`
`
`
`
`Paper No. ___
`Filed: April 19, 2018
`
`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.
`
`NOVARTIS A.G.,
`Patent Owner.
`_____________________________
`
`IPR2017-008541
`Patent No. 9,187,405
`_____________________________
`
`PETITIONERS’ SUR-REPLY REGARDING PATENT OWNER’S
`MOTION TO AMEND
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`
`
`
`I.
`II.
`
`THE PREAMBLES DO NOT DISTINGUISH THE PRIOR
`
`TABLE OF CONTENTS
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`Page
`
`INTRODUCTION. ...................................................................................... 1
`ART. ............................................................................................................ 1
`A.
`There Is No Claim Redundancy Issue ................................................ 1
`B.
`No Support For Efficacy Requirement ............................................... 3
`C.
`Chavez Anticipates The Claims ......................................................... 7
`III.
`“CONSISTING OF” DOES NOT CLOSE THE METHOD......................... 9
`IV. THE PROPOSED CLAIMS DO NOT RESPOND TO
`GROUNDS 1-2 .......................................................................................... 12
`CONCLUSION ......................................................................................... 12
`V.
`
`
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`- i -
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`TABLE OF AUTHORITIES
`
`CASES
`
`In re Montgomery, 677 F.3d 1375, 1383 n.14 (Fed. Cir. 2012) ................... 4, 5, 8, 9
`
`Coalition for Affordable Drubs V LLC, et al. v. Biogen M.A. Inc.,
`IPR2015-01993 ............................................................................................ 5
`
`Curtiss-Wright Flow Control Corp. v. Velan, Inc., 438 F.3d 1374,
`1380-81 (Fed. Cir. 2006).............................................................................. 2
`
`Ex Parte Davis, 80 U.S.P.Q. 448 (Bd. App. 1948) ................................................. 9
`
`Hormone Research Found. v. Genentech, Inc., 904 F.2d 1558, 1567 n.
`15 (Fed. Cir. 1990) ....................................................................................... 2
`
`Jansen v. Rexall Sundown, 342 F.3d 1329 (Fed. Cir. 2003) ................................... 7
`
`Karlin Tech. Inc. v. Surgical Dynamics, Inc. 177 F.3d 968, 971-72
`(Fed. Cir. 1999) ........................................................................................... 1
`
`Sanofi v. Watson Labs., 875 F.3d 636, 646-47 (Fed. Cir. 2017) ............................. 5
`
`- ii -
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`I.
`
`INTRODUCTION.
`
`Novartis itself produced the anticipatory Chavez reference (EX2031) but
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`failed to address Chavez in its Corrected Motion to Amend (“Mot.”). Novartis’s
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`Motion also contained no claim construction section justifying requiring clinical
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`efficacy as a claim element. Instead, Novartis simply argued that the written
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`description support for the claims was found in “the ‘Clinical Trial” example
`
`reciting a daily dosage of 0.5 mg fingolimod as one embodiment.” Mot. at 2, 8; id.,
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`11 (“Clinical Trial example in the patent…is sufficient to meet 35 U.S.C. § 112.”).
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`Then, in its Reply (Paper 64), Novartis introduced new testimony and argument in
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`support of the proposed amended claims. The Board authorized this Sur-Reply “to
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`respond[] to arguments and citations to expert testimony expressly set forth in
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`Patent Owner’s Reply[.]” Paper 66 at 3; Paper 72 at 2.
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`II. THE PREAMBLES DO NOT DISTINGUISH THE PRIOR ART.
`
`A. There Is No Claim Redundancy Issue
`
`Novartis argues that the presumption against claim redundancy requires
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`reading a different efficacy result or intended efficacy result into each of the
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`independent claims beyond simply identifying need of the subject who receives the
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`fingolimod. Reply at 2-3. But Novartis’s case law applies a presumption against
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`reading limitations from dependent claims into their independent claims to limit
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`their plain meaning. See Karlin Tech. Inc. v. Surgical Dynamics, Inc. 177 F.3d 968,
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`971-72 (Fed. Cir. 1999); see also Curtiss-Wright Flow Control Corp. v. Velan,
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`- 1 -
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`
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`Inc., 438 F.3d 1374, 1380-81 (Fed. Cir. 2006) (“[T]he claim differentiation tool
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`works best in the relationship between independent and dependent
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`claims….Beyond the independent/dependent claim scenario, this court has
`
`characterized claim differentiation more generally, i.e., as ‘the presumption that
`
`each claim in a patent has a different scope.’”); Hormone Research Found. v.
`
`Genentech, Inc., 904 F.2d 1558, 1567 n. 15 (Fed. Cir. 1990) (“It is not unusual that
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`separate claims may define the invention using different terminology, especially
`
`where (as here) independent claims are involved.”).
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`Under the plain meaning of the claims, the preamble language defines the
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`needs of the subject receiving the fingolimod. EX2003, ¶20 (cited in Reply at 3)
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`(“The ’405 Patent claims methods for dosing fingolimod for a subject in need of
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`certain effects.”); id., ¶5 (claims 1, 3, and 5 each describe a method for a subject in
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`need of various benefits); see also EX1002, ¶¶15 (no data presented in ’405 patent
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`regarding efficacy of dosing regimen), 43 (“Claims 1, 3, and 5 each contain a
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`preamble identifying ‘a subject in need’ of a method.”); EX1047, ¶¶20-24.
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`Novartis improperly uses claim differentiation to read limitations into the claims.
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`Novartis reasons that the “subject in need” category in each claim
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`encompasses (and is therefore anticipated by) the same species of subject (actively
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`relapsing RRMS patients). Reply at 2-3; EX2096, ¶¶9-11 (agreeing that all actively
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`relapsing RRMS patients have each of the claimed needs). Novartis erroneously
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`- 2 -
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`reasons that the scope of all three categories must therefore be co-extensive. But
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`the fact that a species falls within the scope of all three claims does not mean that
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`the claims have co-extensive or redundant scope.
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`As Dr. Steinman testified, treating RRMS encompasses preventing relapses
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`(as evidenced by reducing relapse rates), alleviating the severity of relapses, and
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`slowing progression, but is also broader than these sub-categories. EX1061 at
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`51:13-56:6. The scope of “a subject in need of a method for treating RRMS”
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`(claim 3) is thus broader than the scope of each of “a subject in need of a method
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`for reducing …relapses” (claim 1) and “a subject in need of a method for slowing
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`progression,” (claim 5). Similarly, the scope of claim 1 is not co-extensive with
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`that of claim 5. EX1061 at 57:20-58:13 (“You agree then an RRMS patient whose
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`relapses are controlled may still be in need of slowing progression of RRMS?
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`[Objection] A. Right[.]”).Thus, each independent claim sets a different scope for
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`the need of the subject even though they overlap and each encompasses the species
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`of actively relapsing RRMS patients.
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`Novartis’s attempts to distinguish Petitioner’s case law (Pet. at 24)
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`establishing that intended use statements in the preamble are precatory and non-
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`limiting are all premised on the alleged claim redundancy. Reply at 7-10. For the
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`reasons discussed above, these efforts fail.
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`B. No Support For Efficacy Requirement
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`- 3 -
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`Novartis attempts to establish efficacy elements in the proposed claims
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`because the specification in In re Montgomery did not describe any clinical studies
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`that showed stroke treatment or prevention. 677 F.3d 1375, 1383 n.14 (Fed. Cir.
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`2012). However, Dr. Steinman agreed during his deposition that the ’405 patent
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`does not disclose the results of administering 0.5 mg of fingolimod to a human and
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`only describes administering 0.5 mg fingolimod in a prophetic clinical trial to
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`investigate the clinical benefit of the administration. EX1061 at 131:6-132:7. Dr.
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`Steinman also agreed “from the perspective of a person with ordinary skill in the
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`art in June of 2006…that the ’405 Patent failed to prove efficacy in treating RRMS
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`of daily administration of 0.5 milligrams of fingolimod.” EX1061 at 149:12-24.
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`Novartis’s reliance (Reply at 7 (citing EX2096, ¶¶13-15)) on the
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`specification’s description of “MS animal model studies” also fails. No animal
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`study in the patent administered a 0.5 mg dose. The only animal doses described in
`
`the patent are 0.3 mg/kg and 0.1 mg/kg. EX1001, 10:61-67. If applied directly to a
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`human weight, even the lower 0.1 mg/kg dose, which the specification does not
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`state “inhibits the relapse phase,” would be 7-14 mg for a 70 kg human. EX1064 at
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`58:18-60:5. Dr. Jusko’s clearance methodology for converting rat to human doses
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`translates a 0.1 mg/kg dose in rats to 1.43 mg in a 75 kg human (EX2095, ¶¶22-
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`25). None of the daily doses administered to rats in the ’405 patent translate to 0.5
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`mg in humans using Dr. Jusko’s methodology. In short, Novartis’s argument that
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`- 4 -
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`animal doses in the patent create an efficacy requirement in the claims is
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`undermined by Novartis’s own positions on animal to human dose conversion.
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`
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`Novartis’s reliance on the specification of the ’405 patent to establish an
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`efficacy requirement in the claims also fails because the claims at issue do not
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`recite an efficacy element. Reply at 7-9; compare Montgomery, 677 F.3d at 1377
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`(no effective amount element recited in claim); id. at 1380-81 (“We are skeptical
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`that the proper interpretation of the claims would include an efficacy requirement”
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`based on “method for” language in preamble, particularly under BRI construction
`
`standard) with Sanofi v. Watson Labs., 875 F.3d 636, 646-47 (Fed. Cir. 2017)
`
`(claims required administering “an effective amount of dronedarone,” appellants
`
`had accepted the burden of proving “the processes claimed would succeed in their
`
`(claimed) aims)” of reducing hospitalizations, and the Federal Circuit affirmed
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`based on district court’s factual finding that defendants failed to establish expected
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`efficacy from publication of a “post hoc” analysis when weighed against prior art
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`teaching of premature termination of clinical trial because of safety concerns, yet
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`“the evidence might well have supported the opposite finding); Coalition for
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`Affordable Drubs V LLC, et al. v. Biogen M.A. Inc., IPR2015-01993, Paper 63 at 3
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`(claims expressly recited treating subject with “therapeutically effective amount”).
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`Dr. Steinman argued that the preambles of the claims establish specification
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`support for an efficacy requirement. EX2096, ¶13; EX1061 at 128:18-129:9,
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`- 5 -
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`135:19-22, 136:24-25. But Novartis cannot rely upon the claims themselves as
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`support for an efficacy requirement because no claim to methods for treating
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`RRMS, preventing/reducing/alleviating relapses in RRMS, or slowing progression
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`of RRMS, appeared in the pre-2011 priority documents. EX1009 at 0032-0033,
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`0188-0189. This language was added in May 2011 (EX1010 at 0491-93), after the
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`publication of Kappos 2010 (EX1038).
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`Dr. Steinman also relies on the specification characterization of prior art
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`treatments as being “only partially effective” (EX2096, ¶13), but he agreed during
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`deposition that two out of three prior art DMTs for RRMS generally were more
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`than partially effective and provided more than only a short delay in disease
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`progression. EX1061 at 100:14-103:16, 106:22-107:8, 110:11-111:6.
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`Novartis’s reliance on the prosecution history (Reply at 3; EX2096, ¶16)
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`also fails. Novartis distinguished Virley for failure to disclose the 0.5 mg dose and
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`Kovarik for disclosing the 0.5 mg dose only after a loading dose regimen. EX1011
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`at 0033. The ’405 patent issued based on applicants’ assertion that the disclosure of
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`the 0.5 mg maintenance dose in Kovarik depended on the preceding loading dose
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`regimen, which assertion has now been proven false.
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`Novartis is left with only the prophetic disclosure of administering 0.5 mg in
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`an investigational clinical study as the alleged support for its new claim
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`interpretation. Reply at 7-10. An equivalent description in the prior art (Chavez)
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`- 6 -
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`anticipates the claims on the same basis.
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`
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`Novartis relies on Jansen v. Rexall Sundown, 342 F.3d 1329 (Fed. Cir. 2003)
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`to argue that the description of the needs of the subjects in the preamble is “a
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`statement of the intentional purpose for which the method must be performed.”
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`Reply at 9. But Jansen dealt with a situation where preamble language specifying
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`“treating or preventing macrocytic-megaloblastic anemia” and specifying
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`administration “to a human in need thereof” were both added simultaneously to
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`gain allowance of the claims after almost twenty years of unsuccessful attempts.
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`As discussed above, the claims of the ’405 patent were allowed because applicant
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`added the “absent an immediately preceding loading dose regimen” limitation.
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`Moreover, in Jansen, the Court concluded that the claims “are properly
`
`interpreted to mean that the combination of folic acid and vitamin B12 must be
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`administered to a human with a recognized need to treat or prevent macrocytic-
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`megaloblastic anemia.” Jansen, 342 F.3d at 1334. The Court did not conclude that
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`a method step of administering a substance to a subject in need of a method of
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`treating rewrites the claim to require actual efficacy or knowledge of a successful
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`phase III trial. It was sufficient that the active be administered to a human
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`recognized to have the claimed need. That is entirely consistent with Petitioner’s
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`claim construction.
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`C. Chavez Anticipates The Claims
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`- 7 -
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`Contrary to Novartis’s argument (Reply at 9), Chavez need not expressly
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`state a “recited purpose” of achieving efficacy. It is sufficient that a POSA
`
`understood from its disclosure that the fingolimod was being administered to
`
`persons known to have the recited needs. EX1042 at 225:4-227:17. Novartis’s
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`argument that the dose was included “to be tested, not for the purpose of treating”
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`(Reply at 9) imports a non-experimental-use element into the claims that is not
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`supported by the specification. As noted in Montgomery, a clinical trial protocol is
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`not merely “an invitation to investigate” and need not disclose results of the trial to
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`anticipate a method for treatment. 677 F.3d at 1382-84 (“HOPE’s protocol for the
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`administration of ramipril is far from an abstract theory—it is an advanced stage of
`
`testing designed to secure regulatory approval.”).
`
`Relying on Dr. Lublin (EX2097, ¶8), Novartis argues that the same method
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`steps disclosed in Chavez and claimed in the ’405 patent would not inherently
`
`result in efficacy. Reply at 10. However, Dr. Lublin agreed that he would expect
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`the same clinical trial to demonstrate efficacy if repeated again and that the
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`efficacy of 0.5 mg fingolimod and its mechanism of action did not somehow
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`change after or because of the publication of the phase III results. EX1062 at 57:8-
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`61:13, 62:8-15, 62:25-63:24. Chavez discloses to a POSA every step of the
`
`method, including the intended effects of “treatment of relapsing-remitting
`
`multiple sclerosis,” “reduction in their annualized relapse rate,” and freedom “from
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`- 8 -
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`lesions showing active inflammation” used as a marker for disease progression,
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`and the desire to use the “Phase III clinical program” to “confirm[ ] the promise of
`
`the Phase II results[.]” EX2031 at 1-3; EX1047, ¶¶79-83, 85-89; EX1002, ¶¶83,
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`86. Any efficacy resulting from that prior art method is inherent in Chavez’s
`
`disclosure. Montgomery, 677 F.3d at 1381 (“We have repeatedly held that newly
`
`discovered results of known processes directed to the same purpose are not
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`patentable because such results are inherent.” (quotation omitted)).
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`III.
`
` “CONSISTING OF” DOES NOT CLOSE THE METHOD
`
`Novartis argues that “consisting of” language modifying “a dosing regimen”
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`allegedly “requires the dosing regimen to be a daily dosage amount of 0.5 mg of
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`fingolimod, no more and no less.” Reply at 1, 3-5; EX2022, ¶188 (asserting “the
`
`Patent’s specification would support” hypothetical claims “that preclude any type
`
`of dosing other than regular daily dosing with 0.5 mg”). As explained in
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`Petitioners’ Opposition (Paper 51 at 9-11), Novartis’s proposed amendment does
`
`not categorically close off the open-ended method to an immediately preceding
`
`loading dose regimen. Novartis’s argument that Petitioners seek to broaden the
`
`“universally-accepted meaning” of “consisting of” is simply a strawman. Reply at
`
`4-5; see Ex Parte Davis, 80 U.S.P.Q. 448 (Bd. App. 1948) (adhesive composition
`
`consisting essentially of three ingredients not disclosed by tacky composition with
`
`fourth ingredient that made the composition tacky instead of non-tacky).
`
`- 9 -
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`Novartis argues that loading dose regimens are species of dosing regimens
`
`and that the term dosing regimen means “a schedule of doses of a therapeutic agent
`
`per unit of time[.]” Reply at 5; EX2096, ¶¶18-20. But none of this establishes that
`
`a method for treating can only comprise one dosing regimen for an active. Methods
`
`of treatment routinely employ more than one dosing regimen for a given active at
`
`different times. See, e.g., EX1065 at 3:60-4:5 (“[A] method is provided for treating
`
`a subject[,]…the agent is administered in a first regimen….In one important
`
`embodiment, the agent is administered in a second regimen…, wherein the second
`
`regimen is separate in time from the first regimen.”); EX1066 at 0011-12, 0026-35
`
`& claim 1 (“A method for treating…wherein CIFN is administered in a therapeutic
`
`regimen comprising a first dosing regimen of CIFN, followed by a second dosing
`
`regimen of CIFN….”); EX1067 at 44 (“interferon receptor agonist is administered
`
`in a first [induction] dosing regimen, followed by a second [maintenance] dosing
`
`regimen” having a lower dosage); EX1068 at 6:3-19 (“[A] method of treating a
`
`subject …comprises…administering the IL-17A antagonist to the subject
`
`according to a first dosing regimen during an initial treatment period…then the
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`subject is treated with the IL-17 A antagonist according to a second dosing
`
`regimen during at least one subsequent treatment period” at a higher dosage), 52:7-
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`53:4 (claim 34); EX1069 at 54:3-9 (“An exemplary treatment regime entails
`
`administration once per day, once per week, ….In some cases, the treatment
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`- 10 -
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`comprises administering a CIA according [to] one of the aforementioned dosing
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`regimens for a first period and another of the aforementioned dosing regimens for a
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`second period.”). Novartis’s argument merely assumes that “a dosing regimen” for
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`fingolimod in a method for treating must be the only dosing regimen for
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`fingolimod in the method. This is incorrect. EX1042 at 76:4-79:25 (treating RRMS
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`with fingolimod can include temporarily using a reduced fingolimod dosing
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`regimen); EX1061 at 330:18-332:14 (POSA would have viewed 5 mg dose as safe
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`and effective); EX1004 at 15 ( preferred loading dose for 0.5 mg goes up to 2 mg).
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`Dr. Steinman argues that a dosing regimen is the manner in which a drug is
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`taken. EX2096, ¶18. But the dosing regimen recited in the proposed amended
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`claim does not purport to provide an exhaustive description of all parameters
`
`defining the manner of administration administered. EX2096, ¶24 (claims do not
`
`specify whether to use “single or divided doses”); EX2061 at 214:23-215:22
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`(claims do not specify duration of administration). Novartis’s “dosing regimen” is
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`not an exhaustive description of all fingolimod dosing parameters.
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`Novartis argues that the word “daily” would be rendered meaningless unless
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`the claims require administration “day after day.” Reply at 6; EX2096, ¶¶20-24.
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`But the word “daily” specifies that 0.5 mg is the total dosage in a 24 hour period
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`regardless of whether doses are divided or undivided. EX1047, ¶¶107-16. Under
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`Novartis’s “dosage amount” hypothetical, divided dosing would be excluded.
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`- 11 -
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`Petitioners’ construction does not render the word “daily” surplus.
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`Novartis argues that “[a] ‘daily dosage’ requires giving it day after day”
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`even though this broader term comprises narrower species of incremental, varying,
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`lower, and standard daily dosages in which a particular daily dosage amount is
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`administered for only one day. Reply at 6. That a dosage can be a daily dosage
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`when administered for one day disproves Novartis’s day-after-day construction.
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`Novartis’s proposed amended claims do not narrow the claims but instead
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`recapture disclaimed subject matter by removing the negative limitation “absent an
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`immediately preceding loading dose regimen.”
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`IV. THE PROPOSED CLAIMS DO NOT RESPOND TO GROUNDS 1-2
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`Novartis argues that the proposed amendments address Ground 1 because
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`they allegedly exclude a loading dose. Reply at 11. But the issued claims
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`categorically did so and the proposed amendments do nothing additional to
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`distinguish Kovarik. Dr. Giesser and Dr. Benet have rebutted Novartis’s arguments
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`that Kovarik is distinguishable from the claims because it does not limit its
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`disclosure only to MS, only to 0.5 dose, or because it used a loading dose regimen.
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`EX1002, ¶¶76-77, 104-08; EX1047, ¶¶25-37. The proposed amendments similarly
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`add no new limitation to distinguish Ground 2. EX1002, ¶¶131-41.
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`V. CONCLUSION
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`Apotex requests that Novartis’s Motion be denied.
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`- 12 -
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`Dated: April 19, 2018
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`
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`Respectfully submitted,
`
`/ Steven W. Parmelee /
`Steven W. Parmelee, Lead Counsel
`Reg. No. 31,990
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`- 13 -
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`CERTIFICATE OF SERVICE
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`This is to certify that I caused to be served a true and correct copy of the
`
`foregoing Petitioners’ Sur-Reply re Patent Owner’s Corrected Motion to Amend,
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`on this 19th day of April, 2018, on the Patent Owner at the correspondence address
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`of the Patent Owner as follows:
`
`Jane M. Love, Ph.D.
`Robert W. Trenchard
`GIBSON, DUNN & CRUTCHER LLP
`200 Park Avenue, 47th Floor
`New York, NY 10166
`Email: jlove@gibsondunn.com
`Email: rtrenchard@gibsondunn.com
`
`
`
`
`Dated: April 19, 2018
`
`
`
`
`
`
`
`
`/ Steven W. Parmelee /
` Steven W. Parmelee,
` Reg. No. 31,990
`
`
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`- 1 -
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