`
`______________________
`
`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
`______________________
`
`
`PATENT OWNER NOVARTIS AG’S AUTHORIZED SUR-REPLY
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`
`
`
`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`TABLE OF CONTENTS
`Introduction ................................................................................................................ 1
`Argument.................................................................................................................... 2
`I.
`The Patent’s Claims Require Efficacy and Daily
`Administration. ...................................................................................... 2
`The Preambles ............................................................................. 2
`“Daily.” ...................................................................................... 4
`B.
`The Prior Art Taught Away From 0.5 mg for RRMS; the
`Results for That Dose Were Unexpected; and Grounds 1 and 2
`Are Without Merit. ................................................................................ 5
`A. Webb, Kahan 2003, and Park 2005 ............................................ 5
`
`A.
`
`II.
`
`B.
`
`The Skepticism of Others and the Clinical Trials’
`Unexpected Results ..................................................................... 9
`Petitioners’ Cherry-Picked References .................................... 12
`C.
`III. Ground 3 Fails For Lack of Legal Basis or Factual Support. ............. 15
`Conclusion ............................................................................................................... 15
`
`
`
`
`i
`
`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`TABLE OF AUTHORITIES
`
`Cases
`Coalition for Affordable Drubs V LLC, et al. v. Biogen M.A. Inc.,
`IPR2015-01993, Paper 63 (PTAB Mar. 21, 2017) ....................................... 11, 13
`Janssen v. Rexall Sundown, Inc.,
`342 F.3d 1329 (Fed. Cir. 2003) ............................................................................ 4
`In re Montgomery,
`677 F.3d 1375 (Fed. Cir. 2012) ............................................................................ 4
`Sanofi v. Watson Laboratories, Inc.,
`875 F.3d 636 (Fed. Cir. 2017) ............................................................................ 11
`Statutes
`35 U.S.C. § 112 ........................................................................................................ 15
`
`
`
`ii
`
`
`
`
`
`
`
`INTRODUCTION
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Inventors Hiestand and Schnell discovered that far lower doses of fingolimod
`
`could help RRMS patients than were previously thought possible. The ’405 Patent
`
`claims these methods for using 0.5 mg daily to reduce relapses, treat the disease, and
`
`slow its progression. Unique EAE rodent model experiments gave the inventors the
`
`insight to see past the art teaching that a dose this low would not work. Later, clinical
`
`trials overcame experts’ skepticism and ultimately proved the dose effective.
`
`The Petition here relied on testimony from only a single expert, MS physician
`
`Dr. Barbara Giesser. (Ex. 1002.) But discovery showed Dr. Giesser conducted no
`
`independent literature review to support her obviousness arguments, instead relying
`
`solely on references supplied by counsel. Courts categorically reject such lawyer-
`
`driven analyses as per se hindsight, and thus unlawful. (Paper 26 at 42-44.) Dr.
`
`Giesser also lacks the qualifications and experience needed to provide the full view
`
`of a person of skill, which the Institution Decision defined to include a
`
`pharmacologist. Dr. Giesser manifestly is not a pharmacologist. (Id. at 44-46.)
`
`Petitioners dispute none of this in their Reply. (Paper 49.) Either the lack of
`
`testimony from a pharmacologist or the undisputed lawyer-driven nature of Dr.
`
`Giesser’s review would, by themselves, defeat the Petition for failing to make out a
`
`prima facie case. Petitioners now seek to back-fill with new testimony from Dr.
`
`Leslie Z. Benet, a pharmacologist. (Ex. 1047.) It is too late. The Board should deny
`
`
`
`1
`
`
`
`
`
`
`the Petition based on its failure to make a prima facie showing. But even if the
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Board were to consider Dr. Benet’s views, they cannot save the Petition.
`
`Petitioners and Dr. Benet begin by trying to recast the Board’s claim
`
`constructions contrary to what the Institution Decision says. They then argue the
`
`prior art says something other than what it says; offer opinions on MS and EAE
`
`models beyond Dr. Benet’s expertise; improperly propound new invalidity theories
`
`beyond the Petition’s scope; and otherwise create a smokescreen around the
`
`Petition’s inadequacies. The Board should deny all three Grounds.
`
`ARGUMENT
`
`Dr. Benet is an eminent pharmacologist, but the wrong witness for this case.
`
`On cross-examination, he admitted his experience with the disease MS, the EAE
`
`animal model system, or the drug fingolimod is limited or non-existent—each key
`
`aspects of this case. (Ex. 2100 at 43:9-46:2; Ex. 2096 at ¶¶ 6-7.) Respectfully
`
`submitted herewith are declarations from experts to address Dr. Benet’s testimony:
`
`Exhibits 2096 (3d Steinman), 2095 (4th Jusko), 2097 (4th Lublin), and 2098 (Chun).
`
`I.
`
`The Patent’s Claims Require Efficacy and Daily Administration.
`The Preambles. The Patent claims methods “for” achieving different
`A.
`
`effects from giving 0.5 mg “daily” to a “subject in need”: (i) “preventing, reducing,
`
`or alleviating” relapses (claims 1 and 2); (ii) “treating” RRMS (claims 3 and 4); and
`
`(iii) “slowing progression” of RRMS (claims 5 and 6). (Ex. 1001 at 12:49-13:9.)
`
`
`
`2
`
`
`
`
`
`
`The Board rejected Petitioners’ non-limiting construction in the Institution Decision.
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Among other things, the Board found that the presumption against claim
`
`“redundancy” requires giving each preamble meaning; otherwise, the claims would
`
`all collapse to the same scope. (Paper 11 at 12.)
`
`Petitioners try to revive their rejected construction by pretending the
`
`Institution Decision only requires the preambles to limit the “subject,” and not to
`
`achieve or intend to achieve the claimed effects. (Paper 49 at 7; Ex. 1047 ¶¶ 20-23.)
`
`Dr. Steinman shows (Ex. 2096 ¶¶ 9-11) this interpretation violates the law against
`
`redundancy. All active RRMS patients need all of the claimed effects. Petitioners
`
`agree. (Paper 49 at 7.) The preambles’ recited effects address different aspects of
`
`RRMS, as Dr. Giesser admitted on cross-examination. (Ex. 2096 ¶ 12.) The
`
`preambles thus must be construed to require that 0.5 mg daily provides these effects.
`
`Tellingly, Petitioners point to nothing in the patent to support their position,
`
`nor could they. As Dr. Steinman shows (id. ¶¶ 13-17), the specification repeatedly
`
`emphasizes the invention’s superior effectiveness over the prior art, as does the file
`
`history. Accordingly, the “ordinary and customary” meaning of the preambles
`
`would include that 0.5 mg be given “for” achieving the claimed effects.
`
`Petitioners rely heavily on In re Montgomery, 677 F.3d 1375 (Fed. Cir. 2012),
`
`to argue otherwise. (Paper 49 at 7.) Montgomery is inapposite. To begin with, the
`
`Federal Circuit, while “skeptical,” assumed the claims there in fact required efficacy.
`
`
`
`3
`
`
`
`
`
`
`677 F.3d at 1380-81. Moreover, the challenged claims all related to only one method
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`with one effect—“treatment or prevention of stroke.” The Montgomery claims thus
`
`presented no redundancy issue, unlike here. Lastly, the Montgomery specification
`
`did not “describe any studies that show” stroke treatment or prevention. Id. at 1381.
`
`Here, the specification describes animal studies that show each of the claimed
`
`effects, as Dr. Steinman shows. (Ex. 2096 ¶¶ 14-15.)
`
`The claims here should thus be read to require efficacy. Alternatively, if the
`
`Board felt differently, the claims at the very least should be read to require that 0.5
`
`mg be given for the “intentional purpose for which the method must be performed.”
`
`Janssen v. Rexall Sundown, Inc., 342 F.3d 1329, 1333 (Fed. Cir. 2003). Without
`
`one or the other reading—requiring efficacy or a purpose—the claims would not be
`
`limiting, contrary to the Board’s Institution Decision.
`
`B.
`
`“Daily.” Besides trying to neuter the preambles, Petitioners strain to
`
`argue that the claimed “daily dosage” would be satisfied with a single, one-time 0.5
`
`mg administration, rather than day-by-day dosing. (Paper 49 at 8-9, 24-25; Ex. 1047
`
`¶¶ 107-16.) Petitioners thereby apparently hope to make one of the instituted
`
`references relevant—Budde 2002 describes a single administration of 0.5 mg in a
`
`Phase I safety study of stable renal transplant patients. (Ex. 1008.) But “daily” does
`
`not mean “once.” It means 0.5 mg per day for more than one day. Dr. Steinman
`
`shows that Dr. Benet’s reading is uninformed by any relevant experience. (Ex. 2096
`
`
`
`4
`
`
`
`
`
`
`¶¶ 21-22.) RRMS has no cure; therapies like fingolimod require continuous
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`administration to be effective. Giving the drug only once would be meaningless.
`
`II. The Prior Art Taught Away From 0.5 mg for RRMS; the Results for That
`Dose Were Unexpected; and Grounds 1 and 2 Are Without Merit.
`Dr. Giesser’s reliance on counsel’s cherry-picked references for her review
`
`missed the full scope of the art in June 2006. Contrary to her view, the art taught
`
`that 0.5 mg daily was unlikely to be effective in RRMS. Dr. Benet’s effort to back-
`
`fill what Dr. Giesser failed to address is improper.
`
`A. Webb, Kahan 2003, and Park 2005: The Art Teaching Away.
`
`Petitioners do not dispute that scientists in June 2006 believed fingolimod worked
`
`by sequestering lymphocytes in lymphatic tissue away from peripheral blood. That
`
`was thought to inhibit these immune cells from attacking transplanted organs or the
`
`body’s own tissues. (See, e.g., Ex. 2096 (3d Steinman) ¶¶ 2-5.)
`
`For RRMS, Webb reported results from EAE animal studies that “a threshold
`
`of about 70% depletion of peripheral lymphocytes was required to see any
`
`efficacy[.]” (Ex. 2014 at 118.) Human PK/PD studies in Kahan 2003 and Park 2005
`
`showed that 0.5 mg daily was unlikely to suppress lymphocytes to these levels. A
`
`person of skill thus would have thought 0.5 mg daily unlikely to be effective. (See
`
`Exs. 2022 (Steinman), 2024 (2d Jusko).)
`
`
`
`5
`
`
`
`
`
`With no experience in performing EAE studies or in MS, Dr. Benet tries to
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`
`reinterpret graphical data to turn Webb and the human PK/PD analyses into
`
`references for Petitioners. Dr. Benet contends that certain averaged data in Webb
`
`shows that only 60% suppression was needed. (Ex. 1047 ¶¶ 40-48.) Having thus
`
`lowered the bar from 70% to 60%, Dr. Benet asserts that the human PK/PD papers
`
`show 0.5 mg daily suppresses lymphocytes by about 60% at peak levels, although
`
`average suppression was far lower. (Id. ¶¶ 49-53.)
`
`Dr. Chun and Dr. Steinman dismantle Dr. Benet’s analysis. (Exhibits 2096
`
`and 2098.) Dr. Chun, a Webb co-author, testifies the authors meant what they
`
`wrote—about 70% suppression was needed for any efficacy. (Ex. 2098 ¶¶ 2-9, 17-
`
`35.) He explains their judgment was informed by multiple data points, not just the
`
`averaged data Dr. Benet manipulates. (Id. ¶¶ 2-8, 36-41.) As is common, the Webb
`
`authors considered information not specifically graphed in the paper, including data
`
`from individual mice and qualitative assessments of various aspects of the EAE
`
`model. (Id.) Dr. Steinman confirms that a person of skill would have believed Webb
`
`as written. (Ex. 2096 ¶¶ 25-40.) The paper’s conclusions were the result of the
`
`collective judgment of the articles’ esteemed authors and had withstood rigorous
`
`peer review. (Id. ¶¶ 33-40.)
`
`In addition, Dr. Steinman explains that Dr. Benet’s reliance on maximum
`
`suppression data from the human PK/PD studies has no foundation. (Id. ¶¶ 41-54.)
`
`
`
`6
`
`
`
`
`
`
`RRMS is a chronic long-term disease that requires continuous, sustained therapy. A
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`dose that provides therapy only intermittently would be unacceptable. (Id. ¶¶ 48-
`
`51.)
`
`A person of skill evaluating 0.5 mg in June 2006 thus would have looked to
`
`average lymphocyte levels. Park 2005 showed that 0.5 mg daily only suppressed
`
`lymphocytes by 42% on average, with wide variation among patients and from
`
`week-to-week. Dr. Steinman explains why such peripatetic effects would be
`
`strongly disfavored for treating RRMS. (Id.) Dr. Chun, too, describes why Dr.
`
`Benet’s effort to use Webb’s analysis as justification for seizing on maximum
`
`suppression levels is misplaced. (Ex. 2098 ¶¶ 42-44.)
`
`Dr. Benet tries to undermine the teaching away evidence by also arguing that
`
`a later EAE study in “Kataoka” (Ex. 1029) supposedly pointed toward doses of 0.5
`
`mg. (Ex. 1047 ¶¶ 64-78.) Kataoka found that doses of 0.1 mg/kg were effective in
`
`treating mouse and rat EAE. Dr. Benet says that the mouse dose in Kataoka scales
`
`up to 0.5 mg in humans using an FDA Guidance on scaling animal doses for the
`
`first-in-human testing. On that basis, Dr. Benet contends that Kataoka would have
`
`undermined the teaching away in Webb, Kahan 2003, and Park 2005.
`
`Dr. Jusko shows why Dr. Benet is wrong. (Ex. 2095.) In June 2006, copious
`
`data existed to permit more accurate estimates of human dosing.
`
`
`
`7
`
`
`
`
`
`First, Webb established an efficacy benchmark that Dr. Benet does not
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`
`disagree would be applied to humans too, and Kahan 2003 and Park 2005 supplied
`
`human data on whether different doses would meet that benchmark. With that
`
`information, a pharmacologist would not just extrapolate from one dose in an animal
`
`to a human dose. More refined methods existed. (4th Jusko, Ex. 2095 ¶¶ 3-18;
`
`Rowland, Ex. 2103; Troncoso, Ex. 2101 at 372.)
`
`Second, if scaling from an animal to a human dose were nonetheless tried, a
`
`pharmacologist would have used existing animal and human PK data to tailor the
`
`scaled dose to what was known about fingolimod in particular. A pharmacologist
`
`would not use a Guidance aimed at general dose scaling for any drug. Dr. Benet did
`
`not perform that analysis, and Dr. Jusko shows it would point to doses of 1.0 mg or
`
`higher for humans. (Id. ¶¶ 19-26.)
`
`Third, if the FDA Guidance were used—and it would not be—then a
`
`pharmacologist would look not only at Kataoka’s mouse but also its rat data, and
`
`would also explore variants permitted by the FDA Guidance. Dr. Benet limited
`
`himself to a single extrapolation from only the mouse, but a more complete review
`
`again would have pointed to doses of 1.0 mg or higher. (Id. ¶¶ 27-44; Mahmood,
`
`Ex. 2102; CDC Data, Ex. 2104 at 7; Tang, Ex. 2106 at 1298.)
`
`Put differently, Dr. Benet’s use of animal scaling—an idea well outside the
`
`scope of the Petition—points exactly the opposite way he and Petitioners contend.
`
`
`
`8
`
`
`
`
`
`B.
`
`The Skepticism of Others and the Clinical Trials’ Unexpected Results.
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`
`Consistent with the prior art teaching away, persons of skill in June 2006 in fact
`
`thought 0.5 mg unlikely to work, and were surprised when it did. Dr. Lublin was
`
`involved in the fingolimod clinical trials and sets out these facts in his Second
`
`Declaration. (Ex. 2025.) Petitioners offer no rebuttal from anyone else involved in
`
`the trials, or who even purports to have been aware of the trials at the time.
`
`Petitioners and Dr. Benet instead argue that Novartis’s press release touting
`
`successful results from the Phase II trial somehow would have told a person of skill
`
`that 0.5 mg was likely to be effective. (Paper 49 at 16.) Chavez (Ex. 2031) and the
`
`April 2006 press release (Ex. 2072) are nearly identical two-page documents
`
`describing the “sustained efficacy and good tolerability” of 1.25 mg and 5.0 mg in a
`
`Phase II MS study. Near the end of these documents, a few sentences describe an
`
`upcoming “Phase III study program.” The only mention of 0.5 mg is in one sentence:
`
`“Study participants will be equally randomized to either receive either 1.25 mg or
`
`0.5 mg of FTY720 or placebo once daily for up to 24 months.”
`
`Petitioners now say for the first time that these documents make the Patent
`
`obvious (if not anticipated). Far from it. Unlike the higher 1.25 mg dose from Phase
`
`II, 0.5 mg had never been given to a human RRMS patient before. As Dr. Lublin
`
`shows (Ex. 2097 ¶¶ 2-13), the mere announcement of a clinical trial would not tell a
`
`person of skill anything about whether 0.5 mg daily was likely to work.
`
`
`
`9
`
`
`
`
`
`Indeed, because 0.5 mg daily had never been given to an MS patient before,
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`
`Novartis adopted an unprecedented futility analysis to cut short that dosing arm if it
`
`proved ineffective. (Id. ¶¶ 14-16.) Mount Sinai nonetheless refused to participate
`
`in one of the trials at all due to concern that the 0.5 mg dose would be ineffective.
`
`(Id. ¶¶ 16-18; Ex. 2025 ¶¶ 45-47, 50-58.) Dr. Lublin shows that FDA was known to
`
`ask sponsors to evaluate doses lower than a person of skill would think effective.
`
`(Ex. 2097 ¶¶ 19-22.) MS has unique safety issues that prompt FDA to probe the
`
`lowest effective dose range for an potential MS medication. Petitioners and Dr.
`
`Benet offer no evidence to the contrary.
`
`Petitioners glaringly ignore Sanofi v. Watson Laboratories, Inc., 875 F.3d 636
`
`(Fed. Cir. 2017), a case Novartis brought to Petitioners’ attention in January (Paper
`
`39 at 9-10). In Sanofi, as here, the patent owner filed an application seeking method
`
`claims after a Phase III trial had begun, but before the trial was done. Before the
`
`application, a paper described the ongoing trial saying the method was “expected”
`
`to work. The Federal Circuit nonetheless upheld the patent finding the clinical trial
`
`paper showed only that the inventors “hypothesized” efficacy. Id. at 647.
`
`Here, the facts are far stronger for Patent Owner. In Sanofi, the claimed
`
`method had already been the subject of extensive “post hoc” statistical analysis
`
`based on data from prior clinical trials (875 F.3d at 640; here, 0.5 mg had never been
`
`tested in an RRMS patient before. Plus, unlike in Sanofi, here nothing said that 0.5
`
`
`
`10
`
`
`
`
`
`
`mg daily was expected to work; on the contrary, Novartis and others commented
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`only on the prospects for 1.25 mg. (Ex. 2072 at 2; Ex. 2031 at 3; Ex. 2036 at
`
`385.) While Dr. Benet tries to characterize those statements as extending to both
`
`doses (Ex. 1047 ¶ 86), Dr. Lublin shows why Dr. Benet is mistaken (Ex. 2097 ¶¶ 9-
`
`11). Lastly, here the prior art taught away from the invention, a situation not present
`
`in Sanofi at all.
`
`The facts here are also stronger than in Coalition for Affordable Drubs V LLC,
`
`et al. v. Biogen M.A. Inc., IPR2015-01993, Paper 63 (PTAB Mar. 21, 2017), in which
`
`the Board nonetheless upheld an MS drug dosing patent (see Paper 26 at 32).
`
`Petitioners try (Paper 49 at 19) to distinguish Biogen on the theory that the claimed
`
`dosage in that case was close to another dose that had already been found ineffective.
`
`But here, the art taught affirmatively away from the claimed dose, an argument not
`
`presented in Biogen. So this distinction cannot withstand scrutiny.
`
`Petitioners and Dr. Benet acknowledge that 0.5 mg was included in the Phase
`
`III trial essentially as a Phase II built into a Phase III trial—precisely because 0.5
`
`had never gone through Phase II before. (Ex. 1047 ¶ 84.) An earlier Biogen case
`
`held that even a public description of a Phase II trial at most states a “hope” of
`
`efficacy; it does not render the claimed dose obvious. Coalition for Affordable
`
`Drugs V LLC v. Biogen MA Inc., IPR2015-01136, Paper 23 at 10 (PTAB Sept. 2,
`
`
`
`11
`
`
`
`
`
`
`2015). So, too, here, where 0.5 mg daily had never been tested before in RRMS
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`patients.
`
`Petitioners argue that the futility analysis and Mount Sinai emails do not
`
`amount to “skepticism” because they were non-public. (Paper 49 at 20-23.) But the
`
`case Petitioners cite only concerns statements by an inventor inside a company,
`
`which these are not. Moreover, whether or not this evidence amounts to formal
`
`“skepticism,” it is objective, contemporaneous evidence of what experts in the field
`
`actually thought about the likelihood that 0.5 mg daily would be an effective dose.
`
`Petitioners and Dr. Benet argue (Paper 49 at 17-20) that the Phase III trial’s
`
`results were not unexpected given their flawed reading of the prior art, an argument
`
`that fails for the reasons stated above and in Novartis’s Response. Petitioners and
`
`Dr. Benet argue also that Kataoka presaged the unexpected result that 0.5 mg was
`
`equally effective with 1.25 mg. (Id. at 18; Ex. 1047 ¶¶ 71-78.) That argument is
`
`based on Dr. Benet’s flawed animal-scaling methodology, hindsight, and his
`
`misunderstanding of Kataoka. In actual fact, Kataoka buttressed Webb. Every
`
`effective mouse dose in Kataoka suppressed lymphocytes by more than 70%. (Ex.
`
`2095 ¶¶ 10-12; Ex. 2096 ¶¶ 70-74.) To the extent Kataoka teaches anything, it is
`
`that Webb’s fundamental finding remained unchallenged in June 2006.
`
`C.
`
`Petitioners’ Cherry-Picked References. Petitioners continue to argue
`
`that any dose that showed any ability to suppress lymphocytes to any extent would
`
`
`
`12
`
`
`
`
`
`
`have been an obvious dose to use to treat RRMS in June 2006. (Paper 49 at 5-6, 18.)
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`But Webb and similar studies in transplant patients demolish that theory—the art
`
`showed that lymphocytes had to be suppressed beyond a minimum threshold to
`
`provide therapeutic benefit. Petitioners’ arguments based on Kovarik (Ex. 1004)
`
`and Kappos 2005 (Ex. 1007) fail for other reasons too.
`
`Kovarik. Petitioners do not dispute that the Board misread Kovarik in the
`
`Institution Decision. (See Paper 26 at 51-52.) But they continue to mischaracterize
`
`Kovarik as disclosing a 0.5 mg daily dose of fingolimod for multiple sclerosis.
`
`(Paper 49 at 1-3, 5-6, 8.) Dr. Steinman shows Kovarik does no such thing. (Ex.
`
`2096 ¶¶ 56-69.)
`
`Kovarik’s putative invention is located in its claims, none of which mentions
`
`any daily dose for any particular condition. (Id. ¶ 61; Ex. 1004 at 20-22.) The
`
`Kovarik invention instead is a dosage regimen in which a given daily dose or target
`
`drug blood concentration is used to calculate the loading dose. Kovarik’s
`
`specification thus provides many examples of many potential daily doses that could
`
`be used to calculate a loading dose for many possible conditions, but it never
`
`discloses any particular daily dose for any particular condition. (Ex. 1004 at 13-18.)
`
`Among these examples is a range of 0.1-0.5 mg for “an” unspecified
`
`autoimmune disease. Dr. Steinman showed that over 100 autoimmune diseases were
`
`known in June 2006 (Ex. 2022 ¶ 146), a fact Petitioners do not contest. They instead
`
`
`
`13
`
`
`
`
`
`
`argue that MS was included in an exemplary list in Kovarik, and thus would be
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`covered. (Paper 49 at 2; Ex. 1047 ¶ 27.) But the list in Kovarik is not exclusive—
`
`it is an “e.g.” list—so Kovarik purports to cover all autoimmune diseases. The
`
`Kovarik example Petitioners cite applies only to “an” autoimmune disease—just
`
`one—and Petitioners point to no reason to think it would be RRMS. In truth,
`
`Kovarik had no need to specify, because the passage Petitioners cite is merely an
`
`illustration of how Kovarik’s general loading dose works. (Ex. 2096 ¶¶ 63-69.)
`
`Kappos 2005. This abstract of the Phase II results showing 1.25 mg having
`
`equal efficacy to 5.0 mg would, among other things, have eliminated a person of
`
`skill’s reason for exploring a lower dose. (Paper 26 at 52.) Both doses were safe
`
`enough to be used for RRMS medications and showed good efficacy. (Ex. 2096
`
`¶¶75-77; Ex. 1007 at II/41.)
`
`Petitioners and Dr. Benet argue that Kappos 2005 should be read in light of
`
`Kataoka, and that both together would have predicted the efficacy curve would
`
`remain flat at 0.5 mg daily. (Paper 49 at 15; Ex. 1047 ¶ 71-78.) This argument is
`
`based on Dr. Benet’s flawed animal scaling theories, and should be rejected for those
`
`reasons. In addition, Petitioners fail to put in any evidence to counter Novartis’s
`
`evidence that the safety results in Kappos 2005 would have been sufficient to use
`
`either or both of the doses in that study as a medicine. (Paper 26 at 52.)
`
`
`
`14
`
`
`
`
`
`
`III. Ground 3 Fails For Lack of Legal Basis or Factual Support.
`Petitioners do not dispute Novartis’s showing (Paper 26 at 57-61) that the
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`statements in the cases Petitioners’ cite are dicta inconsistent with the AIA’s
`
`command that IPRs be limited “only” to 102 or 103 grounds based “only” on printed
`
`publications. The Board should deny Ground 3 for this reason alone.
`
`Petitioners also still provide no evidence to support their 112 theory that
`
`exclusion of loading doses lacks support. Neither Dr. Giesser nor Dr. Benet say a
`
`person of skill would read the specification as Petitioners contend. Dr. Giesser
`
`herself points to the absence of any loading dose discussion in the specification as
`
`evidence that no loading dose would be needed for the claimed method. (Ex. 1002
`
`¶ 123.) Hence, Novartis’s evidence that a person of skill in fact would understand
`
`the specification to describe “daily” dosing that excludes a loading dose—or at least
`
`permits the exclusion of such a dose in an embodiment—is unrebutted. (See
`
`Steinman, Ex. 2022 ¶¶ 10, 182-89.) Ground 3 should be denied for this reason too.
`
`CONCLUSION
`
`For the foregoing reasons, the Board should deny the Petitions and find the
`
`’405 Patent valid.
`
`
`
`
`
`
`
`
`
`
`
`Respectfully submitted,
`
`
`
`Dated: March 23, 2018
`
`
`
` /Jane M. Love, Ph.D./
`
`
`
`
`
`15
`
`
`
`
`
`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`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
`
`16
`
`
`
`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`CERTIFICATE OF SERVICE
`
`Pursuant to 37 C.F.R. § 42.6, I hereby certify that on March 23, 2017, true and
`
`accurate copies of the foregoing Patent Owner Response for IPR2017-00854 (and
`
`accompanying Exhibits 2095-2107) were served via electronic mail, on the
`
`following counsel of record for Petitioners:
`
`For Apotex:
`
`For Argentum:
`
`
`For Sun:
`
`Steven W. Parmelee: sparmelee@wsgr.com
`Michael T. Rosato: mrosato@wsgr.com
`Jad A. Mills: jmills@wsgr.com
`
`Wilson Sonsini Goodrich & Rosati
`701 Fifth Avenue, Suite 5100
`Seattle, WA 98104
`Telephone: 206-883-2542
`
`
`Teresa Stanek Rea: trea@crowell.com
`Deborah H. Yellin: dyellin@crowell.com
`Shannon M. Lentz: slentz@crowell.com
`Tyler C. Liu: TLiu@agpharm.com
`
`Crowell & Moring LLP
`Intellectual Property Group
`1001 Pennsylvania Ave, NW
`Washington, DC 20004-2595
`(202) 624-2620
`
`Samuel Park: SPark@winston.com
`Charles B. Klein: CKlein@winston.com
`Sharick Naqi: SNaqi@winston.com
`
`Winston & Strawn LLP
`35 W. Wacker Drive
`
`i
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Chicago, IL 60601
`Telephone: (312) 558-7931
`
`Amanda Hollis: amanda.hollis@kirkland.com
`Eugene Goryunov: egoryunov@kirkland.com
`Gregory Springsted: gregory.springsted@kirkland.com
`
`Kirkland & Ellis LLP
`300 North LaSalle
`Chicago, IL 60654
`Telephone: (312) 862-2000
`(202) 624-2620
`
`
`
`
`Respectfully submitted,
`
`
`
`
`
`
`
`
`For Teva:
`
`
`
`
`
`
`
`Dated: March 23, 2018
`
`
`
`
`
`
`
` /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
`
`ii
`
`