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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`COALITION FOR AFFORDABLE DRUGS V LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC – PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND, L.P.;
`HAYMAN CAPITAL MANAGEMENT, L.P.;
`HAYMAN OFFSHORE MANAGEMENT, INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS; and ERICH SPANGENBERG,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2015-01993
`Patent 8,399,514 B2
`____________________________________________
`
`DECLARATION OF RONALD A. THISTED, PH.D.
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`Page 1 of 27
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`Biogen Exhibit 2038
`Coalition v. Biogen
`IPR2015-01993
`
`Biogen Exhibit 2035
`Mylan v. Biogen
`IPR2018-01403
`
`
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
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`
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`I, Ronald A. Thisted, Ph.D., hereby declare the following:
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`I.
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`Introduction and Qualifications
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`1.
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`I have been retained by Finnegan, Henderson, Farabow, Garrett &
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`Dunner, LLP as an expert consultant for this inter partes review proceeding. I
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`understand that the patent at issue is U.S. Patent No. 8,399,514 (“the ’514 patent”;
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`Ex. 1001) and that it is owned by Biogen MA Inc. I am being compensated for my
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`time at my standard hourly rate. My compensation is not contingent upon my
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`opinions or the outcome of this or any other proceeding.
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`2.
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`I am a Professor and Vice Provost, Academic Affairs, at the
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`University of Chicago. I hold faculty appointments in the departments of
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`Statistics, Public Health Sciences, and Anesthesia & Critical Care. I am also a
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`Professor in the Committee on Clinical Pharmacology and Pharmacogenomics.
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`3.
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`I received bachelor’s degrees (B.A.) in mathematics and philosophy in
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`1972 from Pomona College in Claremont, California. In 1973 and 1977,
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`respectively, I completed a master’s degree (M.S.) and a doctorate of philosophy
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`(Ph.D.) in statistics at Stanford University in Stanford, California.
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`4.
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`I have more than forty years of research, academic, and practical
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`experience in the area of biostatistics. My research focuses on biostatistics and
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`epidemiology, statistical computation, and the effectiveness of medical
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`intervention from a statistical perspective.
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`5.
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`I have held positions on the faculty of the University of Chicago since
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`1976. I was Co-Director of the Clinical Research Training Program (1999–2012),
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`Chairman of the Department of Health Studies (1999–2012), Director of
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`Population Sciences for the Institute for Translational Medicine (2007–2014), and
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`Scientific Director for the Biostatistics Core Facility at the University of Chicago
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`Cancer Research Center (1999–2014).
`
`6.
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`I have taught courses on biostatistics for over thirty-five years. I have
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`also taught courses on statistical methods, epidemiology, and clinical research
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`methods. I have been awarded the Llewellyn John and Harriet Manchester
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`Quantrell Award for Excellence in Undergraduate Teaching.
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`7.
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`I am an Elected Fellow of the American Association for the
`
`Advancement of Science (1992) and of the American Statistical Association
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`(1988). I have also been a member of several professional societies related to
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`statistics and computation, including the Association for Computing Machinery,
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`the International Biometric Society, the Institute of Mathematical Statistics, the
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`Royal Statistical Society, and the Society for Industrial and Applied Mathematics.
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
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`8.
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`I have authored over one hundred publications in the area of
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`biostatistics and epidemiology, many in peer-reviewed journals including the New
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`England Journal of Medicine, the Journal of the American Medical Association,
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`and The Lancet. I also served as the Associate Editor of the Journal of the
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`American Statistical Association (1979–1985, 1987–1988) and ACM Transactions
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`on Mathematical Software (1990–1992).
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`9.
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`I have served as Database Editor (1994), Managing Editor (1995), and
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`Editor (1996–1998) for Current Index to Statistics. I sat on the editorial board of
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`SIAM Journal of Scientific and Statistical Computing from 1983 to 1985. I have
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`served as a referee for several journals related to biostatistics, including Annals of
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`Statistics, PLoS One, and Statistics in Medicine. As a journal referee, I reviewed
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`submitted articles for scientific quality. I have also acted as a referee for the
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`National Institutes of Health (NIH) and the National Science Foundation (NSF).
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`As a referee for NIH and NSF, I reviewed grant proposals for potential funding.
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`10. Since the late 1970s, I have consulted for the pharmaceutical and
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`medical device industries on the design of clinical trials and statistical analysis of
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`clinical trial results. I have consulted regarding the design of Phase I, Phase II, and
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`Phase III clinical trials; designed data collection methods; planned and overseen
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`statistical analysis of results; prepared reports for use by the FDA; and presented
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`statistical aspects of clinical studies to the FDA.
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`11. As part of my consulting practice, I have served as the principal
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`biostatistician for studies involving MS patients. In particular, I was the principal
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`biostatistician on two randomized clinical trials for treating specific symptoms in
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`MS patients. See Panitch et al., Annals of Neurology 59:780-87 (2006) (Ex. 2027);
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`Pioro et al., Annals of Neurology 68(5):693-702 (2010) (Ex. 2028).
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`12. A copy of my current curriculum vitae is provided as Exhibit 2039.
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`II. Documents Considered
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`13. My opinions are based on my knowledge and experience. In forming
`
`my opinions, I have also considered the documents listed in Appendix A.
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`III. Legal Standards
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`14.
`
`I am not an attorney and do not purport to offer legal opinions.
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`15.
`
`I understand that a claim is unpatentable if it would have been obvious
`
`to a person of ordinary skill in the art at the time of the invention. I understand that
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`an obviousness analysis involves considering the following factors: (1) the scope
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`and content of the prior art; (2) the differences between the prior art and the claims;
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`(3) the level of ordinary skill in the art; and (4) objective indicia of
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`nonobviousness. I understand that one indicator of nonobviousness is if the
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`claimed invention is unexpectedly different from the prior art.
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`IV. Level of Ordinary Skill in the Art
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`16.
`
`I understand that certain legal issues, such as claim construction and
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`obviousness, are determined from the viewpoint of a person of ordinary skill in the
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`art. I understand that a person of ordinary skill in the art is a hypothetical person
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`who is presumed to have known the relevant art at the time of the invention. I
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`understand that factors that may be considered in determining the level of ordinary
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`skill in the art include (1) the types of problems encountered in the art; (2) prior art
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`solutions to those problems; (3) rapidity with which innovations are made;
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`(4) sophistication of the technology; and (5) the educational level of active workers
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`in the field.
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`17.
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`I understand that the petitioner has asserted that a person of ordinary
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`skill in the art “would most likely have held an advanced degree, such as a Ph.D. in
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`one of the life sciences, M.D., a D.O., or a Pharm.D.” and “would have had some
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`experience with clinical trial designs for dose selections.” (Paper 1 at 16-17.) I
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`understand that Biogen has taken the position that a person of ordinary skill in the
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`art in 2007 would have had at least a medical degree with at least three years of
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`training in neurology and at least three years of clinical experience treating MS.
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`My opinions do not depend on which definition is adopted in this proceeding.
`
`V. The ’514 Patent
`
`18. The ’514 patent provides methods for using neuroprotective
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`compounds in therapy for neurological diseases, including multiple sclerosis (MS).
`
`(Ex. 1001 at 1.) The claimed inventions include methods of treating subjects
`
`needing treatment for MS by (claim 1) orally administering a pharmaceutical
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`composition consisting essentially of a therapeutically effective amount of
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`dimethyl fumarate (DMF), monomethyl fumarate (MMF), or a combination of the
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`two, and one or more pharmaceutically acceptable excipients, in which the
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`therapeutically effective amount of DMF, MMF, or the combination is about
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`480 mg/day; (claim 11) orally administering about 480 mg/day of DMF, MMF, or
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`a combination of the two; (claim 15) orally administering a pharmaceutical
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`composition consisting essentially of a therapeutically effective amount of DMF,
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`and one or more pharmaceutically acceptable excipients, in which the
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`therapeutically effective amount of DMF is about 480 mg/day; and (claim 20)
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`treating the subject with a therapeutically effective amount of DMF, MMF, or a
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`combination thereof, where the therapeutically effective amount of DMF, MMF, or
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`the combination is about 480 mg/day. (Ex. 1001 at 29-30.)
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`U.S. Patent No. 8,399,514
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`Declaration of Ronald A. Thisted, Ph.D.
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`VI. Based on Kappos 2006, a person of ordinary skill in the art would have
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`expected the results with 480 mg/day to be closer to those with
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`360 mg/day than with 720 mg/day.
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`19.
`
`I have considered Kappos et al., 16th Meeting of the European
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`Neurological Society (abstract to presentation May 30, 2006) (“Kappos 2006”)
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`(Ex. 1003A). The Kappos 2006 abstract concerned a 24-week randomized,
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`double-blind, placebo-controlled clinical trial of four doses (one of which was
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`placebo) of BG00012 in patients with relapsing-remitting MS “to determine the
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`efficacy of three dose levels of BG00012 […] on brain lesion activity as measured
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`by magnetic resonance imaging (MRI) […].” (Ex. 1003A at 27.) Although
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`BG00012 was described only as “a novel oral single-agent fumarate” and “a novel
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`oral fumarate preparation” in Kappos 2006, I understand that BG00012 referred to
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`a DMF-only pharmaceutical preparation. The doses studied were 0 mg/day (that
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`is, placebo), 120 mg/day, 360 mg/day, and 720 mg/day. (Ex. 1003A at 27.) The
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`prespecified primary treatment effectiveness outcome assessed was the total
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`number of new Gd-enhancing (Gd+) brain lesions seen in four MRI brain scans at
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`12, 16, 20, and 24 weeks into the study. (Ex. 1003A at 27.) Prespecified
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`secondary endpoints included the cumulative number of new Gd+ lesions from
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`week 4 to week 24 and the number of new or enlarging T2-hyperintense lesions at
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`U.S. Patent No. 8,399,514
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`Declaration of Ronald A. Thisted, Ph.D.
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`week 24, both also calculated from MRI brain scan images. Additional
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`prespecified endpoints, including the number of new T1-hypointense lesions, were
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`also studied.
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`20. Kappos 2006 reported that BG00012 at a dose of 720 mg/day
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`“significantly reduced the mean number of new Gd+ lesions (the primary end
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`point) compared with placebo.” (Ex. 1003A at 27.) It also reported that BG00012
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`at a dose of 720 mg/day “reduced the cumulative number of new Gd+ lesions, the
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`number of new/enlarging T2-hyperintense lesions, and the number of new T1-
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`hypointense lesions compared with placebo.” (Ex. 1003A at 27.)
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`21.
`
`I have also considered Kappos et al., 16th Meeting of the European
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`Neurological Society (presentation May 30, 2006) (“Kappos presentation”)
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`(Ex. 1007 at 56-77), which appears to be the slide presentation related to the
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`Kappos 2006 abstract. As summarized in the table below, the Kappos presentation
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`indicated that the 720 mg/day dose of BG00012 showed a statistically significant
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`reduction in brain lesions compared to placebo in each of the four MRI outcome
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`measures described above. (Ex. 1007 at 67-70.) In contrast, neither of the other
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`two doses of BG00012 (120 mg/day and 360 mg/day) were statistically
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`significantly different from placebo in any of the outcome measures. (Ex. 1007 at
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`67-70.)
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`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
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`Total daily dose 120 mg/day 360 mg/day 720 mg/day
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`Dosing regimen 120 mg QD 120 mg TID 240 mg TID
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`New Gd+ lesions, weeks 12-24
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`New Gd+ lesions, weeks 4-24
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`New T2-hyperintense lesions
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`New T1-hyposintense lesions
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`NS
`
`p<0.001
`
`p=0.002
`
`p<0.001
`
`p=0.014
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`Table 1. Comparison of MRI endpoints for each total daily dose compared
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`to placebo. NS=not statistically significant (p>0.05). (Ex. 1007 at 67-70.)
`
`22. Kappos 2006 and the Kappos presentation demonstrated that
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`BG00012 at a dose of 720 mg/day effectively reduced brain lesion activity
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`measured by MRI in patients with relapsing-remitting MS. (Ex. 1003A at 27;
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`Ex. 1007 at 67-70.) Specifically, the number of new lesions seen in patients
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`treated with 720 mg/day (by each of four measures) was lower than that seen in
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`patients taking placebo by an amount that was statistically significant (that is, by
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`an amount that was too large to be plausibly attributable to chance). (Ex. 1003A at
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`27; Ex. 1007 at 67-70.) In contrast, Kappos 2006 and the Kappos presentation
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`revealed that the number of new lesions seen in patients treated with 120 mg/day
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`and 360 mg/day (by each of four measures) was not statistically significantly
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`different compared to that seen in patients taking placebo. (Ex. 1003A at 27;
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`Ex. 1007 at 67-70.)
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`23. Thus, if a person of ordinary skill had access to Kappos 2006 and the
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`Kappos presentation when the ’514 patent was filed, the artisan would have
`
`expected 720 mg/day to be a therapeutically effective dose for reducing brain
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`lesions in MS patients, and would have expected doses at or below 360 mg/day not
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`to be therapeutically effective.
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`24. The Kappos presentation reported that the effects on brain lesions for
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`the 120 mg/day dose group were essentially the same as those for the placebo
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`group and that the differences between 120 mg/day and placebo were not
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`statistically significant. (Ex. 1007 at 67-70.) It further reported that tripling this
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`dose (a 200% increase to 360 mg/day) produced no additional reduction in brain
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`lesions relative to placebo. (Ex. 1007 at 67-70.) Consequently, based on the
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`Kappos 2006 presentation, a person of ordinary skill in the art would not have
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`expected that increasing the dose by an additional 33% (to 480 mg/day) would
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`produce substantial efficacy when the lower dose (360 mg/day) did not.1 At most,
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`
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` I do not believe that a person of ordinary skill in the art, based on the statistical
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` 1
`
`results of Kappos 2006 and the Kappos presentation, would have even selected a
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`a person of ordinary skill in the art would have expected the effects on brain
`
`lesions with 480 mg/day to be closer to those with a 360 mg/day dose than those
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`with a 720 mg/day dose.
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`VII. The EMA Report would not have changed the expectation that the
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`results with 480 mg/day would be closer to those with 360 mg/day than
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`with 720 mg/day.
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`25.
`
`I have considered European Medicines Agency, Assessment Report,
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`Tecfidera (Nov. 26, 2013) (“EMA Report”) (Ex. 1006). The EMA Report is an
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`assessment conducted by the Committee for Medicinal Products for Human Use
`
`(CHMP) of the European Medicines Agency (EMA) of Biogen Idec’s application
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`for marketing authorization for Tecfidera® in Europe.2 (Ex. 1006 at 1, 9.) The
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`report, dated November 26, 2013, did not exist when the ’514 patent was filed
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`(February 13, 2012).
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`26. The report assessed several aspects of the drug, including quality
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`aspects (Section 2.2), non-clinical aspects (Section 2.3), clinical aspects
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`
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`dose of 480 mg/day. I merely provide an opinion regarding 480 mg/day because
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`that is the dose at issue in this proceeding.
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`2 I understand that Tecfidera® is Biogen’s commercial BG00012 product.
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`(Section 2.4), clinical efficacy (Section 2.5), and clinical safety (Section 2.6).
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`(Ex. 1006 at 2.) The EMA Report also included some information about responses
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`to queries submitted by the CHMP to the sponsor (Biogen Idec). (Ex. 1006 at 10-
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`11.)
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`27. The EMA Report contained a discussion of study C-1900, the phase II
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`clinical dose-ranging study underlying Kappos 2006 and the Kappos presentation.
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`(Ex. 1006 at 27-28, 33-34.) Like Kappos 2006 and the Kappos presentation, the
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`EMA Report stated that a 720 mg/day dose showed “statistically significant
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`differences” in comparison to placebo for the primary endpoint and the secondary
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`MRI endpoints. (Ex. 1006 at 34.) Like the Kappos presentation, the EMA Report
`
`stated that there was “a clear difference” in efficacy between the 720 mg/day dose
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`and the 120 mg/day and 360 mg/day doses and that neither of the lower doses
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`demonstrated a significant effect when compared to placebo for any of the MRI
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`endpoints. (Ex. 1006 at 34.)
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`28. According to the EMA Report, the CHMP noted that there were
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`“considerable imbalances” across treatment groups at baseline in the number of
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`Gd+ lesions present. (Ex. 1006 at 34.) The report indicated that Biogen added
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`subgroup analyses to the protocol after database lock and that CHMP requested
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`additional post hoc sensitivity analyses “to further interpret the MRI results.”
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`(Ex. 1006 at 34.) The EMA Report did not provide detailed information about the
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`subgroup analyses or the post hoc sensitivity analyses.
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`29. The purpose of a post hoc sensitivity analysis, such as those
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`referenced in the EMA Report, is not to determine the efficacy of a drug but rather
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`to determine whether the basic efficacy findings about a drug are robust to an array
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`of possible assumptions or alternative statistical models. The relevance of any
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`particular result from an individual sensitivity analysis depends heavily on the
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`specific assumptions made, and in any event can only be regarded as hypothesis-
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`generating. See Wang et al., N. Engl. J. Med. 357(21):2189-94 (2007) (Ex. 2035)
`
`at 2190 (“Post hoc analyses refer to those in which the hypotheses being tested are
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`not specified before any examination of the data. Such analyses are of particular
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`concern because it is often unclear how many were undertaken and whether some
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`were motivated by inspection of the data.”); Rothwell, Lancet 365: 176-86 (2005)
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`(Ex. 2036) at 181 (“Post hoc observations are not automatically invalid (many
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`medical discoveries have been fortuitous), but they should be regarded as
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`unreliable unless they can be replicated.”) and 184 (“A limited number of clinically
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`important analyses must be carefully predefined and justified, and post-hoc
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`observations should be treated with scepticism irrespective of their significance.”);
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`Oxman et al., Annals of Internal Medicine 116(1):78-84 (1992) (Ex. 2037) at 81
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`(“Although post-hoc analyses will sometimes yield plausible results, they should
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`generally be viewed as hypothesis-generating exercises rather than as hypothesis
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`testing. Decisions about which analyses to do and which ones to report are much
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`more likely to be data driven with post-hoc analyses and thereby more likely to be
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`spurious.”).
`
`30. According to the EMA Report, one post hoc analysis requested by
`
`CHMP used a statistical model in which patients with more lesions at baseline
`
`were assumed to produce a greater number of new lesions over the trial than
`
`patients with fewer lesions at baseline, regardless of treatment. (Ex. 1006 at 34.)
`
`In this analysis, treatment efficacy at a particular dose was determined after
`
`“subtracting out” the number of new lesions that the statistical model would have
`
`predicted based only on the number of lesions at baseline. According to the report,
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`the results of this post hoc analysis were that the 360 mg/day dose “reached
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`statistical significance for the various MRI endpoints, at least in one of the
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`requested models.” (Ex. 1006 at 34.) The EMA Report did not describe the
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`details of this statistical analysis, nor did it describe the additional models
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`requested by CHMP that did not achieve statistical significance, so neither its
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`appropriateness nor its clinical relevance can be fully assessed.
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`31. The post hoc analysis addressed a different question than the
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`prespecified statistical analysis underlying Kappos 2006. The Kappos 2006 study
`
`determined whether a particular dose of BG00012 effectively reduced the number
`
`of new brain lesions. (Ex. 1003A at 27.) As discussed herein, the Kappos 2006
`
`study showed that a 720 mg/day dose was therapeutically effective and that
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`120 mg/day and 360 mg/day doses were not statistically different from placebo.
`
`The post hoc analysis referenced in the EMA Report, on the other hand, considered
`
`whether the basic efficacy findings of Kappos 2006 were robust to an assumption
`
`that physiological differences between patients caused some of the new lesions.
`
`(Ex. 1006 at 34.)
`
`32. The post hoc analysis was necessarily influenced by the knowledge of
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`the results of the prespecified statistical analysis underlying Kappos 2006.
`
`Although the post hoc analysis may be useful for suggesting hypotheses about the
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`relationship between treatment with BG00012 and baseline level of disease, it was
`
`not a primary statistical analysis of prespecified endpoints from a blinded clinical
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`study.
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`33. Based on Kappos 2006 and the Kappos presentation, a person of
`
`ordinary skill in the art would have expected the effects on brain lesions with
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`480 mg/day to be closer to those with 360 mg/day than those with 720 mg/day.
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`My opinion does not change in view of the EMA Report.
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`VIII. The DEFINE and CONFIRM phase III studies had the unexpected
`
`result that the effectiveness of 480 mg/day was similar to that of
`
`720 mg/day.
`
`34.
`
`I have considered Gold et al., N. Engl. J. Med. 367(12):1098-107
`
`(2012) and Supplementary Appendix (“DEFINE publication”) (Ex. 2025) and Fox
`
`et al., N. Engl. J. Med. 367(12):1087-97 (2012) and Supplementary Appendix
`
`(“CONFIRM publication”) (Ex. 2026), which report on clinical studies with BG-
`
`12 (or BG00012) known as DEFINE and CONFIRM.
`
`35. The DEFINE and CONFIRM studies were both phase III,
`
`randomized, double-blind, placebo-controlled studies of an orally-administered
`
`DMF-only treatment (BG-12) in patients with relapsing-remitting MS. (Ex. 2025
`
`at 1; Ex. 2026 at 1.) In each study, in addition to a placebo regimen, two dosing
`
`regimens of BG-12 were studied: 240 mg twice daily (480 mg/day) and 240 mg
`
`three times daily (720mg/day).3 (Ex. 2025 at 1; Ex. 2026 at 1.)
`
`
`
` In addition, the CONFIRM study contained a fourth treatment arm in which a
`
` 3
`
`known active agent, glatiramer acetate, was administered by daily subcutaneous
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`- 17 -
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`Page 17 of 27
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
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`
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`36. The primary endpoint in the DEFINE study was the proportion of
`
`patients experiencing relapse within two years. (Ex. 2025 at 1, 3.) MRI scans of
`
`patients were obtained at screening and at weeks 24, 48, and 96. (Ex. 2025 at 3.)
`
`Information for the prespecified secondary endpoints of the number of Gd+ lesions
`
`and the number of new/enlarging T2-hyperintense lesions was also collected.
`
`(Ex. 2025 at 3.)
`
`37. The primary endpoint of the CONFIRM study was the annualized
`
`relapse rate at two years. (Ex. 2026 at 1, 3.) MRI scans were obtained from
`
`patients at screening and at weeks 24, 48, and 96. (Ex. 2026 at 3.) Prespecified
`
`secondary endpoints included the number of new/enlarging T2-hyperintense
`
`lesions and the number of new T1-hypointense lesions. (Ex. 2026 at 3.)
`
`38.
`
`In the DEFINE study, the proportion of patients who had at least one
`
`relapse of MS by two years (the primary endpoint) was significantly reduced with
`
`both the 480 mg/day dose and the 720 mg/day dose. (Ex. 2025 at 4.) The
`
`proportion was 46% for the placebo group, compared to 27% for the 480 mg/day
`
`group (p<0.001) and 26% for the 720 mg/day group (p<0.001). (Ex. 2025 at 4, 6
`
`
`
`injection. (Ex. 2023 at 1.) Because glatiramer acetate was administered by
`
`injection rather than orally, this arm of the study was not blinded to patients.
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`- 18 -
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`Page 18 of 27
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
`
`
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`(Table 2), 7 (Fig. 1A).) Because these p values are less than 0.05, they indicate
`
`that the differences from placebo are statistically significant. The annualized
`
`relapse rate for the 480 mg/day group was 47% of that for the placebo group
`
`(p<0.001), while the annualized relapse rate for the 720 mg/day group was slightly
`
`higher, at 52% of that for the placebo group (p<0.001). (Ex. 2025 at 6 (Table 2).)
`
`For the MRI assessments, placebo-treated patients had an average of 17 new or
`
`newly enlarging T2-hyperintense lesions, compared to 2.6 lesions in the 480
`
`mg/day group and 4.4 lesions in the 720 mg/day group (p<0.001 for both
`
`comparisons). (Ex. 2025 at 6 (Table 2).) For Gd+ lesions at two years, the mean
`
`number was 1.8 in the placebo group, compared to 0.1 in the 480 mg/day group
`
`and 0.5 in the 720 mg/day group (p<0.001 for both comparisons). (Ex. 2025 at 6
`
`(Table 2).)
`
`39.
`
`In the CONFIRM study, the frequency of relapses of MS was
`
`significantly reduced by both the 480 mg/day dose and the 720 mg/day dose. The
`
`annualized relapse rate at two years (the primary endpoint) for the 480 mg/day
`
`group was 44.0% lower than that for the placebo group, and for the 720 mg/day
`
`group the reduction was slightly higher, at 50.5% of that for the placebo group
`
`(p<0.001 for both comparisons). (Ex. 2026 at 4, 7 (Table 2).) The estimated
`
`proportion of patients with a relapse within two years was 41% of placebo-treated
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`- 19 -
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`Page 19 of 27
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
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`
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`patients, compared to 29% for 480 mg/day patients and 24% for 720 mg/day
`
`patients (p<0.001 for both comparisons). (Ex. 2026 at 7 (Table 2).) For the MRI
`
`assessments, placebo-treated patients had 17.4 new or enlarging T2-hyperintense
`
`lesions on average, compared to 5.1 lesions in the 480 mg/day group and 4.7
`
`lesions in the 720 mg/day group (p<0.001 for both comparisons). (Ex. 2026 at 7
`
`(Table 2).) With respect to new T1-hypointense lesions, the placebo group had 7.0
`
`new lesions on average, compared to the 480 mg/day group with 3.0 lesions and
`
`the 720 mg/day group with 2.4 lesions (p<0.001 for both comparisons). (Ex. 2026
`
`at 7 (Table 2).) With respect to new Gd+ lesions at two years, the placebo-treated
`
`patients averaged 2.0 new lesions, compared to the 480 mg/day group which
`
`averaged 0.5 new lesions, and the 720 mg/day group which averaged 0.4 new
`
`lesions (p<0.001 for both comparisons). (Ex. 2026 at 7 (Table 2).)
`
`40.
`
`In my opinion, the DEFINE study as described in the DEFINE
`
`publication was a well-designed and well-executed multi-center clinical trial. For
`
`the clinical endpoints related to relapse, the outcomes for the 720 mg/day group
`
`and the 480 mg/day group were virtually identical, the two dosage groups were not
`
`statistically significantly different from one another, and each of the two dosage
`
`groups showed substantial and statistically significant improvements compared to
`
`placebo. For both of the MRI endpoints examined, the 480 mg/day dose and the
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`- 20 -
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`Page 20 of 27
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
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`
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`720 mg/day dose showed substantial and statistically significant improvements
`
`over placebo.
`
`41.
`
`In my opinion, the CONFIRM study as described in the CONFIRM
`
`publication was also a well-designed and well-executed multi-center clinical trial.
`
`For the clinical endpoints related to relapse, the differences in outcomes between
`
`the 720 mg/day group and the 480 mg/day group were small, the two dosage
`
`groups were not statistically significantly different from one another, and each of
`
`the two dosage groups showed substantial and statistically significant
`
`improvements compared to placebo. For the three MRI endpoints examined, the
`
`differences in outcomes between the 720 mg/day group and the 480 mg/day group
`
`were small, the two dosage groups were not statistically significantly different
`
`from one another, and each of the two dosage groups showed substantial and
`
`statistically significant improvements compared to placebo.
`
`42. The results of the DEFINE study and of the CONFIRM study are
`
`consistent with one another, and demonstrated that both dosage regimens of BG-12
`
`studied are therapeutically effective, one of which was 480 mg/day administered in
`
`two separate daily oral doses of 240 mg each. They also showed that the
`
`therapeutic efficacy of 480 mg/day is essentially the same as that of 720 mg/day.
`
`- 21 -
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`Page 21 of 27
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
`
`
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`This result would have been unexpected based on Kappos 2006 and the Kappos
`
`presentation for the reasons detailed herein.
`
`43. The results from the CONFIRM and DEFINE studies are
`
`commensurate with the inventions claimed in the ’514 patent. For example, the
`
`results encompass methods of treating subjects needing treatment for MS by
`
`(claim 1) orally administering a pharmaceutical composition consisting essentially
`
`of a therapeutically effective amount of DMF, MMF, or a combination of the two,
`
`and one or more pharmaceutically acceptable excipients, in which the
`
`therapeutically effective amount of DMF, MMF, or the combination is about
`
`480 mg/day; (claim 11) orally administering about 480 mg/day of DMF, MMF, or
`
`a combination of the two; (claim 15) orally administering a pharmaceutical
`
`composition consisting essentially of a therapeutically effective amount of DMF,
`
`and one or more pharmaceutically acceptable excipients, in which the
`
`therapeutically effective amount of DMF is about 480 mg/day; and (claim 20)
`
`treating the subject with a therapeutically effective amount of DMF, MMF, or a
`
`combination thereof, where the therapeutically effective amount of DMF, MMF, or
`
`the combination is about 480 mg/day.
`
`44.
`
`I know of no publicly available information at the time of the
`
`Kappos 2006 abstract about the therapeutic effects, if any, of a 480 mg/day dosing
`
`- 22 -
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`Page 22 of 27
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Ronald A. Thisted, Ph.D.
`
`
`
`regimen for DMF, MMF, or a combination of the two. As discussed above,
`
`Kappos 2006 reported that the effects on brain lesions at 120 mg/day of DMF
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