UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO., LTD.,
`Patent Owner
`
`
`
`U.S. Patent No. 8,399,413
`
`________________________
`
`Case IPR2015-00644
`________________________
`
`
`EXPERT DECLARATION OF ARI GREEN, M.D.
`IN SUPPORT OF PETITIONER’S REPLY TO PATENT OWNER’S
`RESPONSE
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 1
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`________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`YEDA RESEARCH & DEVELOPMENT CO., LTD.,
`Patent Owner
`
`
`
`U.S. Patent No. 8,399,413
`
`________________________
`
`Case IPR2015-00644
`________________________
`
`
`EXPERT DECLARATION OF ARI GREEN, M.D.
`IN SUPPORT OF PETITIONER’S REPLY TO PATENT OWNER’S
`RESPONSE
`
`
`
`
`
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 1
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`TABLE OF CONTENTS
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`I.
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`II.
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`Summary of Opinions ........................................................................................... 2
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`Legal Standards .................................................................................................... 5
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`III.
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`Person of Ordinary Skill in the Art ....................................................................... 5
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`IV. The Patent At Issue’s Claims are Obvious Over the Prior Art ............................. 6
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`V. A POSA Was Motivated to Create a Less Frequent Dosing Regimen .............. 11
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`B.
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`C.
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`A. A POSA Recognized That Patients Preferred a Less Frequent
`Dosing Regimen ....................................................................................... 11
`A POSA Recognized Substantial Clinical Benefits to a Less
`Frequent Dosing Regimen ........................................................................ 12
`The Prior Art Repeatedly Suggested that a POSA Further Study
`Less Frequent Dosing Regimens .............................................................. 14
`The Patent Owner’s Two Arguments that the Prior Art Taught
`Away From Less Frequent Dosing Regimens Are Wrong ...................... 18
`1. A POSA Would Not Credit Dr. Fox’s Histamine Theory .................... 18
`2. Dr. Ziemssen’s Mechanism of Action Theory Does Not Teach Away
`from Less Frequent Administration ..................................................... 24
`Dr. Ziemssen’s and Dr. Fox’s Criticisms of Pinchasi and Flechter
`2002A Do Not Refute Motivation to Pursue a Less Frequent
`Dosing Regimen ....................................................................................... 48
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`D.
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`E.
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`VI. All of the Patent At Issue’s Dependent Claims Are Obvious ............................ 56
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`VII. The Patent At Issue Satisfied No Long-Felt But Unmet Need .......................... 56
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 2
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`VIII. The Patent At Issue Provided No Unexpected Benefits ..................................... 57
`VIII. The Patent At Issue Provided No Unexpected Benefits ................................... ..5 7
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 3
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 3
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`1.
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`I am the same Ari Green, M.D. who previously submitted a
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`declaration in this proceeding dated February 5, 2015. I submit this expert
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`declaration on behalf of Mylan Pharmaceuticals Inc. and Amneal Pharmaceuticals
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`LLC to respond to certain opinions expressed in the expert declarations submitted
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`with Patent Owner’s Response to the Petition (Ex. 2129, 2134, 2135).
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`2.
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`My curriculum vitae submitted with my original declaration is current.
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`See Ex. 1004 at Ex. A.
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`3.
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`In addition to the materials identified in my earlier declaration (Ex.
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`1004), and in addition to my experience, education, and training, I have also
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`considered the materials cited herein and the materials identified in Exhibit A, in
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`providing the opinions contained herein.
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`4.
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`I reaffirm that my scope of work and compensation has not changed
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`since I submitted my initial declaration in this proceeding. I have been retained by
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`Mylan as a technical expert in this matter to provide various opinions regarding the
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`patent at issue. I receive $1000 per hour for my services. No part of my
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`compensation is dependent upon my opinions given or the outcome of this case. I
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`do not have any current or past affiliation with Yeda Research & Development Co.,
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`Ltd., or the named inventor on the patent at issue.
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`1
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 4
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`I. SUMMARY OF OPINIONS
`5.
`In my opinion, all claims of the patent at issue are obvious over
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`Pinchasi in view of Flechter 2002A or the SBOA. Pinchasi discloses administration
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`of 40 mg of glatiramer acetate (“GA”) every other day. The claimed regimen is
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`identical to Pinchasi, save for having one less dose every two weeks. This
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`difference is minimal, and is well within GA’s forgiving range. Flechter 2002A and
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`the SBOA provide the POSA additional motivation and a reasonable expectation of
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`success to develop a lower frequency dosing regimen. Flechter 2002A includes
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`clinical data demonstrating that every other day administration of GA may be safe,
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`effective, and well-tolerated. Flechter 2002A also suggests that a total weekly dose
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`of only 70 mg may be efficacious. The SBOA includes a suggestion from an FDA
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`reviewer as early as 1996 advocating for less frequent dosing. Especially in light of
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`other background art—which provided additional clinical data supporting less
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`frequent administration of GA, as well as a potentially therapeutically effective
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`range of total weekly doses between 70 mg and 280 mg—a 40 mg three-times-
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`weekly dosing regimen (total weekly dose of 120 mg) was obvious.
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`6.
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`Further background knowledge and common sense of a POSA
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`provided additional motivation to develop a less frequently administered dosing
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`regimen. For example, both patients and doctors recognized that an effective GA
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`2
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 5
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`dose administered less frequently would be more convenient and tolerable for
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`patients. It was also known that less frequent injections would cause fewer
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`injection site reactions (“ISRs”), and patients would be more likely to comply with
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`the regimen if it involved fewer self-administered injections.
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`7.
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`In fact, many POSAs were exploring less frequent dosing regimens.
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`Flechter 2002A, Pinchasi, Khan 2008, and Caon are all examples of references that
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`disclose less frequent administration of GA. POSAs were thus not just motivated in
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`theory—they were actually conducting clinical trials exploring less frequent
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`administration of GA long before 2009.
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`8.
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`These explorations generated a substantial amount of clinical data on
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`efficacy. These data suggested that less frequent administration of GA had similar
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`efficacy to daily dosing, and Flechter 2002A, Khan 2008, and Caon all expressly
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`state that others perform follow-up research in larger trials. The clinical data also
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`generated a range of potentially therapeutically effective doses from 70 mg weekly
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`to 280 mg weekly. The claimed regimen involves administration of 120 mg of GA
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`per week, which is well within this therapeutic range and practically identical to the
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`FDA-approved 140 mg total weekly dose.
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`9.
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`Patent Owner and its experts argue that various tenuous theories
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`would have taught away from less frequent than daily administration of GA. But
`3
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 6
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`given the ample motivation in the art to pursue a less frequent dosing regimen,
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`combined with substantial data that supports the clinical efficacy of less frequent
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`than daily administration of GA, a POSA would not have been dissuaded from
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`pursuing a less frequently administrated dosing regimen.
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`10. Moreover, Patent Owner’s two theories for why a POSA would have
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`assumed that less frequent dosing would not work are incorrect. Dr. Fox argues
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`that ISRs are caused by dose-dependent histamine release, citing an abstract from
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`1996 involving an experiment in mice (Shalit 1996) and a 2003 abstract (Katz 2003)
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`referring to a two-patient study. However, Teva later (but before 2009) performed
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`clinical trials investigating this theory, and these studies showed that administration
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`of an antihistamine 30 minutes prior to daily GA injection had no effect on ISR
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`frequency or severity (Zwibel 2007, Pardo 2007). A POSA would therefore not
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`have relied upon the histamine theory that Dr. Fox deems relevant.
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`11.
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`Similarly, even assuming that a POSA would have overlooked clinical
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`data and considered Dr. Ziemssen’s mechanism of action theory, a POSA would not
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`have been persuaded by Dr. Ziemssen’s arguments. First, in 2009—and still
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`today—GA’s precise mechanism of action remained unknown. Numerous different
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`theories have been proposed, and the art has not settled on any particular
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`mechanism of action upon which a POSA would rely. In addition, Dr. Ziemssen’s
`4
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 7
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`theory is contradicted by the references he cites, including his own articles. These
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`references show that GA-specific Th2 cells accumulate in the central nervous
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`system where they (under this theory) exert their effect. This accumulation would
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`teach a POSA that daily injections are not necessary for efficacy.
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`II. LEGAL STANDARDS
`12.
`In addition to the legal principles outlined in my initial declaration, I
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`have also been informed that, to combine prior art teachings, the prior art need not
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`contain data sufficient to alter the standard of care. Rather, a POSA must have a
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`reasonable expectation of success in combining the prior art.
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`III. PERSON OF ORDINARY SKILL IN THE ART
`13.
`I continue to believe that a person of ordinary skill in the art would
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`have had as of the priority date of the patent at issue several years of experience as a
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`medical professional, with direct experience administering therapeutic agents for
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`the treatment of MS, as well as familiarity with the dosing schedules and
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`frequencies of the different therapeutic agents available for MS treatment, as well as
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`side effects or adverse events that occur with these treatments, including injection
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`site reactions (ISR) and immediate post-injection reactions (IPIR). A person of
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`ordinary skill in the art would also have experience with the design of studies
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`necessary for drug development. This experience may come from the person of
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`5
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 8
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`ordinary skill in the art’s own experience, or may come through the guidance of
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`other individual(s) with experience in the pharmaceutical industry, e.g., as members
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`of a research team or group. A person of ordinary skill in the art would also be
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`well-versed in the world-wide literature on MS that was available as of the priority
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`date.
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`14. Nonetheless, I recognize that the Board found that “one of ordinary
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`skill in the art would have had (1) several years of experience in the pharmaceutical
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`industry or in practicing medicine; (2) experience with the administration or
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`formulation of therapeutic agents, dosing schedules and frequencies, and drug
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`developmental study and design; and (3) a Ph.D. in pharmacology or be a physician
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`with experience in clinical pharmacology,” along with “experience with MS and
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`GA.” Paper 14 at 4–5. My opinions set forth below are identical under either
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`definition of the POSA.
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`IV. THE PATENT AT ISSUE’S CLAIMS ARE OBVIOUS OVER THE
`PRIOR ART
`15.
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`For the reasons stated in my original declaration, I still conclude that
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`the patent at issue’s claims are obvious over the prior art. In particular, Pinchasi
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`discloses administration of 40 mg every other day, which is only one more dose
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`every two weeks than the 40 mg three-times-weekly regimen claimed by the patent
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`6
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 9
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`at issue. Flechter discloses that 20 mg every other day (70 mg average total weekly
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`dose) has promise for treating MS. A POSA would have reasonably expected that
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`subtracting one dose every two weeks from the regimen disclosed in Pinchasi (140
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`mg average total weekly dose) would not render the regimen ineffective.
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`16.
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`In addition, Pinchasi and Flechter disclose a therapeutically effective
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`range of dosing for GA of 70 mg per week (20 mg every other day) to 280 mg per
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`week (40 mg daily). The claimed regimen is 120 mg per week, which is well
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`within the dosing range known to be therapeutically effective, and nearly identical
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`to another regimen disclosed in Pinchasi—i.e., the prior art FDA-approved 20 mg
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`daily dosing regimen (140 mg per week).
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`17.
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`The Summary Basis of Approval (“SBOA”) also explicitly
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`“recommend[ed] that [Teva] evaluate the necessity of daily s.c. injections as
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`opposed to more infrequent intermittent administration of the drug.” Ex. 1007 at
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`252. From the first approval of COPAXONE® in 1996, there were suggestions in
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`the art to pursue less frequent dosing.
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`18. As I testified in my initial declaration and at my deposition, a host of
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`other prior art confirms skilled artisans’ interest in, and knowledge of, less frequent
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`dosing regimens. For example, Khan 2008 and Caon 2009 describe a pilot study in
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`which subjects were randomized to a 20 mg daily regimen or a 20 mg alternate-day
`7
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 10
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`regimen. See Ex. 1010, 1011. After two years of monitoring patients’ relapse rate,
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`MRI data, EDSS score, and other endpoints, the trial found “no differences in the
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`relapse rate, disease progression, Change [sic] in T2W lesion volume, or Gd
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`enhancing lesions between the two groups.” Ex. 1010. Discussing the same pilot
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`study, Caon 2009 reports that “[i]njection related lipoatrophy was significantly less
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`in the QOD [alternate-day] group.” Ex. 1011. Patent Owner’s expert, Dr.
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`Ziemssen, criticizes Khan 2008 for saying only “that the dosage regimens ‘may’ be
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`equally effective, not that they are, and . . . that larger trials would have to be done
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`to confirm its findings.” Ex. 2135 ¶ 166. Another of Patent Owner’s experts, Dr.
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`Fox, similarly asserts that these studies are too small or poorly run to change the
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`standard of care. Ex. 2129 ¶ 41. But of course Khan 2008 did not overstate its
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`results—it was a pilot trial, which is designed to determine whether a different
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`regimen is worth exploring with more resources. And the Khan 2008 trial was
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`clearly a success. In conclusion, Khan 2008 states that “[t]his pilot study suggests
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`that GA 20 mg SC administered QD [daily] or QOD may be equally effective in
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`RRMS. This may have implications for the long-term use of GA. However, large
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`multi-center studies are warranted to confirm our findings and to identify the
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`optimal dose of GA in RRMS.” Ex. 1010. As Khan 2008 explicitly invites others
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`8
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 11
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`to confirm its findings, it would have motivated a POSA to develop a less frequent
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`dosing regimen.
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`19. GA has long been known to be a forgiving drug, meaning that some
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`variability in patient compliance will not sacrifice GA’s efficacy, safety, or
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`tolerability. See, e.g., Ex. 1004 ¶ 33. For example, Teva instructs patients to skip a
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`missed dose rather than take a double dose, indicating that the therapy’s efficacy
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`will not suffer from isolated adherence failures. See Teva’s Shared Solutions®
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`How to Prepare for Your Injection, http://www.copaxone.com/injection-
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`assistance/preparing-your-injection.html (last visited Mar. 7, 2016) (Ex. 1086 at 2)
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`(“If you miss a dose, take your COPAXONE® as soon as you remember. If it is
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`nearer to the time of your next scheduled dose, skip the missed dose and resume
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`your usual dosing schedule.”). In keeping with Teva’s advice and my own
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`understanding of GA, I tell my own patients to skip missed doses and to continue
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`normally with their schedule. Dr. Ziemssen testified at his deposition that he
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`instructs his patients to take two doses if they miss a dose, but that goes directly
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`against Teva’s recommendations and a skilled artisan’s understanding of GA. Ex.
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`2147 at 134:22–136:5. Dr. Ziemssen’s mechanism of action theory is so strict as to
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`require double dosing for any missed dose. If it were correct, Teva would not
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`recommend that patients skip missed doses, and numerous studies investigating less
`9
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 12
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`frequent dosing (Flechter 2002A, Khan 2008, Caon 2009, among others) would
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`have failed.
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`20. GA’s forgiving nature also manifests in its wide range of likely
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`efficacious doses. As stated above, the prior art shows a likely range of
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`therapeutically comparable doses stretching from 70 mg weekly to 280 mg weekly.
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`This prior art, in conjunction with other background art such as Khan 2008, strongly
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`suggests that dosing in that range, such as 40 mg three-times-weekly (120 mg
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`weekly), would be efficacious.
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`21.
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`In summary, as of 2009 a POSA had amassed compelling learning
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`from a variety of sources and studies all pointing to less frequent administration of
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`GA. The SBOA in 1996 urged Teva to investigate less frequent dosing. Flechter in
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`2002 suggested that 20 mg every other day was effective. In 2007, Pinchasi
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`claimed administration of 40 mg every other day. And in 2008 and 2009, Khan and
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`Caon corroborated Flechter’s results that 20 mg every other day was similarly
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`effective to the approved 20 mg daily treatment. By 2009, the clinical data
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`available in the art overwhelmingly pointed to less frequent administration of GA,
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`so it would have been obvious for a POSA to develop a 40 mg three-times-weekly
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`regimen. This regimen has a nearly identical weekly dose (120 mg) to the approved
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`20 mg daily regimen (140 mg), provides a convenient dosing schedule in which the
`10
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 13
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`drug may be taken on the same three days every week (e.g., Monday, Wednesday,
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`Friday), and it rests in the middle of the range of known effective weekly doses (70
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`mg in Flechter 2002A, Khan 2008, and Caon 2009 to 280 mg in Pinchasi).
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`V. A POSA WAS MOTIVATED TO CREATE A LESS FREQUENT
`DOSING REGIMEN
`22.
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`Prior to August 20, 2009, a POSA knew that patients preferred a less
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`frequent dosing regimen, and a POSA recognized substantial clinical benefits to
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`creating such a regimen.
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`A. A POSA Recognized That Patients Preferred a Less Frequent
`Dosing Regimen
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`23.
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`In 2009, a POSA recognized the common sense notion that patients
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`prefer injecting themselves less often. This patient preference would have
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`motivated a POSA to develop a less frequently administered GA therapy.
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`24. As I detailed in my initial declaration, there are many obvious reasons
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`patients prefer a regimen with fewer injections. Ex. 1004 ¶¶ 51–59. Patients find
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`self-administering injections unpleasant, most patients suffer injection site reactions,
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`and some patients experience injection phobia. Patients also do not like having to
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`set aside time every day to inject. Mentally, it can be difficult for patients to inject
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`every day, indefinitely and—after some time on daily GA injections—patients often
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`experience needle fatigue. In addition, a POSA would have known that a three-
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`11
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 14
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`times-weekly regimen would allow patients the freedom to choose which days of
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`the week to inject—an obvious reason to modify an every other day regimen to
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`three injections weekly.
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`25.
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`Furthermore, Dr. Fox explains that patients want to take the weekend
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`off from worrying about MS, and that less frequent administration makes it easy to
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`pack for an overnight trip or an outdoor excursion, like camping. Ex. 2129 ¶ 37. I
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`agree. As patients had expressed these preferences for years, any POSA would
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`have known that less frequent administration would carry these lifestyle benefits
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`prior to developing such a regimen. These known benefits would have motivated a
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`POSA in 2009 to develop the claimed 40 mg three-times-weekly regimen.
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`B. A POSA Recognized Substantial Clinical Benefits to a Less
`Frequent Dosing Regimen
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`26.
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`In addition to patients’ preference for a more convenient therapy, a
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`POSA in 2009 would have recognized substantial clinical benefits to a less frequent
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`dosing regimen. One substantial clinical benefit known to a POSA in 2009 would
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`be improved tolerability through less frequent injection site reactions. In 2009, a
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`POSA knew that patients would experience fewer ISRs if they inject fewer times.
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`This knowledge is common sense—fewer injections means fewer chances to have
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`an ISR. See, e.g., Ex. 1012 at 5 (“The fact that Copaxone injected on alternate day
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`12
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 15
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`seems to be equally effective as the Copaxone injected daily is important to patients
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`with injection-related adverse events . . . .”); Ex. 1004 ¶ 57. As the Gagnon
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`reference states, “[p]atients who receive daily injections of glatiramer acetate often
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`develop lipotrophy and injection-site reactions . . . . There was interest, therefore, in
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`testing the effects of another treatment regimen, apart from 20 mg daily, with the
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`goal of minimising adverse events . . . .” Louise Gagnon, Every-Other-Day Dosing
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`of Glatiramer Acetate Reduces Adverse Reactions with Comparable Efficacy to
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`Daily Dosing: Presented at WCTRMS, PEERVIEW PRESS, Sept. 21, 2008,
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`http://www.peerviewpress.com/every-other-day-dosing-glatiramer-acetate-reduces-
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`adverse-reactions-comparable-efficacy-daily-dosing-presented-wctrms (last visited
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`Mar. 8, 2016) (Ex. 1087).
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`27. Moreover, studies of less frequent dosing of GA confirm that less
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`frequent dosing is preferred. For example, in Khan 2008 and Caon 2009, patients
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`who were randomized into the 20 mg daily group were given the opportunity to
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`switch to 20 mg every other day after two years of treatment. Every single patient
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`on 20 mg daily switched to every other day administration. Ex. 1010, 1011. Khan
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`2008 and Caon 2009 thus confirm the obvious proposition that less frequent
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`administration of GA is better tolerated by patients. See Ex. 1004 ¶¶ 56–57.
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`13
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 16
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`28. A less frequent dosing regimen also increases patient compliance.
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`The Global Adherence Project study tracked patient compliance with various MS
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`therapies, including interferon beta formulations and GA. Ex. 1037 at 3. Of the
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`therapies, COPAXONE® (20 mg daily) had the lowest compliance, with 34.2% of
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`non-adherent patients. Id. As outlined in my previous declaration, the Global
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`Adherence Project found a strong trend that increased injection frequency is
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`associated with reduced compliance, and that compliance is a good indicator of
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`tolerability. Ex. 1004 ¶ 55.
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`C. The Prior Art Repeatedly Suggested that a POSA Further Study
`Less Frequent Dosing Regimens
`29. Numerous prior art references suggested further investigation of less
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`frequent dosing regimens prior to 2009. These explicit suggestions in the art to
`
`pursue less frequent dosing of GA would have motivated a POSA to create the
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`claimed dosing regimen.
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`30.
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`Suggestions in the art to pursue less frequent dosing regimens existed
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`as early as 1996. As I stated in my initial declaration (Ex. 1004 ¶¶ 82, 102–104), in
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`the SBOA, the reviewer asks: “Are daily injections really necessary?” Ex. 1007 at
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`252. The reviewer then goes on to “recommend that the Sponsor evaluate the
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`necessity of daily s.c. injections as opposed to more infrequent intermittent
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`14
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`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 17
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
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`administration of the drug.” Id. Dr. Ziemssen argues that the reviewer is concerned
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`with toxicity but this is inconsistent with the heading “Are daily injections
`
`necessary?” Ex. 2135 ¶ 128. A discussion of necessity pertains to efficacy, not
`
`safety. The reviewer made this observation with respect to whether daily injections
`
`are necessary “to maintain efficacy” and does not limit the inquiry to toxicity as
`
`Ziemssen characterizes. Ex. 1007 at 252. And even if the reviewer’s statement
`
`concerns only toxicity, Dr. Ziemssen himself states that “the FDA reviewer is
`
`telling Teva that it should consider decreasing the frequency in order to reduce the
`
`total amount of GA that a patient is exposed to.” Ex. 2135 ¶ 128 (emphasis in
`
`original). The claimed dosing regimen decreases both the frequency of injections
`
`and the total amount of GA exposure over time (from 140 mg/week to 120
`
`mg/week).
`
`31.
`
`Following the FDA reviewer’s recommendation in the SBOA, those
`
`in the art investigated less frequent administration of GA. The Flechter 2002A
`
`reference details a study comparing 20 mg of GA daily to 20 mg of GA
`
`administered on alternate days. Flechter 2002A found comparable efficacy and
`
`recommended further study of less frequent dosing: “The results of this trial suggest
`
`that alternate-day treatment with Copolymer 1 is safe, well tolerated, and probably
`
`as effective as daily Copolymer 1 in reducing relapse rate and slowing neurologic
`15
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 18
`
`
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
`
`
`
`deterioration. However, these preliminary observations will have to be examined in
`
`larger studies, preferably comparing daily with alternate-day administration of
`
`Copolymer 1 in a blinded manner.” Ex. 1008 at 5. Despite this clear suggestion to
`
`pursue additional studies of a less frequent GA dosing regimen, Dr. Ziemssen
`
`opines that Flechter 2002A would not motivate a POSA to do further research. See
`
`Ex. 2135 ¶¶ 86–91. However, a 2004 article from Wolinsky—who was later hired
`
`by Teva to be the primary investigator for its GLACIER trial—comments that
`
`Flechter’s research “may provide the clinician with some guidance for alternatives
`
`for patients on GA therapy whose skin reactions to injections might otherwise
`
`compromise compliance.” J. Wolinsky, Glatiramer acetate for the treatment of
`
`multiple sclerosis, EXPERT OPINION ON PHARMACOTHERAPY, 5(4):875–891 (2004)
`
`(“Wolinsky 2004”) (Ex. 1088 at 12). In other words, Wolinsky 2004 states that
`
`Flechter 2002A (Ex. 1008) and Flechter 2002B (Ex. 1012) provide strong enough
`
`data to support alternate-day administration of GA for patients with ISRs.
`
`Therefore, as Wolinsky 2004 acknowledges, frequent ISRs were a well-known
`
`problem in the art, and the Flechter references provide a potential solution: less
`
`frequent administration of GA.
`
`32.
`
`In keeping with the prior art’s teachings, research on less frequent
`
`dosing regimens continued, and, as expected, future studies succeeded. Khan 2008
`16
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 19
`
`
`
`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
`
`
`
`and Caon 2009 report equivalent efficacy between daily and alternate-day
`
`administration of 20 mg of GA. See Ex. 1010, 1011. Based on these results, both
`
`references explicitly encourage “large multi-center studies . . . to confirm our
`
`findings and to identify the optimal dose of GA in RRMS.” Ex. 1010; see also Ex.
`
`1011 at 2. Patent Owner argues that a POSA would not follow the suggestions in
`
`Khan 2008 and Caon 2009 to explore less frequent dosing because POSAs believed
`
`that daily injections were necessary for efficacy. But in fact, before the priority
`
`date, POSAs had completed a clinical trial investigating 20 mg administered twice
`
`weekly, for a total weekly dose of only 40 mg. O. Khan et al., Glatiramer acetate
`
`20mg subcutaneous twice-weekly versus daily injections: results of a pilot,
`
`prospective, randomised, and rater-blinded clinical and MRI 2-year study in
`
`relapsing-remitting multiple sclerosis, MULTIPLE SCLEROSIS, 15:S151–S269 (2009)
`
`(“Khan 2009”) (Ex. 1089 at 2) (“This study provides further evidence that GA
`
`administered less frequently than daily may be as efficacious and better tolerated
`
`than GA administered daily.”). Although the results suggesting that 20 mg
`
`administered twice weekly is safe, efficacious, and well-tolerated were not
`
`officially published until three weeks after the priority date, the Khan 2009
`
`reference demonstrates that—counter to what Patent Owner claims—POSAs were
`
`motivated before the priority date to explore less frequent alternative dosing
`17
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 20
`
`
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
`
`
`
`regimens. Id. at 1 (“We have previously shown that GA administered on alternate
`
`days appears to be as effective as daily GA. There is considerable interest in
`
`studying a more patient friendly dosing regimen of GA that may be as efficacious
`
`and better tolerated than daily GA.”).
`
`33.
`
`Therefore, as of 2009, the prior art had repeatedly and explicitly
`
`suggested large-scale investigation of less frequent GA dosing regimens. See Ex.
`
`1007, 1008, 1010, 1011. The art also had identified less frequent dosing as a
`
`solution for the many patients who experience ISRs affecting compliance. Ex. 1088
`
`at 12. As of 2009, a POSA thus would have been substantially motivated to create
`
`the claimed dosing regimen.
`
`D. The Patent Owner’s Two Arguments that the Prior Art Taught
`Away From Less Frequent Dosing Regimens Are Wrong
`1. A POSA Would Not Credit Dr. Fox’s Histamine Theory
`In his declaration, Dr. Fox opines that a POSA in 2009 would expect
`
`34.
`
`less frequent injections of GA to cause more injection site reactions due to local
`
`histamine release. Ex. 2129 ¶¶ 53–58. For support, Dr. Fox cites two references
`
`involving GA: the 1996 Shalit abstract and the 2003 Katz abstract. See Ex. 2054,
`
`2091. When read in context of the full prior art, neither of these references would
`
`cause a POSA to expect—contrary to common sense and the overwhelming weight
`
`
`
`18
`
`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 21
`
`
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`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
`
`
`
`of the art—that fewer injections would cause more frequent and severe injection
`
`site reactions.
`
`35.
`
`Shalit 1996 is an abstract describing research on “human skin, human
`
`basophils, and rat peritoneal mast cells.” Ex. 2054 at 3. The researchers’ primary
`
`finding was that GA induced histamine release in rat peritoneal mast cells. The
`
`researchers also found that intradermal injection of GA (injection into the skin, as
`
`opposed to subcutaneous injection, which injects into the fat layer underneath the
`
`skin) caused “wheal-and-flare” reactions. Ingestion of terfenadine, an antihistamine
`
`withdrawn from the U.S. market in 1997, reduced the skin’s reaction from
`
`intradermal injection. Id. However, a POSA would read Shalit 1996 with caution.
`
`First, in the patient-based experiment, Shalit 1996 does not mention the number of
`
`patients (both those previously exposed to GA and those naïve to GA) or how
`
`wheal-and-flare was assessed. In the cell or tissue-based experiments, Shalit 1996
`
`does not mention the number of cells tested in its laboratory studies, the source of
`
`these cells, or the number of times the laboratory experiments were replicated. As
`
`such, the quality of these experiments and their reliability cannot be judged.
`
`Second, Shalit 1996 does not establish a causal link between histamine release and
`
`ISRs—GA exposure causing histamine release in rat peritoneal mast cells does not
`
`mean that ISRs are caused by histamine release. Third, Dr. Fox omits that Shalit
`19
`
`
`
`MYLAN PHARMS. INC. EXHIBIT 1085 PAGE 22
`
`
`
`REPLY EXPERT DECLARATION OF ARI GREEN, M.D.
`
`
`
`1996’s evaluation of human cells (basophils) showed that they were “relatively
`
`resistant to the drug” in terms of histamine release. Id. Fourth, Shalit 1996
`
`involves intradermal, and not subcutaneous, administration of GA. Lastly, and
`
`most importantly, Shalit’s results were thoroughly dispelled by later research.
`
`36.
`
`The other reference upon which Dr. Fox relies, Katz 2003, is an
`
`abstract describing rush desensitization1 of two patients with persistent urticaria
`
`reactions to GA. Ex. 2091 at 2. According to the abstract, administration of eight
`
`steadily increasing doses of GA every thirty minutes mini
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