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`Paper No. ___
`Filed: February 16, 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
`_____________________________
`
`PETITIONER’S REPLY
`37 C.F.R. §42.24(c)
`
`
`1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`
`with this proceeding.
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION .............................................................................................. 1
`I.
`POR FAILS TO UNDERMINE PRIMA FACIE OBVIOUSNESS. ................................ 1
`II.
`A. Novartis Misreads and Ignores Prior Art. ............................................ 1
`B.
`POR Errs in Analyzing the Prima Facie Case. .................................... 4
`C.
`Novartis’s Attempts to Impugn Dr. Giesser Should Be Rejected. ........ 9
`III. NOVARTIS’S TEACHING AWAY AND UNEXPECTED RESULTS ARGUMENTS
`ARE INCORRECT. ......................................................................................... 11
`A. Webb Does Not Teach Away From 0.5 mg. ....................................... 11
`B.
`Predict Substantially Equivalent Efficacy. ......................................... 14
`IV. NO UNEXPECTED RESULTS ........................................................................... 17
`NO INDUSTRY SKEPTICISM ........................................................................... 20
`V.
`VI. GROUND 3 IS WITHIN THE BOARD’S JURISDICTION ....................................... 23
`VII. CONCLUSION ............................................................................................... 25
`LIST OF EXHIBITS ................................................................................................... 26
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`Subsequent Publications Confirm No Teaching Away and
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`-i-
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`I.
`
`INTRODUCTION
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`Novartis Response (Paper 27, “POR”) continues to misconstrue or ignore
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`prior art while tacitly conceding efficacy does not depend on loading doses. Failing
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`that, Novartis asks the Board to import result limitations into the claims that are
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`simply not there. Novartis also relies heavily on an alleged teaching away based on
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`animal studies, but these studies instead confirm that the 0.5 mg dose was expected
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`to work. Moreover, anticipatory prior art Novartis disclosed with its POR decimate
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`its erroneous teaching away and objective evidence arguments. Finally, Novartis
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`fails to identify Section 112 support in the priority documents for the no-loading-
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`dose element of the claims. Petitioners have established by a preponderance of the
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`evidence that claims 1-6 are unpatentable under each of Grounds 1-3.
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`II.
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`POR FAILS TO UNDERMINE PRIMA FACIE OBVIOUSNESS.
`
`A. Novartis Misreads and Ignores Prior Art.
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`The Petition established that a loading dose regimen increases the speed of
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`efficacy but is not required to make a maintenance dose effective for MS
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`treatment. Pet. 4-8, 30-31, 34-39, 41-43; Paper 11 at 18; EX1002, ¶¶67, 70-72,
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`108-09, 112-13, 117-22, 126. Petitioner thereby demonstrated the error in
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`Novartis’s prosecution argument that the 0.5 mg maintenance therapy disclosed in
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`Kovarik should be disregarded because it was allegedly dependent on the loading
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`dose regimen. Novartis and its experts have now conceded this point, as they must.
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`-1-
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`
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`EX2024, ¶131 (“achieve the effect of the drug faster”); EX2022, ¶¶157-58 (used to
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`avoid delay); POR 48 (Kappos showed no loading dose needed); see also EX1047,
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`¶¶31-37.
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`Novartis’s continued effort to ignore Kovarik because it used a loading dose
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`is particularly disingenuous because Novartis’s “teaching away” and “unexpected
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`results” arguments repeatedly rely on references describing transplant studies, in
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`which context loading doses were used. POR 9-14, 34-35, 37 (transplant studies
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`provide “insight” for “patients with multiple sclerosis”); EX1019 at 685 (loading
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`dose); EX1031 at 1084 (when rapid effect is “critical”). Novartis’s argument that
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`the Board should ignore Kovarik because it discloses “loading dose methods”
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`should be rejected.
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`Novartis wrongly contends Kovarik’s 0.5 mg maintenance therapy was
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`merely a hypothetical “input” for illustrating loading dose regimens for an
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`unspecified autoimmune disease. POR 4, 36. But the 0.5 mg maintenance therapy
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`was not a hypothetical input, it was “part of a preferred embodiment.” Pet. 7-11;
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`EX1004 at 13, 15, 17; EX1047, ¶¶25-30. Kovarik placed MS at the head of a small
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`list of preferred autoimmune disease targets of the medication. Pet. 10; EX1004 at
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`14, 17. Novartis’s argument is contrary to the express teachings of the reference
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`and should be rejected.
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`-2-
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`Novartis’s identification of RR-MS as the point of novelty also fails.
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`Novartis does not contest that RR-MS patients constituted the vast majority of MS
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`patients, that RR-MS was the target of prior disease-modifying therapies (DMTs),
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`and that reducing relapses and slowing progression in RR-MS patients were the
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`known targets and results of fingolimod treatment. POR 49 (agreeing “Kovarik
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`identifies multiple sclerosis as an autoimmune disease,” and “RRMS is the most
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`common form”), 5 (Thomson reviewed fingolimod’s application to RRMS);
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`EX1042 at 16:6-23:11, 25:8-29:2 (known DMTs reduced relapses and slowed
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`progression in RR-MS patients; progression slowed by reducing relapses).
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`Novartis’s latest attempt to misread Kovarik should be rejected.
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`
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`Unable to rewrite Kovarik, Novartis asks the Board to err by pretending
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`Kovarik does not exist. Randall Mfg. v. Rea, 733 F.3d 1355, 1362-63 (Fed. Cir.
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`2013) (reversing Board for ignoring prior art references); Coal. for Affordable
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`Drugs V LLC v. Biogen MA, Inc., IPR2015-01993, Paper 63 at 6 (POSA
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`“presumed to be aware of” all art “from the same or analogous fields”). Novartis
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`argues that only hindsight identifies Kovarik and Thomson as prior art and that
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`Kovarik was “seized…from the file history.” POR 46-49. But Dr. Giesser
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`explained that she analyzed Kovarik and Thomson because they were published
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`before June 2006 and describe “properties of fingolimod” and its “treatment for
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`MS.” EX2039 at 89:3-21. In other words, like the patent, each reference describes
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`-3-
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`
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`the use of the S1P inhibitor FTY720 for treating the demyelinating autoimmune
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`disease MS. Compare EX1004 at 1, 14 and EX1005 at 1 with EX1001, cover. The
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`asserted references are clearly analogous art. See In re Bigio, 381 F.3d 1320, 1325
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`(Fed. Cir. 2004) (analogous art includes references within the same field of
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`endeavor or reasonably pertinent to a problem addressed by the claims); see also
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`KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007) (“[N]either the particular
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`motivation nor the avowed purpose of the patentee controls.”).
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`B.
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`POR Errs in Analyzing the Prima Facie Case.
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`Novartis contends “elements are missing” from the Ground references (POR
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`49-51), but errs by reading them in isolation. Each of the steps of the claimed
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`methods is disclosed in the prior art.
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`Novartis’s challenges to motivation to combine also fail. As discussed in the
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`Petition, a POSA would have been motivated to combine each set of ground
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`references because they address the therapeutic use of FTY720 for the treatment of
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`MS or discuss relevant properties of FTY720. The Petition sets forth specific
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`rationales for applying specific teachings from one reference to the primary
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`reference in each ground.
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`Novartis contends that there could be no motivation to administer the 0.5 mg
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`dose to RR-MS patients when “Kappos 2005 had shown that 1.25 mg daily could
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`work.” POR 52, 55-56. But Dr. Lublin confirms that it was routine to identify the
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`-4-
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`
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`safest effective dose. EX1042 at 166:13-169:4. Kappos 2005, which favored the
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`lower 1.25 dose because of fewer adverse events, would not have dissuaded a
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`POSA from considering doses lower than 1.25 mg. Indeed, the 0.5 mg dose was
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`known to be safer than the 1.25 mg dose, yet still induced lymphopenia. See, e.g.,
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`Pet. 52-53; EX1008 at 1075-76 (higher doses (≥0.75) caused more bradycardia),
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`1078 (lymphocyte % baseline 46-27% for doses 0.25-3.5 mg), 1082 (“higher doses
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`caused a more rapid and more sustained lymphopenia; however, the degree of
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`lymphopenia showed only minor differences”); EX1005 at 163 (same); EX1042 at
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`75:20-76:14 (administering less than 0.5 mg when “white blood cell count gets too
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`low”); EX1047, ¶¶90-94.
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`Kovarik and Chiba each teach the 0.5 mg and lower doses (or a range
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`including them) as a maintenance therapy for treating autoimmune disease,
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`including MS. The efficacy of this dose was supported by prior art teachings that
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`lymphopenia observed at the relevant doses signaled efficacy against RR-MS by
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`reducing infiltration of inflammation-inducing T-cells into the CNS, which
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`inflammation causes relapses and progression. Pet. 53; EX1002, ¶140 (RR-MS
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`efficacy at 0.5 mg expected because EX1029 teaches doses of FTY720 sufficient
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`to induce lymphopenia reduced T-cells infiltration); Pet. 29, 51 (fingolimod treats
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`MS by reducing T-cell infiltration); EX1002, ¶¶63-64, 136 (lymphopenia includes
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`“decreased T-cell infiltration” (citing EX1029)); Pet. 26 (immunosuppressants treat
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`-5-
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`
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`RR-MS by reducing relapse-causing inflammatory activity); EX1002, ¶52
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`(EX1029 identifies T-cell infiltration “as a marker of active MS disease”); see also
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`Pet. 27, 42, 49-51 (POSA knew inflammation drives relapses; DMTs slow
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`progression by reducing relapses; fingolimod applicable to treatable RR-MS form;
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`fingolimod operates by reducing T-cell infiltration (citing EX1002, ¶¶53-54, 136));
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`EX1029 at 444-45 (describing T-cell infiltration); EX1042 at 16:6-19:17
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`(interferon treats RR-MS and slows progression by reducing relapses).
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`Novartis suggests it was unknown whether 0.5 mg fingolimod would induce
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`lymphopenia when administered repeatedly based on Budde’s single-dose study.
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`POR 53. But nothing suggests a maintenance therapy would be less efficacious
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`than a single dose. As Dr. Benet explains, Kahan 2003 and Park teach that using
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`0.5 mg as a maintenance therapy induces lymphopenia comparable to that seen
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`with doses that were therapeutically effective against an animal model of RR-MS
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`(EAE). EX1047, ¶¶49-56; EX1031 at 180 & Fig. 1 (~60% at steady state); EX1019
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`at 685, 689 (58% nadir, 42% average for weeks 4-12); EX1008 at 1078 Table 3
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`(52% for single dose).
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`Novartis contends a POSA would ignore Kovarik’s 0.5 mg dose because
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`“Kovarik contains no data.” POR 52. Neither does the ’405 patent. EX1001;
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`EX1042 at 93:7-94:15 (no clinical efficacy results); see also EX1050 at 65:15-21
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`-6-
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`(EX2057 “does not disclose administering a dose of 0.5 mg of fingolimod”);
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`EX1047, ¶29 (POSA would notice Novartis’s 0.5 mg dose disclosed in Kovarik).
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`Novartis argues it was only obvious to administer 0.5 mg to “test drugs long
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`before they are shown to be effective,” that Petitioner must prove motivation to
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`administer 0.5 mg “to accomplish the objectives claimed in the Patent,” and that
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`Petitioner must prove a reasonable expectation 0.5 mg “would yield the claimed
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`results.” POR 53. But there is no claim element that the drug must have been
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`“shown to be effective,” that alleged infringers must subjectively believe it will
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`work, or that administration achieve a particular result. “[T]he words in the
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`preambles inform the scope of ‘said subject’ in the body of each claim.” Paper 11
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`at 12. They create no efficacy requirement. In re Montgomery, 677 F.3d 1375,
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`1380 (Fed. Cir. 2012) (method of treating claims impose no “efficacy
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`requirement”).
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`Because relapsing RR-MS patients are “in need of” treating RR-MS by
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`reducing relapses and slowing disease progression, the claims are satisfied.
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`EX1042 at 72:12-74:15 (all Kappos 2005 patients in need of all three).
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`Obviousness is satisfied by “a motivation to combine accompanied by a reasonable
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`expectation of achieving what is claimed in the patent-at-issue.” Intelligent Bio-
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`Systems Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367-68 (Fed. Cir. 2016).
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`Speculation that 0.5 mg might fail to establish superiority over placebo or
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`-7-
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`
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`interferon in Phase III trials is irrelevant to reasonable expectation of success
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`because none of these are elements of the claims.
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`To the extent having an “objective” is a claim element (it is not), it was well-
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`known in June 2006 that fingolimod treated RR-MS by reducing both “patient-
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`oriented (relapse rate) and disease-oriented outcomes” (reducing lesions
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`responsible for progression). See, e.g., EX1005 at 157; EX1007. Thus, treating
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`RR-MS and slowing its progression via relapse reduction was the objective of
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`administering FTY720 to RR-MS patients in the prior art.
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`Novartis argues that Chiba should be ignored because it allegedly discloses
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`“a thousand-fold [dose] range.” POR 56. But Novartis fails to establish criticality
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`of 0.5 mg, which is alleged to work no better or differently than the 1.25 and 5 mg
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`doses. Cf. ClearValue, Inc. v. Pearl River Polymers, Inc., 668 F.3d 1340, 1345
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`(Fed. Cir. 2012). Novartis’s argument also ignores a POSA’s storehouse of
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`knowledge regarding the 0.5 mg dose reflected in Budde, Kovarik, Park, Kahan
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`2003, Kataoka, Chavez, and Press Release. Randall, 733 F.3d at 1362-63.
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`Novartis argues a total dose of 0.5 mg per day is “not a ‘daily’ dose” unless
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`the same dose is administered as a single dose once per day, day after day. POR
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`55. As Dr. Benet explains, however, the broadest reasonable construction of a
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`“daily dosage of 0.5 mg” includes a total dose of 0.5 mg in 24 hours regardless of
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`what unit doses are used or whether the same dose is repeated on consecutive days.
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`-8-
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`EX1047, ¶¶107-16; EX1001, 11:24-25 (“daily dosage” includes “as a single dose
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`or in divided doses”); EX1004 at 15-17, 19, 21 (using “daily dosage” when a total
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`dosage per day is given for only one day). Novartis may not ignore the broadest
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`reasonable interpretation of the claims.
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`C. Novartis’s Attempts to Impugn Dr. Giesser Should Be
`Rejected.
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`Novartis contends Dr. Giesser was “steered away from,” and lacked
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`expertise for, conducting “a proper analysis.” POR 30, 41-42. Novartis apparently
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`refers to its incorrect teaching away analysis. As Novartis’s substantive argument
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`is incorrect (see Section III), its “process” arguments should similarly be rejected.
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`They are also factually incorrect and hyperbolic. For example, Novartis
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`asserts that Dr. Giesser testified she only “spent” 7-8 hours on her declaration. But
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`Novartis’s counsel never asked Dr. Giesser how many hours she spent preparing
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`her declaration, instead asking: “How many hours did you bill on this matter
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`before your declaration was final?” EX2039 at 95:18-22.2 Novartis’s own expert
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`testified in deposition that he still had only billed Novartis for “a minority” of the
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`hours he spent preparing his declaration. EX1042 at 64:3-66:21; EX2025, ¶10.
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`Novartis’s attacks are based on misplaced assumptions and unfounded innuendo.
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`
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`2 All emphases added unless otherwise noted.
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`-9-
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`Novartis’s other attacks on Dr. Giesser’s character are likewise meritless.
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`EX2039 at 50:7-9, 67:1-7 (obtained copies of references from counsel), 91:20-21
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`(“the opinions in my declaration are my own”), 95:25-96:1 (“I read the exhibits
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`mentioned in the declaration on which I’ve rendered an opinion.”); see also id. at
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`96:24-97:2 (“I’m trying to be conservative and not just say that I’ve read all the
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`references listed in the appendix.”), 97:8-13 (“I just don’t remember it off the top
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`of my head.”).
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` Dr. Giesser compares favorably against Novartis’s experts, who identically
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`testified that Novartis’s counsel wrote their declarations. EX2022, ¶22; EX2024,
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`¶4; EX2025, ¶10. Novartis selected and provided documents for its expert to
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`include and its counsel provided the (undisclosed) bases for testimony. EX1042 at
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`157:25-158:14 (only saw excerpts of briefing book and FDA minutes),169:5-
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`170:25 (counsel sole basis for testimony that EX2064 contains the final study
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`plan), 174:21-175:6 (never asked to see FDA submissions justifying 0.5 mg dose),
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`178:6-179:6 (received EX2065-EX2066 from counsel and relied on Novartis as to
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`their veracity), 180:17-20 (EX2063 from counsel), 195:5-196:15 (“relying on the
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`assertion” that two sentences “actually come from the FDA minutes” but never
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`reviewed them), 199:19-24 (expert does not know context around excerpt). The
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`Board should reject Novartis’s specious character attacks.
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`-10-
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`
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`Dr. Jusko erroneously assumed that Dr. Giesser confused the 0.03 mg/kg
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`dose with the 0.3 mg/kg dose. EX2024, ¶76. Dr. Giesser relied on the “graphs” in
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`Figures 5A, 6B, and 8B to conclude that “the statement that you need 70 percent
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`[lymphopenia] to show any efficacy is plainly not supported” and that all tested
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`doses showed some signs of efficacy. EX2039 at 77:6-78:13. She also observed
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`that it was the 1 mg/kg dose in 6B that achieved 70% lymphopenia, not the 0.3
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`mg/kg dose. EX2039 at 85:15-86:4. Novartis’s unhinged attacks against Dr.
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`Giesser are unfounded.
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`III. NOVARTIS’S TEACHING AWAY AND UNEXPECTED RESULTS ARGUMENTS
`ARE INCORRECT.
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`A. Webb Does Not Teach Away From 0.5 mg.
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`Novartis calls Kovarik “irrelevant” in the face of “art teaching away [that]
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`would ‘discredit’ Kovarik.” POR 36-37. Novartis relies on Webb to argue that
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`clinical efficacy requires “at least 70% lymphopenia,” and on Kahan 2003 and
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`Park to establish that the 0.5 mg dose did not achieve at least 70 percent
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`lymphopenia and therefore would not have been expected to provide clinical
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`efficacy. POR 10-19, 33-39; EX1042 at 210:2-211:2. Novartis also relies on this
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`theory for unexpected results. POR at 39-40. As explained by Dr. Benet, a
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`pharmacologist having extensive experience in drug development, Novartis’s
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`arguments fail. EX1047, ¶¶1-19, 117; EX1048.
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`-11-
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`
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`Webb does not support Novartis’s “at least 70%” lymphopenia argument.
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`Novartis’s experts agree that Webb established the 0.3 mg/kg dose was
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`therapeutically effective, but Webb reports this dose did not achieve at least 70%
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`lymphopenia. EX1047, ¶¶38-48; EX2014 at 115 & Figs. 6B-C; EX1042 at 211:3-
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`215:25; EX2024, ¶¶72-75; EX2022, ¶¶80-81. Rather, it achieved only about 60%,
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`the same level of lymphopenia that 0.5 mg achieved in humans in Kahan 2003 and
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`Park after 4 weeks. EX1047, ¶¶49-56; EX1031 at 1081-82 & Fig. 1 (60%
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`maximum lymphopenia and 200 hr half-life); EX2003, ¶31 (“0.5 mg daily
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`achieved a maximum average lymphopenia of about 60%. This data would
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`certainly inform further drug dose development….”); EX1019 at 684 (4 weeks to
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`reach steady-state), 689 & Table 3 (58.2% lymphopenia for 0.5 mg after four
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`weeks). Webb thus suggests the 0.5 mg daily dose would be clinically effective.
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`A POSA would not have been dissuaded from the 0.5 mg dose for RR-MS
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`because of week-to-week or interpatient variability in lymphopenia or because
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`higher lymphopenia (80%) was correlated with “best efficacy” for preventing
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`transplant rejection. EX1047, ¶¶56-62 (discussing EX1019, EX2048, EX1007).
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`Indeed, the Phase II study had already proven efficacy of a lower 1.25 mg dose for
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`RR-MS than the 2.5 mg dose that had been proven for transplant rejection, and
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`Park’s predicted lymphopenia for the 1.25 dose was not “at least 70%.” Id.
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`-12-
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`Dr. Steinman’s argument that the 0.5 mg dose was discredited for RR-MS
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`treatment because average absolute lymphocyte counts in two outlier weeks rose
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`above 1,000/µL is not supported by the record. EX1019 at 689 (average counts of
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`“675 to 1085” for 0.5 mg); EX1042 at 76:23-81:16 (Lublin does not even monitor
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`lymphocytes to ensure they stay below 1,000); EX1031 at 1080 (1,200
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`lymphocyte/µL required for study participation); EX1047, ¶¶57-62 (T-cell
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`sequestration more precise measure for efficacy than all lymphocytes).
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`Novartis’s interpretation of Webb also misapprehends basic statistics by
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`conflating failure to prove efficacy as proving the absence of efficacy. As Dr.
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`Lublin testified, statistical power is the “ability to answer the question that you’re
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`asking.” EX1042 at 107:3-108:8. “If an underpowered study produced a negative
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`result, that does not mean that the drug doesn’t work….It means the study was
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`inconclusive.” Id. at 108:24-110:23. In Webb, each dose was administered to only
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`4 mice and only for about 10 days. EX2014 at 111, 114-15 & Figs. 5-6; EX1047,
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`¶41. Webb did not rule out efficacy for doses below 0.3 mg/kg. See EX1042 at
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`107:6-108:23 (“[I]f you put ten people in a group to study this over two years, you
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`couldn’t answer the question, because there’s not enough information that would
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`be obtained”).
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`Although Dr. Giesser agreed statistical significance was important to rule
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`out chance variation, she correctly noted that Webb Figure 5 did not rule out
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`-13-
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`efficacy at doses lower than 0.3 mg/kg dose. EX2039 at 68:20-69:1, 76:6-79:11,
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`81:21-82:19, 84:6-85:1 (“all of the doses produce a very visible reduction in
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`clinical score”). As Dr. Benet explains, a POSA would not conclude that 0.3 mg/kg
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`was the minimum effective dose because a 10-fold dose-reduction (to 0.03 mg/kg)
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`results in a very small reduction in cumulative clinical score that was unlikely to be
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`statistically significant. EX1047, ¶¶41-44.
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`B.
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`Subsequent Publications Confirm No Teaching Away and
`Predict Substantially Equivalent Efficacy.
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`Novartis argues the 0.5 mg dose would be discredited because it was
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`allegedly lower than the 0.1 mg/kg dose that Novartis concedes Kataoka had
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`shown to be therapeutically effective. POR 15, 19-20. Kataoka, however, supports
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`efficacy of the 0.5 mg dose against RR-MS. EX1047, ¶¶63-72 (discussing EX1029
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`at 439, 442-46 & Figs. 1-5, 9-10). Kataoka demonstrated that the 0.1 mg/kg dose in
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`mice reduced, alleviated and prevented relapses in EAE and inhibited progression.
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`Id. It also demonstrated efficacy where interferon, the FDA-approved control
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`treatment in the TRANSFORMS study, did not. Id. at ¶65; EX1042 at 16:6-19:18.
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`Kataoka teaches that therapeutic efficacy of fingolimod against EAE comes
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`from preventing T-cell infiltration. EX1047, ¶¶66, 73-76 (citing EX1029 at 439,
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`442-45 & Figs. 3-5, 9-10; EX1005 at 162). Lymphopenia is useful to confirm
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`fingolimod anti-EAE activity because it indicates reduced T-cell infiltration.
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`Kataoka demonstrates substantially equivalent effects in T-cell reductions, T-cell
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`-14-
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`
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`infiltration, relapse reduction, and demyelination prevention between the 0.1
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`mg/kg and 1 mg/kg doses in mice. Id.
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`Kataoka confirms the efficacy of 0.5 mg FTY720. The lowest dose already
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`shown to be effective in animal EAE studies (Kataoka’s 0.1 mg/kg in mice) is
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`equivalent to the 0.5 mg dose in humans. EX1047, ¶¶67-70. This equivalence is
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`determined from standard FDA conversions described in a prior art FDA Guidance
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`publication (EX1049). The 0.3 and 1 mg/kg doses of fingolimod administered to
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`mice in Kataoka and Webb translate to doses of about 1.5 and 5 mg in humans. Id.
`
`In other words, Kataoka’s teachings predicted substantially equivalent efficacy
`
`against RR-MS of 0.5 to 5 mg FTY720. The Phase II study confirmed these
`
`results. EX1047, ¶¶66-74.
`
`Novartis relies on Kataoka Figure 1 to argue dose-dependent efficacy across
`
`this same range. POR 19; EX2022, ¶¶86-89. Notably, therapeutic administration
`
`resulted in nominally lower histological scores for the 0.1 mg/kg dose than the
`
`higher 0.3 mg/kg dose, meaning the higher dose did not improve scores. EX1047,
`
`¶¶75-78. Further, the Figure 1 tests were performed in rats and thus used higher
`
`doses (equivalent to ~1, ~3, and ~10 mg in humans) than those administered in the
`
`mice experiments. Id. Figure 1 does not discredit the findings of the Phase II study
`
`that there was no substantial difference within this dose range. Id.
`
`-15-
`
`
`
`
`
`Subsequent prior art publications confirm FDA and Novartis were extending
`
`the Phase II findings of substantially equivalent efficacy to the 0.5 mg dose in
`
`Phase III studies. EX1047, ¶¶79-82. Novartis submitted with its Response two
`
`previously undisclosed prior art publications, Chavez (EX2031) and Press Release
`
`(EX2072). POR 25; EX1042 at 89:2-91:14, 221:6-222:14, 243:13-244:21;
`
`Montgomery, 677 F.3d at 1378-1380 (published description of ongoing phase III
`
`study anticipated claims).
`
`Dr. Lublin testified that, as of April 2006, a POSA would understand from
`
`these publications that 0.5 mg daily doses of fingolimod were being administered
`
`orally to RR-MS patients who had a need for reducing, preventing, or alleviating
`
`relapses, for RR-MS treatment, and for slowing the progression of RR-MS, absent
`
`an immediately preceding loading dose regimen. EX1042 at 223:4-18, 225:4-
`
`226:22, 227:8-17, 231:15-23, 237:2-11, 241:3-242:16, 243:13-245:8; EX1047,
`
`¶¶20-24, 82-83. Each reference thus describes an embodiment comprising each
`
`element of each claim.3 Chavez and Press Release thus decimate Novartis’s
`
`teaching way and unexpected results arguments.
`
`
`3 A POSA would have recognized that Novartis would not administer the 0.5
`
`mg dose to RR-MS patients in the Phase III trial unless there was a reasonable
`
`-16-
`
`
`
`
`
`IV. NO UNEXPECTED RESULTS
`
`Novartis bears the burden of producing objective evidence of
`
`nonobviousness. Prometheus Labs., Inc. v. Roxane Labs., Inc., 805 F.3d 1092,
`
`1101-02 (Fed. Cir. 2015). There must be “a nexus to establish that the evidence
`
`relied upon traces its basis to a novel element in the claim and not to something in
`
`the prior art.” BioMarin Pharmaceutical Inc. v. Genzyme Therapeutic Products
`
`Lmt. P’ship, IPR2013-00537, Paper 79 at 22; see also Ormco Corp. v. Align
`
`Technology, Inc., 463 F.3d 1299, 1311-12, n.14 (Fed. Cir. 2006). Novartis’s
`
`objective evidence arguments fail for lack of nexus.
`
`As explained above in Section III.B, Exhibits 2031 and 2072 confirm that
`
`every step of the methods was disclosed by the prior art in the claimed
`
`combination. Novartis is thus attempting to use “unexpected” results to
`
`monopolize a prior art method. Because the claimed method was in the public
`
`domain, whatever benefits may flow from it, even if they were unexpected (they
`
`were not) or remained to be definitively proven, cannot remove the prior art
`
`method from the possession of the public. See Montgomery, 677 F.3d at 1381
`
`(“efficacy is inherent in carrying out the claim steps”); see also Santarus, Inc. v.
`
`
`expectation that it would be clinically efficacious. EX1047, ¶82; accord EX1042 at
`
`147:15-150:8.
`
`-17-
`
`
`
`
`
`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); see also EX1047, ¶¶95-97.
`
`Novartis attempts to establish unexpected results in the form of substantially
`
`equivalent efficacy to the 1.25 mg daily dose. But equivalent efficacy is certainly
`
`not a difference in kind; it is not even a difference in degree. Bristol-Myers Squibb
`
`Co. v. Teva Pharms. USA, Inc., 752 F.3d 967, 976 (Fed. Cir. 2014). Moreover,
`
`1.25 mg is not the closest prior art; that is the prior art 0.5 mg daily dose. Id.
`
`Novartis’s unexpected results arguments fail for these reasons alone.
`
`Novartis’s argument that it was unexpected that the 0.5 mg dose would have
`
`any efficacy also fails for all of the reasons discussed in Section III. Further, even
`
`if the 0.5 mg dose “was expected to have submaximal effect on lymphocyte
`
`recirculation,” this does not mean that clinical efficacy or substantially equivalent
`
`clinical efficacy to the 1.25 mg dose was “a total surprise.” POR 27. As Dr. Benet
`
`explains, each of Webb and Kataoka predicted that maximal lymphocyte
`
`suppression was not required to achieve clinical efficacy, and Kataoka predicted
`
`substantially equivalent efficacy across this dose range. EX1047, ¶¶98-99. The
`
`Phase II and III publications confirmed these results in humans. Id.
`
`-18-
`
`
`
`
`
`Relying on Biogen, Novartis contends a claim with an “effective amount”
`
`element was patentable because “a prior art Phase II study” had shown that a
`
`higher dose was effective but that lower doses “were not,” rendering the
`
`“magnitude of clinical efficacy” a surprise. POR 32-33, 39. But in Biogen the
`
`Petitioner failed to substantively address patentee’s argument that efficacy was
`
`unexpected, leaving “Biogen’s expert testimony on this point” unchallenged.
`
`Biogen, Paper 63 at 25. That is not the case here. Further, here there is no Phase II
`
`trial that demonstrated a lack of efficacy for doses just below the claimed dose, and
`
`the present claims have no “effective amount” element.
`
`Novartis also relies on Avanir where “[a] prior clinical trial had shown that a
`
`60 mg dose was likely to yield the maximal biological effect.” POR 40. That Court
`
`noted that “Defendants’ references neither teach nor suggest lowering the dose of
`
`Q[uitidine] to the claimed [10-30 mg/day] ranges in combination with DM”
`
`(dextromethorphan) as the prior art only disclosed doses of 150 and 60 mg/day for
`
`any similar disease. Here, the claimed 0.5 mg dose was already disclosed for MS
`
`treatment in at least EX1004, EX1006, EX2031, and EX2072. Moreover, the dose-
`
`response relationship here was not unknown. See EX1005; EX1007; EX1008;
`
`EX1029; EX1049.
`
`Novartis’s reliance on
`
` to claim unexpected results of intermittent
`
`dosing and angiogenesis embodiments is unavailing. The claims of this patent do
`
`-19-
`
`
`
`
`
`not recite either embodiment. Novartis’s angiogenesis claims are in a different
`
`patent, and reducing angiogenesis for MS treatment and from fingolimod
`
`administration were each disclosed in the prior art. EX1047, ¶¶100-01 (discussing
`
`EX1013; EX1039 at 221; EX2043 at 353; EX2044 at 125); EX1042 at 94:17-95:6.
`
`It was not unexpected that fingolimod had an additional mechanism of action.
`
`Moreover, Dr. Steinman’s analysis
`
` is fatally flawed
`
`
`
` EX1047,
`
`¶¶102-06. Novartis’s unexpected results arguments should be rejected.
`
`V. NO INDUSTRY SKEPTICISM
`
`Novartis’s skepticisms arguments fail. Internal misgivings and design
`
`contingencies do not demonstrate industry skepticism. See, e.g., AstraZeneca LP v.
`
`Breath Ltd., 88 F.Supp.3d 326, 383-385 (D.N.J. 2015) (“whether or not
`
`AstraZeneca’s employees believed…is not the proper inquiry.”), affirmed by 603
`
`F.App’x 999 (Fed. Cir. 2015); AstraZeneca LP v. Breath Ltd, 2013 WL 1385224,
`
`at * (D.N.J. April 3, 2013) (designing multiple studies is not industry skepticism
`
`but merely “a relatively simple precaution”), affirmed in relevant part by 542
`
`F.App’x 971 (Fed. Cir. 2013) (“[T]his simply is evidence of corporate prudence
`
`based on AstraZeneca’s own misgivings rather than industry skepticism.”).
`
`Moreover, Dr. Lublin confirmed that neither he nor Dr. Kappos published
`
`their alleged concerns, voiced them to FDA, or decided to withhold their prestige
`
`-20-
`
`
`
`
`
`from the studies. EX1042 at 114:5-116:17, 122:14-123:23, 200:19-201:14. Their
`
`alleged skepticism was clearly not persuasive or unanimous,
`
`
`
`
`
`84; EX1051 at 7; EX1042 at 171:21-173:18.
`
`Similarly, the “futility” analysis reflects Novartis’s confidence in the 0.5 mg
`
` EX2064 at 25; EX1047, ¶¶83-
`
`dose more than skepticism.
`
`
`
`
`
`
`
` was reasonably predictive of the
`
`asserted therapeutic utility. See Montgomery, 677 F.3d at 1378-1382-83; MPEP
`
`§2107.03. Indeed, an ongoing clinical trial provides more evidence of efficacy than
`
`the prophetic trial in the ’405 patent.4 Using a lower effective dose (0.5 mg) with
`
`fewer side effects
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