UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SAWAI USA, INC. AND
`
`SAWAI PHARMACEUTICAL CO., LTD.
`
`Petitioners,
`
`v.
`
`BIOGEN MA, INC.
`
`Patent Owner.
`
`_______________________________
`
`Patent No. 8,399,514
`
`_______________________________
`Inter Partes Review IPR2019-00789
`
` _______________________________
`
`DECLARATION OF RONALD G. MARKS, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,399,514
`
`137987113v2
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`Sawai (IPR2019-00789), Ex. 1058, p. 001
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`SAWAI USA, INC. AND
`
`SAWAI PHARMACEUTICAL CO., LTD.
`
`Petitioners,
`
`v.
`
`BIOGEN MA, INC.
`
`Patent Owner.
`
`_______________________________
`
`Patent No. 8,399,514
`
`_______________________________
`Inter Partes Review IPR2019-00789
`
` _______________________________
`
`DECLARATION OF RONALD G. MARKS, Ph.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,399,514
`
`137987113v2
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`Sawai (IPR2019-00789), Ex. 1058, p. 001
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`
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`TABLE OF CONTENTS
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`Page
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`INTRODUCTION ......................................................................................... 3
`I.
`EDUCATION AND PROFESSIONAL BACKGROUND ........................ 3
`II.
`III. MATERIALS CONSIDERED ..................................................................... 5
`IV. LEGAL STANDARDS .................................................................................. 5
`V.
`SUMMARY OF OPINIONS......................................................................... 7
`VI. BACKGROUND ............................................................................................ 8
`A. Clinical Trials Investigating Dimethyl Fumarate ................................... 8
`B.
`Statistical Principles ..............................................................................10
`VII. 360 MG DIMETHYL FUMARATE MOST LIKELY ACHIEVED
`STATISTICAL SIGNIFICANCE ..............................................................12
`VIII. BIOGEN’S EXPERTS’ CONCLUSION THAT 480 MG
`DIMETHYL FUMARATE IS “EQUALLY” OR “SIMILARLY”
`EFFECTIVE TO 720 MG DIMETHYL FUMARATE IS
`UNSUPPORTED .........................................................................................16
`IX. BIOGEN’S
`STATISTICIAN DRAWS
`INAPPROPRIATE
`MEDICAL EFFICACY CONCLUSIONS THROUGHOUT HIS
`REPORT .......................................................................................................19
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`137987113v2
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`2
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`Sawai (IPR2019-00789), Ex. 1058, p. 002
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`
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`I, Ronald G. Marks, Ph.D., do hereby declare:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am making this declaration at the request of Petitioners Sawai USA,
`
`Inc. and Sawai Pharmaceutical Co., Ltd. (“Petitioners” or “Sawai”), in the matter of
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`the Inter Partes Review (“IPR”) of U.S. Patent No. 8,399,514 (the “’514 patent”),
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`as set forth in the above caption.
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`II. EDUCATION AND PROFESSIONAL BACKGROUND
`
`2.
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`I received a B. Ed. In mathematics from Millersville State College in
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`1970. I received a M.S. and Ph.D. in statistics from the University of Florida in 1972
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`and 1974, respectively. I authored a Ph.D. thesis titled An Analysis of Data with
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`Multiple Outliers. My curriculum vitae is attached as Exhibit A.
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`3.
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`After completing my Ph.D., I took a position as a Visiting Professor
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`and then Assistant Professor in the Department of Statistics at University of Florida.
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`I held that position until 1980, when I was promoted to Associate Professor, a title I
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`held until 1990, when I was promoted to Professor. In 1975, I was appointed
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`Director of the Division of Biostatistics and I held that position until 1985 and then
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`again from 1995-2000. In 2009, I took a position as Chief Scientific Officer and
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`Director of Biostatics at Clinipace. In 2018, I transitioned to Contract Chief
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`Scientific Officer, a position I hold to this day. In addition, I have held joint
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`appointments in other colleges including Department of Pharmacy Practice (1976-
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`137987113v2
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`Sawai (IPR2019-00789), Ex. 1058, p. 003
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`
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`2004), Department of Occupational Therapy (1980-2004), and College of Nursing
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`(1981-2004).
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`4.
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`During my academic career, I served on the Editorial Board of
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`Occupational Therapy in Mental Health and as a journal referee for Journal of Dental
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`Research, Occupational Therapy in Mental Health, Statistics in Medicine, Archives
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`of Ophthalmology, Medical and Pediatric Oncology, Journal of Public Health
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`Dentistry, and Journal of Myocardial Ischemia. I also served as a grant reviewer for
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`numerous NIH groups during my academic career.
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`5.
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`As a biostatistician, I have more than forty years of experience in
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`clinical trial design, statistical analysis, and the reporting of results from these
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`studies from Phase 1 through Phase 4 clinical trials. In particular, I have been
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`involved in the clinical trials, randomization, and proper protocols and practices for
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`clinical studies. I have published dozens of papers analyzing clinical trial data. I
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`have also presented widely at conferences, symposia, and seminars on clinical trials.
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`For example, I was the Keynote Speaker and Conference Chair at the e-Clinical
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`Trials 2003, Vision in Business conference in Las Vegas, Nevada in 2003. I am a
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`named author on 137 peer-reviewed articles and 6 books, including Analyzing
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`Research Data: The Basics of Biomedical Research Methodology. I have received
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`grants from a number of organizations including the NIDR and NHBI.
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`137987113v2
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`Sawai (IPR2019-00789), Ex. 1058, p. 004
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`6.
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`I taught biostatistics courses for 25 years on the design and analytical
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`methods required for research. I taught graduate students in MS, PhD, and MD
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`programs who were required to conduct their own research to receive their graduate
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`degree. In 2003, I received the Exemplary Teacher Award from the College of
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`Medicine.
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`7.
`
`I am being compensated at an hourly rate of $350/hour and am available
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`to appear live for testimony in support of my opinions. My compensation in no way
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`depends on the outcome of this proceeding. The opinions to which I will testify are
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`based on the education, experience, training, and skill that I have accumulated in the
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`course of my career as a biostatistician and researcher, as well as materials I have
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`reviewed in connection with this case.
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`III. MATERIALS CONSIDERED
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`8.
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`The list of materials I considered in forming the opinions set forth in
`
`this declaration is set forth in Exhibit B.
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`IV. LEGAL STANDARDS
`
`9.
`
`I understand that this IPR involves U.S. Patent No. 8,399,514 (the “’514
`
`patent”), which claims treating multiple sclerosis (“MS”) with about 480 mg
`
`dimethyl fumarate (“DMF”) per day. Ex. 1001. I understand that a previous IPR
`
`proceeding, brought by the Coalition for Affordable Drugs, was instituted against
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`the same ’514 patent (“the CFAD IPR”). See IPR2015-01993. I have reviewed
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`137987113v2
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`5
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`Sawai (IPR2019-00789), Ex. 1058, p. 005
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`certain materials from the CFAD IPR, including the expert declaration of Patent
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`Owner Biogen MA Inc.’s (“Biogen’s”) statistician. IPR2015-01993, Ex. 2038
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`(Thisted Decl.).
`
`10.
`
`I have been informed of the relevant legal principles as part of preparing
`
`and forming my opinions set forth in this declaration. I have applied my
`
`understanding of those principles in forming my opinions. My understanding of
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`those principles is summarized below.
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`11.
`
`I have been informed that Mylan bears the burden of proving
`
`unpatentability by a preponderance of the evidence, which means that Mylan must
`
`show that more likely than not, the claims of the ’514 patent are invalid. I understand
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`that one way to cancel patent claims is to find that they are obvious over the prior
`
`art. I understand that unpatentability, including obviousness, is assessed from the
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`viewpoint of a person of ordinary skill in the art (“POSA”) at the patent’s priority
`
`date.
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`12.
`
`I understand that the obviousness inquiry is a question of law based on
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`four factual inquiries: (1) the scope and content of the prior art (i.e., the literature
`
`existing at the time of the patent’s priority date), (2) the differences between the prior
`
`art and the claims, (3) the level of ordinary skill in the art, and (4) secondary
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`considerations of non-obviousness, which may rebut evidence that a patent’s claims
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`are obvious. I also understand that to demonstrate obviousness based on multiple
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`6
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`Sawai (IPR2019-00789), Ex. 1058, p. 006
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`
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`pieces of prior art, or changing something from what was disclosed in the prior art,
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`Mylan must prove that a POSA would have been motivated to combine the prior art,
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`and would have had a reasonable expectation of success in making that change or
`
`combination to come to the claimed invention.
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`13.
`
`I have been told that one secondary consideration of non-obviousness
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`is unexpected results. I further understand that, to show unexpected results, Patent
`
`Owner Biogen must prove that the alleged invention produced benefits that were
`
`unexpected in light of the prior art, from the viewpoint of a POSA at the patent’s
`
`priority date. I understand that the parties can look to references and other evidence
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`after a patent’s priority date to assess unexpected results.
`
`14.
`
`I have been told that evidence of secondary considerations such as
`
`unexpected results is only relevant to the obviousness analysis if the patentee can
`
`show a direct link, or nexus, between the secondary consideration and the claims of
`
`the patent, and that the evidence must be commensurate in scope with the asserted
`
`claims. I also understand that for results to be considered unexpected for these
`
`purposes, there must be a substantial difference from the prior art. In other words, a
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`difference of kind, and not merely of degree.
`
`V.
`
`SUMMARY OF OPINIONS
`
`15. From my review of certain materials relating to my opinions herein
`
`from the CFAD IPR, I understand that Biogen’s experts argued that 360 mg
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`Sawai (IPR2019-00789), Ex. 1058, p. 007
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`
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`DMF/day did not achieve statistically significant efficacy in treating MS. It is my
`
`opinion that 360 mg DMF/day most likely achieved statistically significant efficacy,
`
`as detailed below in the Fox and Gold book chapter and the EMA Report.
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`16. Also from my review of certain materials from the CFAD IPR, I
`
`understand that Biogen’s experts conclude that 480 mg is similarly effective to
`
`720 mg/day DMF, relying on data from Biogen’s phase III clinical studies. It is my
`
`opinion that Biogen’s phase III clinical trials do not allow for any such conclusion
`
`to be drawn. Instead, one can only conclude from the studies’ design that both
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`480 and 720 mg DMF produced statistically significant results over placebo in
`
`certain efficacy endpoints—the relative efficacy of the two doses cannot be
`
`compared to one another.
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`17. Finally, after reviewing Biogen’s statistician’s report in the CFAD IPR,
`
`I find most of his opinions inappropriate, because they are far outside the scope of a
`
`statistician’s expertise. Dr. Thisted is a statistician, not a medical doctor or
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`pharmacokinetics/pharmacodynamics (“PK/PD”) expert, yet he opined that a POSA
`
`would not have expected 480 mg/day DMF to be therapeutically effective, because
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`it was closer in proximity to a dose he deemed therapeutically ineffective
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`(360 mg/day) than to 720 mg/day.
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`VI. BACKGROUND
`
`A. Clinical Trials Investigating Dimethyl Fumarate
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`137987113v2
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`8
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`Sawai (IPR2019-00789), Ex. 1058, p. 008
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`
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`18. The Kappos 2006 study was a
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`randomized, double-blind,
`
`placebo-controlled phase II study testing three separate doses of BG00012 (DMF)
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`in patients with relapsing-remitting multiple sclerosis (RRMS), the results of which
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`are reported in Kappos 2006. Ex. 1007 (Kappos 2006) at 27. This study included a
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`placebo arm, as well as three different doses of DMF—120 mg/day, 360 mg/day,
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`and 720 mg/day. Id. The study measured the drug’s effect on brain lesion activity
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`by measuring the total number of gadolinium-enhancing (Gd +) lesions in MRI scans
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`as the primary endpoint. Id. Kappos 2006 reported that “BG00012 (720 mg/day)
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`significantly reduced the mean number of new Gd + lesions (the primary end point)
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`compared with placebo.” Id. Kappos 2006 concluded that “BG00012 significantly
`
`reduces brain lesion activity, in a dose-dependent manner, as measured by MRI in
`
`patients with RRMS over 24 weeks of treatment.” Id.
`
`19. The DEFINE
`
`study was
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`a
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`randomized,
`
`double-blind,
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`placebo-controlled phase III study, the results of which are reported in the Gold 2012
`
`publication. Ex. 1038 (DEFINE paper). The DEFINE study included three arms:
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`480 mg/day DMF, 720 mg/day DMF, and placebo. Id. at 1. The primary objective
`
`of the DEFINE study was “to determine whether BG00012, when compared with
`
`placebo, is effective in reducing the proportion of relapsing subjects at 2 years.” See,
`
`e.g., id. at 45. The secondary and tertiary objectives similarly measured effects of
`
`the DMF doses individually against placebo. See, e.g., id. at 45–46, 57–58. The
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`137987113v2
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`Sawai (IPR2019-00789), Ex. 1058, p. 009
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`study concluded that “both BG-12 regimens, as compared with placebo, significantly
`
`reduced the proportion of patients who had a relapse, the annualized relapse rate, the
`
`rate of disability progression, and the number of lesions on MRI.” Id. at 1.
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`20. The CONFIRM
`
`study was
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`a
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`randomized,
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`double-blind,
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`placebo-controlled phase III study, the results of which are reported in the Fox 2012
`
`publication. Ex. 1039 (CONFIRM paper). The CONFIRM study included four
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`arms: 480 mg/day DMF, 720 mg/day DMF, 20 mg/day glatiramer acetate, and
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`placebo. Id. at 1–2. The primary objective of the CONFIRM study was “to
`
`determine whether BG00012, when compared with placebo, is effective in reducing
`
`the proportion of relapsing subjects at 2 years.” Id. at 46. The secondary and tertiary
`
`objectives similarly measured effects of the DMF doses individually against
`
`placebo. See, e.g., id. at 46–47, 58–59. The publication reporting the CONFIRM
`
`results clarified that “[t]he study was not designed to test the superiority or
`
`noninferiority of BG-12 versus glatiramer acetate.” Id. at 1. The study concluded
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`that “BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates
`
`and improved neuroradiologic outcomes relative to placebo.” Id.
`
`B.
`
`Statistical Principles
`
`21. One of the main goals of statistics is to evaluate whether study results
`
`are meaningful. The most common way to draw this conclusion is by measuring
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`whether results achieve “statistical significance.” This is necessary because studies
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`137987113v2
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`10
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`Sawai (IPR2019-00789), Ex. 1058, p. 010
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`
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`measure a particular result or outcome at the sample, and the sample is ideally
`
`representative to a population of people. The end goal is to extrapolate the study’s
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`results to the population to draw conclusions about that population. At a high level,
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`if a study result achieves statistical significance, it means that the investigator has
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`sufficiently ruled out the possibility that the result was merely due to random chance
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`(as opposed to, for example, a treatment effect).
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`22.
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`In the clinical trial context, studies can be designed to compare
`
`treatments. Phase III clinical trials typically have two arms (but sometimes have
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`more)—a treatment arm and a comparator arm. The comparator arm can comprise
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`a placebo comparator or an active comparator, which allows the treatment arm to be
`
`compared with another effective intervention. A well-designed clinical trial allows
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`the investigator to measure the effectiveness of a treatment over the placebo or active
`
`comparator. This type of clinical trial is called a “superiority” trial, because it is
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`proactively designed to test whether a treatment has a statistically significant effect
`
`compared with a placebo or control.
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`23. Other types of study designs are available if a superiority trial design is
`
`not feasible or desired. For example, clinical trials can be designed as non-inferiority
`
`studies, which (when designed correctly) can measure whether a particular treatment
`
`is not materially worse than the control. See, e.g., Ex. 1049 (FDA Guidance) at 5.
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`Part of the correct design of a non-inferiority trial is the pre-specification of the
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`Sawai (IPR2019-00789), Ex. 1058, p. 011
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`
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`study’s non-inferiority margin(s) before commencing the trial. Id. at 7–17, 22–34.
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`If an investigator desires to establish the equivalence of two active treatments to one
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`another, the investigator must conduct a properly designed non-inferiority trial.
`
`VII. 360 MG DIMETHYL FUMARATE MOST LIKELY ACHIEVED
`STATISTICAL SIGNIFICANCE
`
`24.
`
`In the CFAD IPR, I understand that Biogen’s experts argued that
`
`360 mg/day DMF did not achieve statistical significance in certain efficacy variables
`
`in the Kappos 2006 study, and that CFAD supplied no evidence to counter that point.
`
`However, the Kappos 2006 study most likely achieved statistically significant results
`
`for both 360 mg and 720 mg DMF.
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`25. For example, in 2011, Biogen’s main expert in the CFAD IPR—Dr.
`
`Rudick—edited a book chapter that acknowledged that the 360 mg/day group in the
`
`Kappos 2006 study most likely achieved statistical significance. Ex. 1036 (Fox and
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`Gold Book Chapter)1 at 5–7. Specifically, after noting that the phase II study
`
`reported in Kappos 2006 did not technically achieve statistical significance for the
`
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`1 This book chapter was edited by Biogen’s CFAD IPR expert, Dr. Richard Rudick.
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`Notably, the two authors of the book chapter are Robert Fox and Ralf Gold, the lead
`
`authors on the CONFIRM and DEFINE study publications, respectively. Dr. Gold
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`was also an investigator on the Kappos phase II trial. See Ex. 1048 (Kappos 2008)
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`at 9.
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`Sawai (IPR2019-00789), Ex. 1058, p. 012
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`
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`two lower DMF doses tested (120 mg/day and 360 mg/day), the chapter observes,
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`“However, the middle (240 mg/d)2 [sic] dose group had a 76% higher mean
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`number of Gd-enhancing lesions at baseline, which may have obscured a
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`treatment effect.” Id. at 6 (emphasis added). In the next sentence, the chapter goes
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`on to say, “If the primary outcome is re-displayed as % reduction from each group’s
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`baseline enhancing lesion activity, a dose-response becomes more apparent (Fig.
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`31.4).” Id.
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`26.
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`In other words, Drs. Gold and Fox recognized that the group of patients
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`receiving 360 mg/day DMF had about a 75% higher mean number of Gd+ lesions at
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`baseline, and that may have affected the study’s original conclusion that 360 mg/day
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`DMF did not rise to the level of statistical significance in the primary outcome. Drs.
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`Gold and Fox then went a step further and adjusted the data to remove this perceived
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`bias, thereby demonstrating a stronger dose response relationship.
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`27. The European Medicines Agency made a similar observation in 2013.
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`See Ex. 1037 (EMA Report) at 33–34, 79. While analyzing the results of the phase II
`
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`2 It is my understanding that this number is supposed to be 360 mg/day, and not 240
`
`mg/day. This is because the Phase II study the book chapter is discussing did not
`
`test any dose of 240 mg/day, and the “middle dose group” depicted in the figures
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`referenced in this section of the book chapter is 360 mg/day.
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`Sawai (IPR2019-00789), Ex. 1058, p. 013
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`
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`dose response study within a larger evaluation of Biogen’s Tecfidera® (DMF) drug,
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`the EMA initially acknowledged that only the highest dose (720 mg/day DMF)
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`appeared to achieve statistical significance. Id. at 34, 79. However, it noticed that
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`“[t]here were considerable imbalances at baseline for the mean number of
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`Gd-enhancing lesions across the groups (notably in the 120 mg TID [i.e., 360
`
`mg/day] group which presented patients with higher disease activity i.e. higher
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`number of Gd enhancing lesions).” Id. at 34 (emphasis added); see also id. at 79
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`(same). The EMA Report went on to describe that once the data were reanalyzed,
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`“BG00012 [DMF] 120 mg TID [i.e., 360 mg/day] also provided statistically
`
`significant results for the primary endpoint (p=0.009).” Id. at 34 (emphasis
`
`added); see also Id. at 79 (same).
`
`28.
`
`I understand that in the CFAD IPR, Biogen’s statistician, Dr. Thisted,
`
`attempted to distance the EMA Report’s observations, on the basis that it was a post
`
`hoc analysis. See IPR2015-01993, Ex. 2038 (Thisted Decl.) ¶¶ 25–33. A post hoc
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`analysis is an analysis that is performed after obtaining data in a study. Post hoc
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`analyses can sometimes be less reliable than pre-defined analyses, because the
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`analyses may not be specifically planned out before commencing the study and
`
`obtaining some data. Therefore, an investigator must be careful not to allow a
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`study’s results to suggest a particular hypothesis that is likely to lead to a desired
`
`positive result. However, post hoc analyses can be useful in certain situations, such
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`Sawai (IPR2019-00789), Ex. 1058, p. 014
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`as for understanding how a key imbalance at baseline may have affected the study’s
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`original results.
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`29. Post hoc analyses can be appropriate in certain circumstances—in fact,
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`it is my opinion that this is precisely one circumstance in which a post hoc analysis
`
`is appropriate. Namely, the EMA Report noticed (as did Drs. Rudick, Gold and Fox
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`in their book chapter) that the 360 mg/day group had a higher number of
`
`Gd-enhancing lesions at baseline. Ex. 1037 (EMA Report) at 34, 79. In my opinion,
`
`the number of Gd-enhancing lesions at baseline is a very reasonable covariate to
`
`build into a regression model to conduct a post hoc analysis with the goal of
`
`controlling for possible bias affecting this study’s results. For example, this variable
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`can be measured accurately, and is clearly related to the endpoint investigated in the
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`study—indeed, it was related to the primary endpoint in the Kappos 2006 study.
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`Ex. 1007 (Kappos 2006) at 27.
`
`30.
`
`I also find an unambiguous description of the post hoc analysis in the
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`EMA Report, which strengthens my opinion that the analysis conducted was
`
`appropriate in this situation. See, e.g., Ex. 1037 (EMA Report) at 34 (“CHMP
`
`requested analyses using the number of baseline Gd-enhancing lesions as
`
`covariates”); 34 (“correcting for the baseline number of Gd-enhancing lesions in the
`
`statistical models as a covariate”); 79 (same). This is all the detail necessary to
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`Sawai (IPR2019-00789), Ex. 1058, p. 015
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`inform one that the post hoc analysis conducted was a linear regression that used the
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`number of baseline Gd-enhancing lesions as the sole covariate.
`
`VIII. BIOGEN’S EXPERTS’ CONCLUSION THAT 480 MG DIMETHYL
`FUMARATE IS “EQUALLY” OR “SIMILARLY” EFFECTIVE TO
`720 MG DIMETHYL FUMARATE IS UNSUPPORTED
`
`31.
`
`I understand that in the CFAD IPR, all of Biogen’s experts interpreted
`
`the results of Biogen’s phase III studies, DEFINE and CONFIRM, to conclude that
`
`480 mg/day DMF is similarly or equivalently efficacious to 720 mg/day DMF. It is
`
`my opinion that the DEFINE and CONFIRM studies only allow for the conclusion
`
`that each respective dose (480 mg/day or 720 mg/day) is efficacious over placebo,
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`and these studies do not allow for comparing the equivalency of the two DMF doses
`
`tested.
`
`32. The DEFINE and CONFIRM trials investigated the efficacy of two
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`different doses of DMF, 480 mg/day (the dosage claimed in the ’514 patent) and
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`720 mg/day. Ex. 1038 (DEFINE paper) at 1; Ex. 1039 (CONFIRM paper)3 at 1.
`
`Both studies measured the effect of these two dosages against placebo in certain
`
`efficacy endpoints. See, e.g., Ex. 1038 (DEFINE paper) at 45 (“The primary
`
`objective of this study is to determine whether BG00012, when compared with
`
`
`3 The CONFIRM study also included an arm administering patients a different
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`multiple sclerosis drug, glatiramer acetate. Ex. 1039 (CONFIRM paper) at 1–2.
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`16
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`Sawai (IPR2019-00789), Ex. 1058, p. 016
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`
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`
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`placebo, is effective in reducing the proportion of relapsing subjects at 2 years.”);
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`Ex. 1039 (CONFIRM paper) at 46 (same). These trials were superiority trials vs.
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`placebo only—they investigated whether each individual dose—480 mg/day and
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`720 mg/day DMF—was superior to placebo.
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`33. Neither study investigated the relative efficacy of 480 mg/day DMF as
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`compared to 720 mg/day DMF. In other words, neither study was designed to
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`measure whether 480 mg/day DMF was less effective, equally as effective, or more
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`effective than 720 mg/day DMF. When I reviewed the DEFINE and CONFIRM
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`publications, both publications appropriately limited the conclusions to the efficacy
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`of each dose as compared to placebo—not as compared to the other DMF dose. See,
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`e.g., Ex. 1038 (DEFINE paper) at 1 (“[B]oth BG-12 regimens, as compared with
`
`placebo, significantly reduced the proportion of patients who had a relapse, the
`
`annualized relapse rate, the rate of disability progression, and the number of lesions
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`on MRI.”);4 Ex. 1039 (CONFIRM paper) at 1 (“BG-12 (at both doses) and
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`
`4 See also Ex. 1038 (DEFINE paper) at 4 (“The proportion of patients who had at
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`least one relapse of multiple sclerosis by 2 years was significantly reduced with each
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`BG-12 regimen as compared with placebo.”); 6 (“As compared with placebo, BG-12
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`reduced the risk of confirmed progression of disability”); 7 (“As compared with
`
`placebo, BG-12 reduced the number of new or enlarging hyperintense lesions on
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`137987113v2
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`17
`
`Sawai (IPR2019-00789), Ex. 1058, p. 017
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`
`
`
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`glatiramer acetate significantly reduced relapse rates and improved neuroradiologic
`
`outcomes relative to placebo.”).5 The CONFIRM paper even reminds the reader that
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`the active arms are not to be compared to one another. Ex. 1039 (CONFIRM paper)
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`at 1 (“The study was not designed to test the superiority or noninferiority of BG-12
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`versus glatiramer acetate.”); see also id. at 3 (same).6
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`34. Any conclusion that 480 mg/day DMF is similarly or equivalently
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`efficacious to 720 mg/day DMF would be incorrect and misleading. I have reviewed
`
`
`T2-weighted images”); 9 (“BG-12, as compared with placebo, significantly reduced
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`the proportion of patients who had a relapse by 2 years, the annualized rate of
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`relapse, and the cumulative progression of disability.”)
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`5 See also Ex. 1039 (CONFIRM paper) at 5 (“As compared with placebo, twice-daily
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`BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the risk of
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`relapse”); 9 (“The CONFIRM study showed that in patients with relapsing-remitting
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`multiple sclerosis, BG-12 at a dose of 240 mg two or three times daily, as compared
`
`with placebo, significantly reduced the rate of relapse, the proportion of patients with
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`a relapse, and disease activity as measured by a range of MRI end points.”).
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`6 In fact, the CONFIRM paper notes (Ex. 1039 at 10) that the BG-12 and glatiramer
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`acetate active arms of the CONFIRM study were only able to be compared in an
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`indirect manner by using a post hoc analysis.
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`137987113v2
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`18
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`Sawai (IPR2019-00789), Ex. 1058, p. 018
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`
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`
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`the supplementary appendices attached to both papers reporting the DEFINE and
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`CONFIRM study results, which includes the clinical trial protocols for each study.
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`Ex. 1038 (DEFINE paper) at 33–126; Ex. 1039 (CONFIRM paper) at 34–127. My
`
`review has identified that the DEFINE and CONFIRM studies were not designed to
`
`compare the 480 mg/day dose to the 720 dose—they were simply designed as
`
`superiority studies to measure superiority over placebo only. See, e.g., Ex. 1038
`
`(DEFINE paper) at 45 (“The primary objective of this study is to determine whether
`
`BG00012, when compared with placebo, is effective in reducing the proportion of
`
`relapsing subjects at 2 years.”); Ex. 1039 (CONFIRM paper) at 46 (same).
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`Therefore, any conclusion comparing the equivalency of these two doses based on
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`the results of the DEFINE and CONFIRM studies would be improper.
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`IX. BIOGEN’S STATISTICIAN DRAWS INAPPROPRIATE MEDICAL
`EFFICACY CONCLUSIONS THROUGHOUT HIS REPORT
`
`35. While reviewing Biogen’s statistician’s expert report from the CFAD
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`IPR, I observed that Dr. Thisted made sweeping conclusions on the therapeutic
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`efficacy of the drug that exceed the expertise of a statistician. The main argument
`
`of Dr. Thisted’s declaration—that a POSA would not have expected 480 mg/day
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`DMF to be therapeutically effective—is an argument a statistician is not qualified to
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`make. See IPR2015-01993, Ex. 2038 (Thisted Decl.) ¶¶ 19–24, 33, 44–46.
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`Throughout his report, Dr. Thisted drew conclusions about the expected medical
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`efficacy of dimethyl fumarate to treat multiple sclerosis. See, e.g., id. ¶¶ 44
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`137987113v2
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`19
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`Sawai (IPR2019-00789), Ex. 1058, p. 019
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`
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`(“[B]ased on Kappos 2006, a person of ordinary skill in the art would not have
`
`expected that increasing the dose by an additional 33% (to 480 mg/day) would
`
`produce substantial efficacy. Indeed, 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
`
`360 mg/day than those with 720 mg/day. A person of ordinary skill in the art would
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`not have expected the results reported in the DEFINE and CONFIRM
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`publications.”); 45 (“It is stunning and unexpected to see, in two large independent
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`studies, that increasing an ineffective dose (360 mg/day) by a small amount
`
`(120 mg/day) produces a strong therapeutic effect, and that a further, larger dose
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`increase (to 720 mg/day) produces virtually no additional therapeutic benefit.”)
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`(emphasis added). Dr. Thisted is not a medical doctor and has no expertise in
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`PK/PD, and he made no statement that he relied on a medical treatment or PK/PD
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`expert to support such strong characterizations.
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`36.
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`In my experience as a biostatistician, it is inappropriate to offer
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`opinions such as these, that are clearly outside the expertise of even the most
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`experienced statisticians. I would not feel comfortable opining on, for example,
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`whether a skilled artisan would have expected therapeutic efficacy, the details of a
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`drug’s predicted or actual dose-response curve, or whether observed therapeutic
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`efficacy of 480 mg/day dimethyl fumarate was “stunning.” Id. ¶ 23, 33, 44, 45. I
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`have reviewed Dr. Thisted’s qualifications, as outlined by him in his previous report
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`137987113v2
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`20
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`Sawai (IPR2019-00789), Ex. 1058, p. 020
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`
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`(id. ¶¶ 2–11), and I do not see any experience that would render Dr. Thisted qualified
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`to give the sweeping therapeutic efficacy opinions that he gave to support Biogen’s
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`case.
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`137987113v2
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`21
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`Sawai (IPR2019-00789), Ex. 1058, p. 021
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`
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`I declare that all statements made herein on my own knowledge are true and
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`that all statements made on information and belief are believed to be true, and
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`further, that these statements were made with the knowledge that willfiJl false
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`statements and the like so made are punishable by fine or imprisonment, or both,
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`under Section 1001 of Title 18 of the United States Code.
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`
`
` Dated: 3/1?(9 01? QM; 3 h/l AA»
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`Ronald G. Marks, PhD.
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`137987113‘11
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`22
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`Sawai (IPR2019-00789), EX. 1058, p. 022
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`Sawai (IPR2019-00789), Ex. 1058, p. 022
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`
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`EXHIBIT A
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`137987113v2
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`Sawai (IPR2019-00789), Ex. 1058, p. 023
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`Curriculum Vitae
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`
`
`Ronald G. Marks
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`
` Home
`
`2736 NW 22nd Terrace
`Gainesville, FL 32605
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`
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`
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`
`
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`
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`(352) 870-9843
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`July 27, 1948
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`Married, two children
`
`
`PERSONAL:
`
`NAME:
`
`
`ADDRESS:
`
`
`
`
`
`
`
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`TELEPHONE:
`
`
`EMAIL ADDRESS: ronmarks06@cox.net
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`BIRTH DATE:
`
`
`MARITAL
`STATUS:
`
`
`EDUCATION:
`
`
`Degrees:
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`
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`Thesis Topic: "An Analysis of Data with Multiple Outliers"
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`
`
`EMPLOYMENT HISTORY:
`
`
`Clinipace Contract Chief Scientific Officer (part-time), 2018 - Present
`Clinipace Chief Scientific Officer and Director of Biostatistics, 2009 - 2017
`Biostatistics Expert Witness, 2004 - 2009
`Director, Division of Biostatistics, University of Florida, 1995 - 2000
`Professor, Dept. of Statistics, University of Florida, 1990 - 2004
`Interim Director, Division of Biostatistics, University of Florida, 1990 - 1992
`Associate Prof., Dept. of Statistics, University of Florida, 1980 - 1990
`Director, Division of Biostatistics, University of Florida, 1975 - 1985
`Assistant Professor, Dept. of Statistics, Univ. of Florida, 1975 - 80
`Visiting Professor, Dept. of Statistics, Univ. of Florida, 1974 - 75
`
` B. Ed. In mathematics, Millersville State Colle
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