mot. 8. Thus, a subject who
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`is in need of reducing, preventing or alleviating relapses in RR-MS or who is in
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`need of slowing progression of RR-MS is also necessarily a subject in need of
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`treating RR-MS. This same construction should be applied to the proposed claims.
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`As explained in the Petition and by Dr. Giesser, RR-MS relapses cause
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`progression as RR-MS patients accrue neurologic disability over time. Petition 23;
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`EX1002, ¶¶43-45; EX1001, 9:64-10:5; EX1023 at 193, 195. Novartis’s expert, Dr.
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`Lublin, agreed that the prior art RR-MS disease modifying therapy interferon also
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`treats RR-MS and slows progression of RR-MS by reducing relapses, confirming
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`the Board’s conclusion that “treating” subsumes each of reducing, preventing, and
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`alleviating relapses in, and slowing progression of, RR-MS. EX1042 at 16:6-19:17.
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`The same is true with respect to proposed amended claims 7, 9, and 11.
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`None of original claims 1-6 or proposed amended claims 7-12 have an
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`efficacy requirement. The preambles certainly do not create one. See Bristol-Myers
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`Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1375 (Fed. Cir. 2001) (the
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`“method [is] performed in the same way regardless [of] whether or not the patient
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`experiences” an efficacious result); see also Catalina Mktg. Int’l v.
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`Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed. Cir. 2002) (“[P]reambles
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`describing the use of an invention generally do not limit the claims….”); Sanofi-
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`Aventis U.S. LLC et al. v. Fresenius Kabi USA, LLC, et al., Case No. 14-7869, at
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`10-11 (D.N.J. October 7, 2016) (inclusion in preamble of antecedent description of
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`patient recited in body of the claim does not make the purpose described in the
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`preamble limiting); Aspex Eyewear, Inc. v. Marchon Eyewear, Inc., 672 F.3d 1335,
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`1347 (Fed. Cir. 2012) (“as a general rule preamble language is not treated as
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`limiting.”); Braintree Labs., Inc. v. Novel Labs., Inc., 749 F.3d 1349, 1357 (Fed.
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`Cir. 2014) (preamble “not limiting ‘where a patentee defines a structurally
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`complete invention in the claim body and uses the preamble only to state a purpose
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`or intended use for the invention,’” (quoting Rowe v. Dror, 112 F.3d 473, 478
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`(Fed. Cir. 1997))); In re Montgomery, 677 F.3d, 1375, 1380 (Fed. Cir. 2012)
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`(method of treatment claims do not create “an efficacy requirement”).
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`Neither the original nor the proposed amended claims require that the
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`methods achieve any particular therapeutic outcome, that the method have received
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`regulatory (i.e., FDA) approval, or that the method has been proven to be clinically
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`effective through a successful phase III trial. Indeed, the specification
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`acknowledges that MS therapy “is only partially effective[.]” EX1001, 8:64-67;
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`EX1002, ¶¶45-47. Moreover, Novartis argues that the Section 112 support for the
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`0.5 mg daily dose in the original and proposed amended claims comes from the
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`specification’s description of a prophetic clinical trial in which 20 patients with
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`RR-MS receive fingolimod “at a daily dosage of 0.5, 1.25 or 2.5 mg p.o.” Mot. 10-
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`11. Administration of fingolimod to RR-MS patients in a clinical trial at a daily
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`dosage of 0.5 mg absent an immediately preceding loading dose regimen similarly
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`satisfies the original and proposed amended claims.
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`B.
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`PO’s Construction: “at a daily dosage of 0.5” mg”
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`Novartis relies on Drs. Steinman and Jusko to argue that “a daily dosage”
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`excludes a loading dose, or an up-titration dose, or any other variation other than a
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`dosage amount of 0.5 mg daily. Mot. 10-12, 16-18. Drs. Steinman and Jusko
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`respectively assert that the term “at a daily dosage of 0.5 mg” means “once a day
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`for more than one day” or “once a day for a number of days in a row.” EX2022,
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`¶¶178-79, 184; EX2024, ¶114. They base this construction on the prophetic
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`clinical trial described in the ’405 patent in which RR-MS patients orally “receive
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`said compound at a daily dosage of 0.5, 1.25 or 2.5 mg,” “receive treatment for 2
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`to 6 months” and “remain on treatment for as long as their disease does not
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`progress and the drug is satisfactorily tolerated.” EX1001, 11:8-16. But the claims
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`contain no limitation of once a day dosing, treatment for 2 to 6 months, of
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`continuing treatment until progression is observed or drug toleration ceases, or
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`continuing treatment for any length of time. Novartis’s construction would limit
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`the claims incorrectly to an embodiment falling within the claims. See In re Am.
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`Acad. of Sci. Tech. Ctr., 367 F.3d 1359, 1369 (Fed. Cir. 2004). Novartis does not
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`apply the broadest reasonable interpretation.
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`The specification confirms that Novartis’s construction does not apply the
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`broadest reasonable interpretation. For example, the ’405 patent provides that a
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`“daily dosage” may be administered “as a single dose or in divided doses.”
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`EX1001, 11:24-25. Novartis’s construction that “daily dosage” requires “once a
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`day” administration is thus unsupported by the record.
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`Similarly, Novartis’s contention that “daily dosage” can only reasonably
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`mean administration of the same dose for more than one day is incorrect. Dr. Jusko
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`relies on Kovarik’s disclosure that “treatment continued with the maintenance
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`therapy, e.g. a daily dosage of 0,5 mg” to argue that a daily dosage requires
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`administration of the same dose for more than one day. EX2024, ¶114. But
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`Kovarik repeatedly identifies “daily dosage[s]” that were administered for only one
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`day, with a different total dosage per day administered on subsequent days,
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`including in loading dose, or an up-titration dose. See, e.g., EX1004 at 15 (“During
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`the initial 3 to 6 days, preferably 4 or 5 days, most preferred 4 days, of treatment
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`the daily dosage of the S1P receptor modulator or agonist is raised stepwise….”),
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`16 (incremental daily dosage), 17 (varying daily dosage), 19 (up-titration, “once
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`daily” administration), 21 (“daily units…of varying daily dosage…incrementally
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`increased”). A daily dosage thus reasonably refers to a total dose per day,
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`regardless of whether the dose is administered in a single or in divided dose, and
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`regardless of whether the total dose changes on subsequent days.
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`Just as the ’405 patent specified a duration of treatment to indicate repeated
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`administration of the same “daily dosage” (EX1001, 11:8-16), Kovarik also used
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`additional language to describe day-after-day administration of a particular daily
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`dosage, calling it a “maintenance therapy.” See, e.g., EX1004 at 14 (“Thereafter
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`the treatment is continued with the maintenance therapy with the standard daily
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`dosage or with a lower daily dosage.”), 15 (“Thereafter the treatment is continued
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`with the maintenance therapy, e.g. a daily dosage of 2.5 mg or 5 mg, or at a lower
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`daily dosage, e.g. 0.1 to 0,5 mg.”). Although the broadest reasonable interpretation
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`of administering fingolimod at a daily dosage of 0.5 mg does not rule out
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`administering the same daily dosage day after day, neither the original claims (1-6)
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`nor the proposed amended claims (7-12) are so limited.
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`III. THE PROPOSED AMENDMENTS ARE BROADENING.
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`The AIA forbids patentees from enlarging claim scope during an IPR. See 35
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`U.S.C. §316(d)(3); 37 C.F.R. §42.121(a)(2)(ii). Novartis’s contention that the
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`proposed amended claims do not enlarge the scope of the claims (Mot. 12-13) is
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`entirely conclusory and completely incorrect. Even after Novartis’s correction, the
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`proposed claims delete the negative limitation “absent an immediately preceding
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`loading dose regimen.” Mot. 17. The proposed amended claims also comprise “a
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`dosing regimen consisting of a daily dosage amount of 0.5 mg.” Representative
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`original claim 3 and proposed claim 9 are shown below:
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`3. (Original) A method for treating
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`9. (Proposed) A method for treating
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`Relapsing-Remitting multiple sclerosis
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`Relapsing-Remitting multiple sclerosis
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`in a subject in need thereof, comprising
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`in a subject in need thereof, comprising
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`orally administering to said subject 2-
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`orally administering to said subject 2-
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`amino-2-[2-(4-
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`amino-2-[2-(4-
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`octylphenyl)ethyl]propane-1,3-diol,
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`in
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`octylphenyl)ethyl]propane-1,3-diol,
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`in
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`free form or in a pharmaceutically
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`free form or in a pharmaceutically
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`acceptable salt form, at a daily dosage
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`acceptable salt
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`form, wherein
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`the
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`of 0.5 mg, absent an
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`immediately
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`subject receives a dosing regimen
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`preceding loading dose regimen.
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`consisting of a daily dosage amount of
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`at a daily dosage of 0.5 mg of 2-amino-
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`2-[2-(4-octylphenyl)ethyl]propane-1,3-
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`diol, absent an immediately preceding
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`loading dose regimen.
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`Mot. 21. But as Novartis itself concedes, “[w]hen the phrase ‘consisting of’
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`appears in a clause of the body of a claim, rather than immediately following the
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`preamble, it limits only the element set forth in that clause; other elements are not
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`excluded from the claim as a whole.” Mot. 12 (citing Mannesmann Demag Corp.
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`v. Engineered Metal Prod. Co., 793 F.2d 1279, 1282 (Fed. Cir. 1986); In re Crish,
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`393 F.3d 1253, 1257 (Fed. Cir. 2004)). Novartis’s proposed amendments remove
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`the negative limitation from constraining the method as a whole, and thereby
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`impermissibly broaden the claims.
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`“[A] claim is broader in scope than the original claims if it contains within
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`its scope any conceivable apparatus or process which would not have infringed the
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`original patent.” In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1283 (Fed. Cir.
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`2015) (quotations omitted). The hypothetical dependent claim below demonstrates
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`that the proposed amended claims encompass subject matter that would not have
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`infringed the original claims:
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`The method of claim 9, wherein the method further comprises
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`administering to said subject a loading dose regimen immediately
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`preceding the dosing regimen consisting of a daily dosage amount of
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`0.5 mg of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,2-diol .
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`This hypothetical claim would be outside the scope of claim 3, and therefore an
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`improper dependent claim, at least because claim 3 categorically excludes an
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`immediately preceding loading dose regimen. In contrast, the hypothetical claim
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`would not exceed the scope of proposed claim 9 at least because the method of
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`claim 9 does not categorically exclude using a loading dose regimen before giving
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`the subject a dosing regimen consisting of a daily dosage amount of 0.5 mg.
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`Novartis apparently removed the negative limitation because the original
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`claims are not entitled to a pre-2010 priority date necessary to avoid the
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`anticipation shown in Ground 3 of the Petition. In removing the negative limitation
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`Novartis broadened the claims. Its Motion can be denied on this basis alone.
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`IV. THE PROPOSED AMENDED CLAIMS ARE ANTICIPATED.
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`A prior art reference anticipates a claim if it discloses all of the elements of
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`the claim in the claimed combination. Wm. Wrigley Jr. Co. v. Cadbury Adams USA
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`LLC, 683 F.3d 1356, 1361 (Fed. Cir. 2012). Novartis submitted with its Response
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`two previously undisclosed prior art references, each of which anticipates the
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`claims under Pre-AIA 35 U.S.C. §102(b). POR 25 (citing EX2031 and EX2072);
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`EX2025, ¶48. Chavez (EX2031) has a publication date of April 10, 2006 and was
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`published by Medical News Today. Novartis published Press Release (EX2072) on
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`April 6, 2006. Each reference is therefore prior art to the claims of the ’405 patent
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`under pre-AIA 35 U.S.C. §102(b). Novartis’s expert, Dr. Lublin, confirmed the
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`publication dates for each reference and confirmed that each of these references
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`was a prior art publication to the ’405 patent. EX1042 at 221:6-222:14, 243:13-
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`244:21; Montgomery, 677 F.3d at 1378-1380 (published description of ongoing
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`clinical study anticipated claims).
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`The Chavez and Press Release references have substantially identical
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`disclosures. Indeed, Dr. Lublin testified that “[t]hey look identical.” EX1042 at
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`244:22-245:6. They each first describe the results of the extension phase of the
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`Phase II study described in Kappos 2005 and Thomson. They each state:
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`The data…showed that both patient groups taking FTY720
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`[fingolimod hydrochloride] (1.25 mg and 5 mg) who had experienced
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`more than a 50% reduction in their annualized relapse rate during the
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`study’s first six months compared to placebo maintained this low
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`relapse rate during the subsequent 12-month extension. Currently
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`marketed MS therapies afford an average reduction in relapse rates of
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`only 30%....Consistent with what was seen in MRI scans at month six,
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`the vast majority of patients were free from lesions showing active
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`inflammation at month 18….All patients in the extension study are
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`now continuing with the 1.25 mg dose since both the 5 mg dose,
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`which had a higher rate of adverse events, and 1.25 mg doses were
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`equally effective in reducing disease activity.
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`EX2031 at 1-2; EX2072 at 1-2. Regarding the Phase III study, they each state:
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`Novartis has initiated its first Phase III pivotal study called
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`“FREEDOMS” (Fingolimod Research Evaluating Effects of Daily
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`Oral therapy in Multiple Sclerosis). The 24-month, randomized,
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`double-blind, placebo-controlled FREEDOMS study will include
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`more than 1,000 patients with relapsing-remitting MS between age
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`18-55. Study participants will be equally randomized to either receive
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`either 1.25 mg or 0.5 mg of FTY720 or placebo once daily for up to
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`24 months. The study has begun enrolling patients in several
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`European countries.
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`EX2031 at 2-3; EX2072 at 2.
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`Dr. Lublin agreed that he had “the expertise to opine on the understanding of
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`a person of ordinary skill in the art at the relevant time” at least as it regards
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`clinical trial activity for multiple sclerosis discussed in Exhibits 2031 and 2072.
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`EX1042 at 235:17-236:8. He also testified that a person of ordinary skill in the art
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`as of April 2006 would understand from these references that 0.5 mg daily doses of
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`fingolimod were being administered orally to RR-MS patients who had a need for
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`reducing, preventing, or alleviating relapses, for RR-MS treatment, and for slowing
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`the progression of RR-MS, absent an immediately preceding loading dose regimen:
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`Q. Please take a look at page 2 of the Chavez prior art publication
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`under the heading “phase III Study Program.”….You agree that the
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`Chavez reference discloses that the study participants will be a
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`thousand patients with relapsing-remitting multiple sclerosis?
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`A. Yes.
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`***
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`Q. Is it your understanding from reviewing the Chavez reference that
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`those one thousand patients, were patients in need of reducing,
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`preventing, or alleviating relapses?
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`A. Yes.
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`Q. And it’s also your understanding that those one thousand patients
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`were in need of treatment for RRMS. Correct?
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`A. Yes.
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`Q. And it’s also your understanding that those one thousand patients
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`were in need of slowing the progression of RRMS. Correct?
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`A. Yes.
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`Q. And you agree that that same understanding that you have from
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`reading Chavez is the understanding that a person of ordinary skill in
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`the art would have had reading the Chavez reference on the 10th of
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`April 2006?
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`A. Yes.
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`***
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`Q. Now, that approximately three hundred-thirty patients with
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`relapsing-remitting MS who were, for example, in need of reducing
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`relapses, would be receiving 0.5 milligrams of Fingolimod once daily
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`for up to 24 months?
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`A. Yes.
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`***
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`Q. So it’s your belief that the person of ordinary skill in the art
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`reading this regimen would understand that there is no immediately
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`preceding loading dose. Correct?
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`A. Yes.
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`***
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`My question is whether a person of ordinary skill in the art, as of the 6
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`of June 2006, would understand from this disclosure that there is no
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`loading dose immediately preceding the daily dose of 0.5 milligrams
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`Fingolimod?
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`A. Yes.
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`***
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`Q. You can take a look back at Exhibit Novartis 2031, the Chavez
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`reference. The same paragraph we were looking at before on page 2. I
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`have just a couple of follow up questions on it. The title of the study
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`is: “Daily Oral Therapy in Multiple Sclerosis.” Correct?
`
`A. The title is “Fingolimod Research Evaluating Effects of Daily Oral
`
`Therapy in Multiple Sclerosis.”
`
`Q. You agree that the person of ordinary skill in the art in April of
`
`2006 would understand that the administration of Fingolimod
`
`described in this reference [i]s oral administration. Correct?
`
`A. Yes.
`
`***
`
`Q. And you agree that the person of ordinary skill in the art as of April
`
`2006 would understand that that means that this administration, the
`
`oral administration, described in the preceding paragraph had already
`
`begun. Correct?
`
`A. Yes.
`
`
`EX1042 at 223:4-18, 225:4-226:22, 227:8-17, 231:15-23, 237:3-11; 241:3-242:16
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`- 15 -
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`
`
`
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`(objections omitted). Each of these references thus sets forth a single embodiment
`
`comprising each element of the original claims.
`
`Novartis argues the Section 112 support for the original and the proposed
`
`amended claims comes from the ’405 patent’s disclosure of a prophetic clinical
`
`trial “[i]nvestigation of clinical benefit” at a daily dose of 0.5 mg, and concedes
`
`that this is “the exact dosing regimen in the proposed amended claims (and original
`
`claims)….” Mot. 10-11; EX1001, 11:4-9. Each of the Chavez and Press Release
`
`references therefore anticipate the original claims, and the proposed amended
`
`claims. Dr. Lublin agreed that the disclosure found in the Chavez and Press
`
`Release references discloses the same “consisting of” dosing regimen that Novartis
`
`proposed as the point of novelty to overcome the prior art of record:
`
`Q. In this administration regimen that's described here in paragraph 2
`
`of the Chavez reference, you agree that the patients receive a dosing
`
`regimen consisting of a daily dosing amount of 0.5 milligrams of
`
`Fingolimod. Correct?
`
`A. They will receive 1.25 milligrams or .5 milligrams or placebo.
`
`Q. I understand what you’re saying. Let me try again. For the patients
`
`receiving the 0.5 milligrams of Fingolimod, you agree that those
`
`patients are receiving a dosing regimen consisting of a daily dosage
`
`amount of Fingolimod of 0.5 milligrams?
`
`A. Yes.
`
`EX1042 at 242:17-243:12. Novartis’s Motion should be denied because the
`
`proposed amended claims are anticipated by each of the Chavez and Press Release
`
`- 16 -
`
`
`
`
`
`references.
`
`The steps of the methods were in the public domain. Whatever benefits may
`
`flow from them cannot remove them from the possession of the public. See
`
`Montgomery, 677 F.3d at 1381 (“efficacy is inherent in carrying out the claim
`
`steps”); Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012);
`
`In re Kao, 639 F.3d 1057, 1070, 1072-73 (Fed. Cir. 2011); King Pharmaceuticals,
`
`Inc. v. Eon Labs, Inc., 616 F.3d 1267, 1275-76 (Fed. Cir. 2010); PharmaStem
`
`Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007).
`
`V. THE PROPOSED AMENDED CLAIMS ARE OBVIOUS.
`
`
`The proposed amended claims are also unpatentable over the prior art of record
`
`under Pre-AIA 35 U.S.C. §103.
`
`A. The Proposed Amended Claims Are Not Responsive To Ground 1.
`
`Ground 1 of the Petition demonstrated that Kovarik disclosed oral
`
`administration of a 0.5 mg daily dose of FTY720 as a maintenance therapy for
`
`treating autoimmune diseases, including MS. Petition 32-36 (citing EX1004 at 1-2,
`
`13-20; EX1002, ¶¶57, 63-64, 79-80, 104-06, 117-23; EX1019 at 684; EX1020 at
`
`591; EX1022 at 309). The Petition also demonstrated that the efficacy of Kovarik’s
`
`maintenance therapy dose did not depend on a loading dose regimen. Petition 36-
`
`39 (citing EX1002, ¶¶21, 28, 57, 60, 68, 119, 121-22, 124; EX1005 at 160, 163;
`
`EX1010 at 0110; EX1021 at 93; EX1025 at 956; EX1026 at 546S; EX1027 at
`
`- 17 -
`
`
`
`
`
`3083; EX1031 at 1084; EX1033 at 896, 954, 2625, 3120, 3224; EX1034 at 10, 12;
`
`EX1036 at 1). The Petition thus argued that it would have been obvious to
`
`administer Kovarik’s 0.5 mg maintenance therapy dose of FTY720 to an MS
`
`patient in need of immunomodulatory treatment absent an immediately preceding
`
`loading dose. Petition 39-41.
`
`The Petition also demonstrated that a POSA would have read Kovarik’s
`
`teaching as readily applicable to a patient with the RR-MS form of the disease
`
`because fingolimod was known to treat MS by reducing inflammation responsible
`
`for relapses and progression in RR-MS. Petition 41-42 (citing EX1004 at 2;
`
`EX1005 at 161, 166; EX1002, ¶¶49-50, 87, 107-08; EX1018 at 236; EX1023 at
`
`201, 228-29; EX1024 at 942; EX1029 at 444-45).
`
`The Petition also argued that Thomson provides additional motivation to
`
`administer 0.5 mg FTY720 to a patient with RR-MS who is in need of treatment, is
`
`in need of reducing, preventing, or alleviating relapses, and is in need of slowing
`
`progression of RR-MS, because FTY720 had been shown to have efficacy in
`
`reducing relapse rates and in slowing progression of RR-MS in the Phase II clinical
`
`trial and the 0.5 mg dose was known to result in a substantial and relevant
`
`pharmacological response. Petition 42-44 (citing EX1005 at 157-58, 162-63, 167;
`
`EX1002, ¶¶84, 87-88, 109-13; EX1018 at 238). The Petition demonstrated that a
`
`POSA would have recognized from the results of the Phase II trial using 1.25 mg
`
`- 18 -
`
`
`
`
`
`and 5 mg doses that it would be beneficial to use the lower 0.5 mg dose to decrease
`
`the risk of adverse events. Petition 44 (citing EX1005 at 163, 165; EX1002, ¶¶62,
`
`114-16; EX1019 at 691; EX1030 at 2522). The Petition explained that a POSA
`
`would have had reason to evaluate the teachings of Kovarik and Thomson together
`
`because each reference describes the therapeutic efficacy of FTY720 for the
`
`treatment of MS. Petition 44-45.
`
`The Petition thus demonstrated the obviousness of the original claims over
`
`Kovarik and in further view of Thomson. Petition 45-48. For those same reasons, it
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`would have been obvious to orally administer a dosing regimen consisting of a
`
`daily dosage amount of 0.5 mg of fingolimod hydrochloride to a subject in need of
`
`reducing, preventing, or alleviating relapses in RR-MS, in need of slowing
`
`progression of RR-MS, and in need of treating RR-MS.
`
` Novartis contends its proposed amendments “address” Ground 1. Mot. 13-
`
`14. But Novartis simply repeats the same argument for distinguishing Kovarik that
`
`it made in its Response (Paper 27, POR), that a POSA “would not believe”
`
`Kovarik’s disclosure of a 0.5 mg maintenance therapy for MS treatment because,
`
`allegedly, “[t]he main point of Kovarik is to teach using a loading dose.” Mot. 14.
`
`Novartis’s attempts to distinguish Kovarik fail.
`
`The Petition established that a loading dose regimen merely increases the
`
`speed of efficacy but is not required to make a maintenance dose effective for MS
`
`- 19 -
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`
`
`
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`treatment. Petition 4-8, 30-31, 34-39, 41-43; Paper 11 at 18; EX1002, ¶¶67, 70-72,
`
`108-09, 112-13, 117-22, 126. Petitioner thereby demonstrated the error in
`
`Novartis’s prosecution argument that the 0.5 mg maintenance therapy disclosed in
`
`Kovarik should be disregarded because it allegedly depended on a loading dose
`
`regimen. Novartis and its experts have now conceded that Petitioner was correct.
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`EX2024, ¶131 (“achieve the effect of the drug faster”); EX2022, ¶¶157-58 (used to
`
`avoid delay); POR 48 (Kappos showed no loading dose needed”).
`
`Novartis’s continued attempt to ignore Kovarik because it used a loading
`
`dose is particularly disingenuous because Novartis’s “teaching away” and
`
`“unexpected results” arguments in the POR repeatedly rely on references
`
`describing transplantation studies, in which context loading doses were used. POR
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`9-14, 34-35, 37 (transplant studies provide “insight” for “patients with multiple
`
`sclerosis”); EX1019 at 685 (loading dose); EX1031 at 1084 (when rapid effect is
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`“critical”). Further, Kovarik’s 0.5 mg maintenance therapy was not a hypothetical
`
`input; it was “part of a preferred embodiment.” Petition 7-11; EX1004 at 13, 15,
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`17. Novartis ignores Kovarik’s placement of MS at the head of a small list of
`
`preferred autoimmune disease targets of the medication. Petition 10; EX1004 at 14,
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`17. Novartis’s argument that the Board should ignore Kovarik because it discloses
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`“loading dose methods” should be rejected. Novartis’s proposed amended claims
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`fail to add
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