UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., AND SUN PHARMA GLOBAL FZE,
`Petitioners,
`V.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-008541
`U.S. Patent No. 9,187,405
`______________________
`THIRD DECLARATION OF LAWRENCE STEINMAN, M.D.
`
`
`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.
`
`
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2096
`
`
`______________________
`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
`______________________
`THIRD DECLARATION OF LAWRENCE STEINMAN, M.D.
`
`
`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.
`
`
`
`
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2096
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`
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`I, Lawrence Steinman, M.D., declare as follows:
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`I.
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`Introduction
`I am the same Lawrence Steinman who submitted a prior declaration in
`1.
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`this matter, Exhibit 2022 (“First Declaration”). I also executed an additional
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`declaration, Exhibit 2077 (“Second Declaration”), which was served on December
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`5, 2017 as supplemental evidence. I submit this Third Declaration in support of
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`Novartis’s sur-reply, and in particular to address certain opinions by Dr. Leslie Z.
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`Benet (Ex. 1047). I use the same terms and abbreviations here that I used in my
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`prior declarations.
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`2.
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`In my First Declaration (Ex. 2022), I showed how the art taught away
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`from the ’405 Patent’s invention—methods of using a 0.5 mg daily dosage of
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`fingolimod to (a) prevent, reduce, or alleviate relapses in relapsing-remitting
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`multiple sclerosis (RRMS) (claims 1 and 2); (b) treat the disease (claims 3 and 4);
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`or (c) slow its progression (claims 5 and 6). (Ex. 1001 at 12:49-13:9.) Scientists in
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`June 2006 believed that fingolimod worked primarily by sequestering lymphocytes
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`out of the blood stream in the lymphatic system. That mechanism was thought to
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`prevent the lymphocytes from attacking either transplanted organs or the body’s own
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`tissues in an autoimmune disease.
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`3. With respect to RRMS in particular, the Webb paper reported that
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`experiments in an EAE animal model showed that “a threshold of about 70%
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`depletion of peripheral lymphocytes was required to see any efficacy[.]” (Ex. 2014
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`at 118.) That was consistent with data from transplant studies showing fingolimod
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`effective only at about 80% suppression. But human transplant studies of
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`fingolimod in Kahan 2003 (Ex. 1031) and Park 2005 (Ex. 1019) showed that 0.5 mg
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`daily suppressed average lymphocyte by less than 50%. Scientists believed this
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`transplant data applied to RRMS patients too, and thus pointed away from the 0.5
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`mg daily dosage claimed in the ’405 Patent.
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`4.
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`Dr. Benet does not appear to disagree with many of these facts,
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`including that (i) lymphocyte suppression was viewed as the central mechanism of
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`action for fingolimod in June 2006; (ii) prior studies showed that higher doses tended
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`to suppress lymphocytes to a greater extent than lower doses, and produce better
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`clinical outcomes; (iii) Webb provided a benchmark for potential human efficacy;
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`and (iv) PK/PD data from transplant patients applied to RRMS patients too.
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`5.
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`But Dr. Benet implies (Ex. 1047 at ¶¶ 20-22) that any prior art about
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`the dose’s likely efficacy is irrelevant here because the ’405 Patent’s claims
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`allegedly require no efficacy. If the claims do require efficacy, Dr. Benet argues
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`(Ex. 1047 at ¶¶ 46-48) that a person of skill would have viewed Webb’s 70%
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`suppression efficacy threshold as inconsistent with data in that paper pointing to a
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`60% threshold. Dr. Benet then says (id. at ¶¶ 49-62) that maximum rather than
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`average suppression data in Kahan 2003 and Park 2005 meet Webb’s alleged 60%
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`threshold, and (id. at ¶¶ 63-99) that other information in the art pointed toward 0.5
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`mg daily, including the instituted references (especially Kovarik).
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`6.
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`Dr. Benet is an eminent pharmacologist, but his experience with MS,
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`EAE models, and fingolimod is limited or non-existent. He testified on cross-
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`examination that he has never published any peer-reviewed articles on any of these
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`subjects (Ex. 2100 at 44:15-45:6); run an EAE experiment himself (id. at 45:25-
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`46:2); or conducted any fingolimod experiments (id. at 44:2-17). His experience
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`with MS drugs seems limited to a few confidential consulting projects 15-20 years
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`ago, in which he “used” data from EAE studies. (Id. at 46:4-47:6.) Dr. Benet
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`accordingly acknowledged that he is not an expert in MS research. (Id. at 41:18-
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`42:15.)
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`7.
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`This lack of experience pervades his declaration. In particular:
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`• Dr. Benet’s contention that the ’405 Patent’s claims require no
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`efficacy misunderstands the Patent and the state of MS drug research
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`at the time of the invention.
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`• Dr. Benet’s reading of Webb misunderstands EAE models, the data
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`available to the authors, and the interpretation of that data by the
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`authors.
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`• Dr. Benet’s view that maximum rather than average lymphocyte
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`suppression would guide dose development misunderstands the
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`chronic nature of MS and the need for sustained treatment.
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`• Dr. Benet’s interpretation of key references—especially Kovarik
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`(Ex. 1004), Kataoka (Ex. 1029), and Kappos 2005 (Ex. 1007)—is
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`colored by hindsight rather than knowledge of the field of MS drug
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`research at the time.
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`8.
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`I address each of these issues in further detail below. I also address a
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`skilled person’s view as of June 2006 of the meaning of the claimed phrases “ dosing
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`regimen” and “daily dosage” of fingolimod.
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`II. Analysis
`A. Claim Construction
`The ’405 Patent Claims 0.5 mg Daily of
`i.
`Fingolimod for the Purpose of Achieving,
`or to Actually Achieve, Specific Effects
`Dr. Benet argues (Ex. 1047 at ¶¶ 20-22) that the ’405 Patent’s claims
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`9.
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`require that 0.5 mg of fingolimod be given merely to a “subject in need” of the
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`claimed effects. The claims supposedly do not require that the dose achieve those
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`effects, or even be intended to do so. From this, Dr. Benet argues that the expected
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`efficacy the 0.5 mg daily dosage would have been irrelevant to a person of skill
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`evaluating whether the dose was obvious in June 2006.
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`10. Dr. Benet is mistaken. Dr. Benet relies on the Board’s Institution
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`Decision for his analysis (id. at ¶¶ 20-23), but he does not address the Decision’s full
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`reasoning. The Board gave the preamble language its “ordinary and customary”
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`meaning to a person of skill (Paper 11 at 12), but found that the “the presumption
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`against redundancy” weighs against reading the terms as synonymous with each
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`other. (Id.) Yet that is what Dr. Benet’s reading does—it reads the claims to
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`eliminate the any distinctions among them.
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`11. All active RRMS patients are “subjects in need” of all the claimed
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`effects—relapse reduction, prevention, and alleviation; treatment for their disease;
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`and slowing of its progression. (Ex. 2022 at ¶¶ 34-38.) In other words, a patient in
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`need of one of these claimed effects would be in need of all of them. Dr. Giesser
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`agreed in her declaration. (Ex. 1002 at ¶ 44.) Dr. Benet’s reading thus collapses the
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`claims into a single method: giving 0.5 mg daily to an RRMS patient. That is not
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`the plain and ordinary meaning that a person of skill would give the claims. Rather,
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`a person of skill in June 2006 would read the claims to require 0.5 mg daily to
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`produce certain effects, or at least be intended to do so.
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`12.
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`I showed in my First Declaration that the effects the claims identify—
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`preventing, reducing, and alleviating relapses; treating the disease; and slowing its
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`progression—are all understood by physicians to be different aspects of the disease.
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`(Ex. 2022 at ¶¶ 34-38.) Different treatments can affect one or more of these disease
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`features, as I understand Dr. Lublin explained in his First Declaration. (Ex. 2003 at
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`¶¶ 50-52.) Dr. Giesser agreed in her deposition (Ex. 2039 at 32:22-33:19), and Dr.
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`Benet does not argue otherwise. Having a single improved medicine to address all
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`these aspects of the disease was a major breakthrough.
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`13. Here, the claims are to a method expressly “for” improving these
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`different aspects of the disease (Ex. 1001 at 12:49-13:9; Ex. 2022 at ¶ 169), and the
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`Patent specification repeatedly emphasizes the invention’s therapeutic benefits. The
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`specification introduces the invention by pointing out that then-existing therapies
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`were “only partially effective” and “in most cases only offer[ed] a short delay in
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`disease progression.” (Ex. 1001 at 8:65-66 (emphasis added).) There was thus “a
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`need for agents which are effective in the inhibition or treatment of … multiple
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`sclerosis … including reduction of, alleviation of, stabilization of or relief from the
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`symptoms which affect the organism.” (Id. at 9:1-5 (emphasis added).)
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`14. The specification then explains that “[a] firm link has recently been
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`established between chronic inflammation and angiogenesis and neovascularization
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`seems to have a significant role in the progression of the disease.” The ’405 Patent
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`inventors had discovered that fingolimod has an “inhibitory effect on the neo-
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`angiogenesis associated with … MS.” (Id. at 9:14-15.) In other words, the discovery
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`was of a new mechanism of action that produced certain effects.
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`15. The specification then lists several “embodiments” of these effects (id.
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`at 9:18-63), and then describes animal data showing doses of fingolimod that “fully
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`block[] disease-associated angiogenesis and completely inhibit[] the relapse phases”
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`(id. at 10:65-11:2 (emphasis added)). In humans, the specification says the treatment
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`would be used only “for so long as [a patient’s] disease does not progress[.]” These
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`passages would have told a person of skill in June 2006 that the invention was
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`focused on achieving specific effects, and should be used for so long as it produced
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`those effects. The invention was not just about giving 0.5 mg daily to RRMS
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`patients.
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`16. The file history, too, shows that the inventors were focused on their
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`method’s efficacy. During prosecution, Novartis distinguished the prior art as “not
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`provid[ing] the skilled person with any guidance regarding a favorable human
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`dosage, i.e., favorable with respect to the balance of safety and efficacy, to use in
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`RRMS.” (Ex. 1011, July 6, 2015 Amendment at 34.) The dose the inventors
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`discovered was “favorable” in part because it was effective.
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`17.
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`In light of the above, a person of skill in June 2006 would read the
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`claims to require that the dose be administered to achieve the effects of the claimed
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`benefits, or at least be intended to do so. As I now address, the prior art taught that
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`0.5 mg daily was unlikely to provide these benefits to patients.
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`ii.
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`A Person of Skill Would Have Understood
`“Dosing Regimen” to Encompass a “Loading
`Dose Regimen.”
`18. As of June 2006 a person of skill would have understood that the
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`general phrase “dosing regimen” is an umbrella term that encompasses different
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`aspects of dosing. The definition of a dosing regimen is a schedule of doses of a
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`therapeutic agent per unit of time, including the time between doses or the time when
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`the doses are to be given and the amount of the therapeutic agent to be given at each
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`specific
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`time.
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` The textbook by Rowland & Tozer, entitled Clinical
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`Pharmacokinetics (Ex. 2105) provides a definition of “dosing regimen” that is
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`simply: “the manner in which a drug is taken.” (See Ex. 2105 at, inter alia, page 1
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`and Figure 1-2 and Table 5-1.) As such, a person of skill would understand a loading
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`dose regimen to be encompassed by the broader term “dosing regimen.” There are
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`other types of dosing regimens as well, such as incremental, weekly, etc.
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`19. The Kovarik reference uses both terms—“dosing regimen” and
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`“loading dose regimen”—and is an example of how a person of skill would
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`understand these terms. Kovarik states: “It has now surprisingly been found that a
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`specific dosage regimen, e.g., a loading dose regimen, will provide further
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`unexpected results.” (Ex. 1004 at 1.) The person of skill would have understood, as
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`shown in Kovarik, that a loading dose regimen is a specific type or aspect of a dosing
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`regimen.
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`20. Also, a person of skill in the art would have understood that a loading
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`dose regimen is a specific type or aspect of a dosing regimen because it is apparent
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`from the grammar. The adjective “loading” modifies and thereby narrows the
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`general term “dosing regimen.”
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`iii.
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`A Person of Skill Would Have Understood the
`Meaning of “Daily Dosage”
`I understand the Petitioners take the position that the term “daily
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`21.
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`dosage” includes within its meaning just a single, one-time administration. (Paper
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`49 at 8-9.) I disagree with this view. A skilled person would understand “daily
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`dosage” to refer to once a day for a number of days. A single, one-time dose can be
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`referred to by the phrase “a dosage” and the word “daily” is not needed. As I showed
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`in my First Declaration (Ex. 2022 at ¶ 179.), the word “daily” indicates dosing day-
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`by-day.
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`22. A person of skill with any familiarity with RRMS or disease-modifying
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`therapies like fingolimod would understand that these DMTs are never proposed as
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`a single-dose cure, but are always envisioned to be taken on a regular basis over an
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`extended period. (First Declaration, Ex. 2022 at ¶ 174; see also PDR, Ex. 1033 at
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`896, 954, 2625, 3120, 3224 (Betaseron®, Avonex®, Rebif®, Novantrone®, and
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`Copaxone® all require continuous administration).) That’s because RRMS is a
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`chronic disease that must be controlled over the course of a patient’s lifetime.
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`23. The ‘405 Patent specification supports this view. The specification
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`describes “daily dosages,” including the range of dosages, routes of administration,
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`dosage forms, etc. (Ex. 1001, e.g., at 11:20-38) The specification also says: “As
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`already mentioned, the S1P receptor modulator … may alternatively be administered
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`intermittently, e.g. at a dose of 0.5 to 30 mg every other day[.]” (Id. at 11:35-38
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`(emphasis added).) These passages show that the invention is meant to apply to
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`dosing over time, not to a single administration.
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`24.
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`I also understand that Petitioners contend that single or divided doses
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`are possible within the meaning of the term “daily dosage.” (Paper 49 at 8-9.) I
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`agree with this view so long as the administration of the “single or divided dosage”
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`results in a 0.5 mg total daily being given day after day as required by the word
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`“daily.” The specification is consistent with this view as it describes “daily dosage”
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`as “single or divided doses” at 11:24-25.
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`B. A Person of Skill Would Have Understood Webb To
`Mean What It Says—A Threshold of 70% Suppression
`Was Needed for “Any Efficacy”
`25. Dr. Benet says a person of skill would have discounted Webb’s
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`conclusion that fingolimod needed to suppress circulating lymphocytes by at least
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`70% to have “any efficacy[.]” (Ex. 1047 at ¶ 40.) According to Dr. Benet, other
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`data in Webb supposedly showed efficacy at 60% suppression. (Id. at ¶ 47.)
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`26. But a person of skill in June 2006 would have read Webb to mean what
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`it says: “In dose response experiments, we found that a threshold of about 70%
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`depletion of peripheral lymphocytes was required to see any efficacy[.]” (Ex. 2014
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`at 118.) Webb was published in a respected, peer-reviewed journal. The paper
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`describes experiments that generated data sufficient for the authors’ conclusions (Ex.
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`2022 at ¶ 74-85), and those conclusions resonated with similar results in transplant
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`patients showing that fingolimod had to suppress lymphocytes by 80% to be
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`effective (id. at ¶ 127).
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`27. Figures 5 and 6 in Webb show one dose (0.3 mg/kg) that reduces
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`average clinical scores to a statistically significant degree in EAE mice while only
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`suppressing lymphocytes by 60% on average in the same mice. (Ex. 2014 at 115.)
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`Dr. Benet argues that these data undermine Webb’s conclusion that efficacy begins
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`at 70% suppression. (Ex. 1047 at ¶ 47.) This argument betrays a lack of familiarity
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`with EAE experiments.
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`28. EAE models are not precise, statistically rigorous systems. They are
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`observational and directional in nature. Webb’s conclusion that efficacy began at
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`70% suppression was thus an observation based on both the data in the paper, and
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`data that was not published (such as data from individual mice). It was entirely
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`consistent with the averaged data on which Dr. Benet relies for his argument.
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`29.
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`In that vein, I wrote about the need for judgment in interpreting and
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`using EAE results in my June 2006 article, “How to Successfully Apply Animal
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`Studies in [EAE] to Research on Multiple Sclerosis.” (Ex. 2051.) As I set out there,
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`EAE studies have been reported in more than 5,000 publications since 1933. (Id. at
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`13) An enormous number of different models have been explored. The model has
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`led been used to study and develop numerous MS drugs. But as I state: “One must,
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`however, examine the process of drug development to realize that preclinical
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`research in EAE is merely just ‘exploratory[.]’” (Id. at 16.)
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`30.
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`In other words, EAE models are screening devices used to identify
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`potential biological targets and mechanisms early in drug development. They can
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`be used to develop “insights to understand pathology, [and] to identify surrogate
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`biomarkers and therapeutic targets.” (Id. at 17.) That is exactly the sort of analysis
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`Webb performs—it identifies a “surrogate biomarker” of at least 70% lymphocyte
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`suppression. But EAE models are not the equivalent of statistically-powered,
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`“rigorous” human clinical trials, and must be understood in that context. (Id. at 16.)
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`31. With that in mind, Dr. Benet is mistaken in over-reading the data in
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`Figures 5 and 6. Those figures showed only average results for a group of mice—
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`Figure 5 showed a statistically significant benefit on average cumulative clinical
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`scores for a dose (0.3 mg/kg), and Figure 6 showed that the same dose suppressed
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`lymphocytes by about 60%. But a person of skill would have understood that the
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`authors had access to data from individual mice too, and that data would have
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`informed their judgment as well.
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`32. Data from individual mice would have allowed the authors to observe
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`trends that the averaged data in Figures 5 and 6 would have obscured. The
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`distribution of that data around the averages in those Figures was likely significant.
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`Webb scored clinical efficacy using a scale from “0” for a healthy mouse to “5” for
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`a fatality. (Ex. 2014 at 110.) The paper further says that “[m]ortality was seen at
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`levels which varied between experiments from between about 10% to about 30%,”
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`with almost all mortality in the first acute phase of the EAE disease. (Id. at 112.)
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`All experiments thus would have had at least some clinical scores of “5” during the
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`first acute phase. But Figure 5A reports average scores of less than “3” for all dose
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`groups. Accordingly, each group would have had a distribution of results both
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`higher and lower than “3.” Likewise, a person of skill would expect a similar
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`distribution of results within the averaged lymphocyte data in Figure 6.
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`33. A person of skill in June 2006 would have understood that the authors’
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`conclusions were made with access to this more granular, mouse-by-mouse data. I
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`would not expect Webb to actually report this mouse-by-mouse data. Practical
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`constraints on article length would normally preclude the publication of data like
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`this. Instead, I would expect scientists who observe an important trend in
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`disaggregated data to note their observation in summary form in the discussion
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`section, just as the authors did here. If another scientist wanted the more granular
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`data, he or she could contact the Webb authors for it.
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`34.
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`In addition to individual mouse data, other information could have
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`informed the authors’ judgment. For instance, a person of skill would have
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`understood that the authors’ assessment of “efficacy” would demand an assessment
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`at least partly qualitative in nature, not simply a quantitative result. Not all
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`reductions in clinical scores would necessarily show “efficacy.”
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`35. The authors clearly did not consider achieving a score of “4” to be
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`efficacious; mice with that score were euthanized. (Ex. 2014 at 110.) Nonetheless,
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`a reduction in scores from (control) 5 to (tested) 4 could have contributed to a
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`statistically significant reduction in clinical scores in a given dosing group. A
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`scientist running such an experiment would need to bring judgment to evaluating
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`“efficacy” in this context. Further informing that judgment would be that MS
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`relapses generally are not fatal, and that a drug that results in a paralyzed human
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`patient—a score of “4” in the Webb scale—is not an efficacious medicine.
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`36. Given Dr. Benet’s limited experience with EAE models and MS, I
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`would not expect him to appreciate these subtleties. These are not purely
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`quantitative systems; they are screening devices that can shed light on relevant
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`biomarkers and other aspects of a possible therapy. But false precision in
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`interpreting the results must be avoided.
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`37. This is why I emphasized in my First Declaration (Ex. 2022 at ¶ 127-
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`142) that a scientist would also have taken account of the prior art transplant studies
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`as buttressing Webb. Those transplant papers showed fingolimod had to suppress
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`circulating lymphocytes by 80% to reduce transplanted organ rejection—a similar
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`result to Webb, focused on a similar mechanism of action. (Id. at ¶ 127.) Dr. Benet
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`does not disagree that the prior art reported those results. But he argues that the
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`transplant data would have been irrelevant to RRMS in June 2006 because the Phase
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`II clinical trial had already shown less suppression was needed for RRMS. (Ex. 1047
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`at ¶¶ 56-62.)
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`38. Dr. Benet misses the point of the transplant studies. Those papers lent
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`credibility to the finding of a minimum efficacy threshold in Webb involving the
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`same mechanism of action. Drugs usually do not have such a sharp efficacy trigger
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`point, an “on/off” switch. (I understand pharmacologists call such an all or none
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`response “quantal,” in contrast to a continuous response, which they call “graded.”
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`(Ex. 2105 at 55.) Most have a more gradual curve. But the transplant papers showed
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`that fingolimod had just such a threshold, in the context of the same posited
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`mechanism of action as in RRMS. The transplant data accordingly would have
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`buttressed Webb’s conclusions, even if the threshold in RRMS was a bit lower than
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`in transplant patients.
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`39. As I explained in my First Declaration (Ex. 2022 at ¶ 127), a person of
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`skill would have interpreted Webb’s threshold as likely reflecting the level of
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`suppression needed to consistently drive lymphocytes below “normal” levels for a
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`species. Lower-than-normal lymphocyte levels would then lead to a response
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`outside the norm for a person with MS, i.e., fewer attacks by the immune system on
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`the CNS. Dr. Benet appears not to disagree that reducing lymphocyte levels below
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`normal would have these effects.
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`40.
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`In sum, a person of skill would have understood Webb to mean what it
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`says: “In dose response experiments, we found that a threshold of about 70%
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`depletion of peripheral lymphocytes was required to see any efficacy[.]” (Ex. 2014
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`at 118.) That finding was the product of the nine authors’ collective judgment. All
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`were scientists at pharmaceutical giant Merck; their conclusion went through peer
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`review; and their finding was consistent with similar findings in another condition.
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`As I stated in my First Declaration, a person of skill thus would have found the
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`finding in Webb “compelling.” (Ex. 2014 at ¶ 85.)
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`C. A Person of Skill Would Have Assessed Likely Human
`Efficacy Based on Average Suppression, Not Extremes
`41. Dr. Benet next argues that Webb’s benchmark should be measured
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`against a dose’s maximum lymphocyte suppression, rather than against the dose’s
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`average suppression. (Ex. 1047 at ¶ 53.) On this basis, Dr. Benet argues that the
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`Kahan 2003 and Park 2005 would have led a person of skill to believe 0.5 mg daily
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`was likely to be effective. (Id. at ¶¶ 49-62.) Each paper shows 0.5 mg daily
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`suppressing lymphocytes by a maximum of about 60% at some point in treatment.
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`Dr. Benet says (incorrectly, as shown above) that Webb showed efficacy at that
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`level.
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`42. Dr. Benet’s theory, however, misunderstands RRMS’s chronic nature
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`and the need for sustained, consistent therapy to prevent the next relapse and disease
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`progression. Dr. Benet again also over-reads Webb.
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`43. RRMS is a life-long condition. Relapses occur roughly 1.5 times per
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`year. With each relapse (or even without), the disease progresses. More lesions
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`develop on the CNS. Often, baseline function worsens with a relapse; that is, the
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`effects of an attack can linger after the relapse is done. (First Declaration, Ex. 2022
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`at ¶¶ 29-30, 118.) Disability thus accumulates over time. As a result, MS doctors
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`focus on sustained, consistent relapse prevention and slowing progression of the
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`disease. Even with some side-effects, the benefits of such sustained prevention are
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`likely to outweigh the costs.
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`44.
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`In June 2006, medicines already existed that could provide these
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`benefits, such as interferon-beta, copaxone, and Tysabri. Fingolimod held promise
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`too, but only if it could provide consistent, sustained benefits to patients. The data
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`in Kahan 2003 and Park 2005 showed that a 0.5 mg daily dose was unlikely to do
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`so, especially when those two references are read together.
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`45. Kahan 2003 measured suppression over 28 days, while Park 2005
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`measured suppression over the two month period thereafter. As I showed in my First
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`Declaration (Ex. 2022 at ¶ 138), Kahan 2003 showed that daily 0.5 mg of fingolimod
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`suppressed lymphocytes to an average of about 50% in the period before day 28. In
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`that period, lymphocyte levels fluctuated between about 40% to 60%, and ended up
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`with a maximum suppression at day 28 of about 60%.
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`46. Dr. Benet (Ex. 1047 at ¶¶ 49-53) criticizes this reading of Kahan 2003.
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`He says that the 60% maximum suppression on day 28 occurred when fingolimod
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`had reached steady-state in the blood. Before then, Dr. Benet says the drug had not
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`reached steady-state, and thus average suppression. But Dr. Benet does not read
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`Kahan 2003 and Park 2005 together, as a person of skill would in June 2006.
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`47. Park 2005 measured suppression for the two-month period after Kahan
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`2003—that is, when the drug was entirely at steady-state. Nonetheless, 0.5 mg daily
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`suppressed lymphocytes by only about 42% on average, with wide variation week-
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`to-week and among individual patients. (Ex. 1019 at 689.) A person of skill would
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`read the fluctuations in Kahan 2003 in light of the similar (though more extreme)
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`fluctuations in Park 2005 as pointing toward average suppression from the 0.5 mg
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`dose at less than 50%—well below Webb’s benchmark. In contrast, doses of 1.0 mg
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`or higher approached or exceeded that benchmark.
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`48. Dr. Benet argues that maximum rather than average suppression is what
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`matters under Webb, pointing to Webb’s measurement of maximum suppression on
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`day 25 in that paper. (Ex. 1047 at ¶ 53.) This over-reads Webb’s EAE study and its
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`application to MS. Unlike MS, EAE manifests over a short, defined period of weeks.
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`Mice can have only so much blood drawn in that period. EAE thus can only identify
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`and measure lymphocyte suppression at discreet moments. That can be useful for
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`identifying a surrogate efficacy biomarker like lymphocyte suppression. But it does
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`not define how the marker works over the lifetime of a human MS patient. The
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`marker must be capable of consistent, sustained manipulation to be of use in human
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`MS.
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`49.
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`I addressed this issue before in showing why Park 2005 would have led
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`a person of skill to be especially skeptical of the 0.5 mg daily dose. (Ex. 2022 at
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`¶¶ 61-62.) Park 2005 shows significant week-by-week and inter-patient variability
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`in lymphocyte suppression for the 0.5 mg daily dose. Figure 7 shows fingolimod
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`suppressing lymphocytes in one patient by only about 20%, and in no patient by
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`more than 60%. (Ex. 1019 at 690.) As I explained, a dose that produced such
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`variability in the presumed mechanism of action would not be a viable therapy. (Ex.
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`2022 at ¶¶ 140-41.) It would expose patients to too much risk that a relapse would
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`occur while the patient’s lymphocytes were not being suppressed enough. And with
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`every relapse, permanent disability may advance. MS requires consistent, sustained
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`efficacy to be held at bay.
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`50. Dr. Benet says he “disagrees” with this analysis because it presumes
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`70% suppression is required for efficacy. Dr. Benet is mistaken—the inter-patient
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`and week-by-week variation in Park would, by itself, have been viewed as weighing
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`heavily against a 0.5 mg daily dose as of June 2006, regardless of whether the target
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`for efficacy was 70% or something else. Patients cannot be exposed to the risk that
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`the medicine would not work for them, or would work only sometimes.
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`51. Worse, as I showed in my First Declaration (Ex. 2022 at ¶¶ 24-32),
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`RRMS is highly variable in any given patient. That makes evaluating whether a
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`medicine is working for that patient very difficult. A perceived change in the disease
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`could be the result of the medicine, or of natural variation in that patient’s disease
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`progression. A dose that did not produce consistent effects would thus create a
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`dilemma. A physician would not know if the medicine was helping that patient. If
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`the medicine was secretly not working for that patient, then the patient’s disease
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`would progress. The patient would lose out on the chance to take other effective
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`medicines.
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`52. Accordingly, Dr. Benet is mistaken in arguing that the inter-patient and
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`week-by-week variability for 0.5 mg in Park 2005 would not be of independent
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`concern to a person of skill designing a fingolimod dose. As Park 2005 shows also,
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`higher doses did not display that variability, and could consistently meet or exceed
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`Webb’s 70% benchmark. (Ex. 1019 at 690.) A person of skill would thus have
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`believed that doses above 0.5 mg daily would be needed provide an effective
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`therapy.
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`53. As I showed in my First Declaration (Ex. 2022 at ¶¶ 94-108), the
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`inventors were able to see through these data by connecting efficacy to a different
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`marker, angiogenesis, and by focusing on the effects of lower doses on later disease
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`stages than others had examined. Dr. Benet claims (Ex. 1047 at ¶ 100) that
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`fingolimod’s ability to inhibit angiogenesis was known in the art, and thus that the
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`inventors’ contribution was insigni
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