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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 RICHARD A. RUDICK, M.D.
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`Page 1 of 36
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`Biogen Exhibit 2044
`Coalition v. Biogen
`IPR2015-01993
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`U.S. Patent No. 8,399,514
`Case: IPR2015-01993
`Declaration of Richard A. Rudick, M.D.
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`I.
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`Introduction
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`1.
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`I, Richard A. Rudick, M.D., am a medical doctor with expertise in the
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`field of multiple sclerosis (MS). I have over thirty-five years of experience in MS-
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`related research, teaching, and clinical practice.
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`2.
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`Since 2014, I have been Vice President of Development Sciences,
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`Value-Based Medicine Group at Biogen. This group focuses on using new
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`technology to develop innovative programs and tools to better understand,
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`measure, and manage the treatment of MS.
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`3.
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`I am serving as an expert consultant for this inter partes review
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`proceeding. I am not being compensated for my time beyond my compensation as
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`a Biogen employee. Neither my employment with Biogen nor my salary is
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`contingent upon my opinions or the outcome of this or any other 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), owned by Biogen.
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`II. Qualifications
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`A. Education
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`4.
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`I earned my medical doctorate (M.D.) from Case Western Reserve
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`University School of Medicine in Cleveland, Ohio in 1975. Before that, I earned a
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`bachelor of science (B.S.) in zoology from Ohio University in Athens, Ohio in
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`1971.
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`5.
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`From 1975 to 1977, I served as Resident in Medicine at the University
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`of Connecticut School of Medicine in Farmington, Connecticut. I was Resident in
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`Neurology at Strong Memorial Hospital in Rochester, New York from 1977 to
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`1979, and then Chief Resident in Neurology from 1979 to 1980.
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`B. Research Experience Related to MS
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`6. My over thirty-five years of experience in research related to MS
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`includes pivotal clinical trials involving MS treatments that are now approved by
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`the U.S. Food and Drug Administration (FDA). I was the co-principal investigator
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`on a National Institutes of Health (NIH)-supported, investigator-initiated clinical
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`trial of intramuscular recombinant interferon beta (rIFN) for relapsing MS (1990-
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`1994). This study was supported in part by Biogen, and led to registration of the
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`rIFN product and marketing under the trade name Avonex®. Over the subsequent
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`years, I conducted numerous studies on Avonex®, with support from Biogen, the
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`NIH, and the National MS Society. I was Chairman of the Advisory Committee for
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`the Biogen-sponsored clinical trial of natalizumab in combination with Avonex®
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`(the SENTINEL trial, 2002 to 2005). The SENTINEL trial was one of two pivotal
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`trials of natalizumab that resulted in registration of natalizumab and marketing
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`Declaration of Richard A. Rudick, M.D.
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`under the name Tysabri®. I have conducted many clinical research studies of
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`natalizumab. I have also participated in many other clinical trials, and in clinical
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`research protocols in the general field of MS, translational research, outcome
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`measures, magnetic resonance imaging (MRI), clinical trials, and biomarkers.
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`7.
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`I have been awarded dozens of research grants and fellowships
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`totaling over $170 million, including for “Evaluating Selected Monitoring
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`Techniques in MS Clinical Trials” from the National MS Society ($118,852 from
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`1989 to 1990), “IM Recombinant Beta Interferon as Treatment for MS” from the
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`NIH ($4,200,000 from 1990 to 1994), “Monitoring Brain Atrophy During the
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`Course of MS” from the NIH ($1,303,967 from 1999 to 2004), and “Biomarkers of
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`the Therapeutic Response to Interferon in MS” from the NIH ($1,106,015 from
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`2004 to 2009). I have also received research grants and fellowships from
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`pharmaceutical companies, including two from Biogen ($70,000 from 1993 to
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`1995 and $624,900 from 1994 to 2001). I was co-principal investigator on two
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`cycles of a grant to Case Western Reserve University School of Medicine, the
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`Cleveland Clinical and Translational Research Collaborative (CTRC) ($64,000,000
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`from 2007-2012; and $64,600,000 from 2012-2017). The purpose of this grant was
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`to establish educational programs for clinical and translational research, and
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`infrastructure to accelerate clinical research progress across the medical institutions
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`in Cleveland, Ohio. This grant covered research in neurology as well as many other
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`fields. I transitioned to Biogen in 2014, prior to completion of the second cycle of
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`this grant.
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`8.
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`I was Director of the Mellen Center for MS Treatment and Research
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`at the Cleveland Clinic from 1987 to 2014. During this time, I also served as
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`Chairman of the Division of Clinical Research at the Cleveland Clinic (2001-
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`2007), Vice-Chairman of Research and Development at the Neurological Institute
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`at the Cleveland Clinic (2007-2014), and Co-Director of the Cleveland CTSC
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`(2004-2014).
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`C. Teaching Experience Related to MS
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`9. My over thirty-five years of experience teaching others about MS
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`includes teaching at the Rochester University School of Medicine as Instructor in
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`Neurology (1979-1980), Assistant Professor of Neurology (1980-1986), Associate
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`Professor of Neurology (1986-1987), and Adjunct Associate Professor of
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`Neurology (1987-1995).
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`10. From 1995 to 2014, I was Hazel Prior Hostetler Professor of
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`Neurology at the Cleveland Clinic. I was also Professor in the Department of
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`Medicine, Primary Appointment, in the Cleveland Clinic Lerner College of
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`Medicine (CCLCM) from 2003 to 2014, and Professor in the Department of
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`General Medical Sciences and Center for Clinical Investigation in the Case School
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`of Medicine from 2006 to 2014. I have trained dozens of students, neurology
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`residents, and post-doctoral research fellows, many of whom are now leaders in the
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`field of MS.
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`D. Clinical Experience Related to MS
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`11. My over thirty-five years of clinical experience with MS includes
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`diagnosing and treating many thousands of patients with MS, including patients
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`who have been referred to me from physicians all over the world. I diagnosed and
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`treated MS patients as an Associate Neurologist at Strong Memorial Hospital from
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`1980 to 1987. I also had clinical experience at the Mellen Center, where I
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`diagnosed and treated patients with MS from 1987 to 2014. In addition to my own
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`medical practice and providing ongoing clinical care and consultation to other
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`physicians, I also supervised a medical staff of eleven other neurologists who
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`specialized in MS and worked full-time at the Mellen Center, and seven advanced
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`practice clinicians (master’s prepared nurses and physician assistants). In 2013, my
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`last full year at the Mellen Center, over 5,000 individual patients were evaluated or
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`treated.
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`12.
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`I was certified by the American Board of Internal Medicine in 1978
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`and by the American Board of Psychiatry and Neurology in 1981.
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`E. Additional Experience and Qualifications
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`13.
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`I have authored over 230 peer-reviewed publications related to MS. I
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`have also held editorial positions on journals including Neurotherapeutics, Lancet
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`Neurology, and Multiple Sclerosis - Clinical Issues. I have authored ten books and
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`over thirty book chapters, including several editions of Multiple Sclerosis
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`Therapeutics (Martin Dunitz Publishers, London 1st ed. 1999; Martin Dunitz
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`Publishers, London 2nd ed. 2003; Informa Healthcare, Oxon 3rd ed. 2007;
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`Cambridge University Press, New York 4th ed. 2011).
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`14.
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`I have given over seventy invited lectures related to MS, including
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`“Three Decades of MS Research: What We Have Learned, Where We Are Going”
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`at the National Board of Directors Meeting of the National MS Society in 2007,
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`and “MS Functional Composite: What Works and What Doesn’t Work” at the
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`International Conference on Disability Outcomes in MS in 2011.
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`15. Since 2007, I have been engaged as an expert consultant for
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`pharmaceutical companies, including Biogen (National Faculty Meeting (2008);
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`European Committee for Treatment and Research in MS (ECTRIMS) Meetings
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`(2008, 2013); National Consultant Meetings (2009, 2010, 2011); Advisory Board
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`Meeting (2009); Avonex® Biomarker Advisory Board Meeting (2010); National
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`Advisory Committee Meeting (2011); Medical Affairs Advisory Board on Value-
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`Based Medicine Meeting (2013)).
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`16.
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`I have been a member of a dozen or so professional societies,
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`including the American Academy of Neurology, the American Association for the
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`Advancement of Science, the American Association of Physicians, and the
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`American Neurological Association. I have served on over a dozen committees and
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`advisory boards, including research peer-review committees for the National MS
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`Society, the NIH, and the MS International Federation. I have served on and also
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`chaired the National MS Society Research Program Advisory Committee, the NIH
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`Council for the National Council for Research Resources, and the NIH Council of
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`Councils. I currently co-direct the MS Outcomes Assessment Consortium
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`(MSOAC), under the aegis of the Critical Path Institute. MSOAC, sponsored by
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`the National MS Society, is a collaboration of eight pharmaceutical companies, MS
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`academic leaders from around the world, the FDA, and European Medicines
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`Agency (EMA). The goal of MSOAC is to establish an improved clinical outcome
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`measure for MS disability, in order to accelerate progress in treating progressive
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`forms of MS.
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`17.
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`I have received many awards for my work related to MS, including
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`the Alfred and Norma Lerner Humanitarian Award (the Cleveland Clinic’s most
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`prestigious physician honor) and the Health Care Professional Hall of Fame Award
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`from the National MS Society.
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`18. My curriculum vitae (Ex. 2045) provides further information about
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`my experience and qualifications.
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`III. Documents Considered
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`19. My opinions are based on my knowledge and experience. In forming
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`my opinions, I have also considered the documents listed in Appendix A, attached
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`to this declaration.
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`IV. Overview of MS
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`20. MS is a chronic, unpredictable, and often disabling disease of the
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`central nervous system (CNS). MS was first detected in the 1800s and became a
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`common diagnosis by the early 1900s. (Ex. 2065 at 3.) By the 2007 filing date of
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`the ’514 patent, MS affected about 2.5 million individuals worldwide. (Ex. 2065 at
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`3, 221.)
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`21. The CNS, which includes the brain, optic nerves, and spinal cord, is
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`responsible for transmitting information within the brain and between the brain and
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`the body. This transmission of information is accomplished by neurons, which are
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`nerve cells that process and transmit information through electrical and chemical
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`signals. Each neuron consists of a cell body, an axon, and dendrites (see figure
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`below). Axons are nerve fibers that are covered with a fatty substance known as
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`myelin (or myelin sheath). Myelin serves to maintain the health of the axons, and
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`to speed the transmission of information along the axons. Myelin is essential for
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`normal CNS function.
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`
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`22. The cause of MS is not known, but scientists believe that the
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`
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`interaction of immunologic, environmental, and genetic factors are involved. It is
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`believed that the immune system attacks healthy tissue in the CNS in certain
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`individuals, leading to damaged or destroyed myelin, oligodendrocytes (the cells
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`that produce myelin), and the underlying axons. This in turn leads to damaged
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`areas along the nerve (lesions or scars), slowing or stopping the transmission of
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`information necessary for normal thinking and bodily function.
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`23. MS can adversely affect nearly any bodily function. Symptoms of MS
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`are unpredictable and vary in type and severity from one person to another and in
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`the same person over time. Symptoms may disappear completely, may improve but
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`only partially, or may steadily worsen over time. As the illness advances, repeated
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`immune-mediated inflammatory attack on different parts of the CNS leads to
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`increasing symptom burden. Symptoms may include numbness, tingling, walking
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`difficulty, tremors, slurred speech, memory problems, concentration problems,
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`spasticity, bladder problems, sexual dysfunction, weakness, pain, fatigue, blurred
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`vision, blindness, loss of balance, poor coordination, or paralysis.
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`24. The progress and severity of MS in an individual are also
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`unpredictable. Most people diagnosed with MS have relapsing-remitting MS
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`(RRMS) at disease onset. In RRMS, people experience clearly defined attacks of
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`new or increasing neurologic symptoms (relapses or exacerbations) followed by
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`periods of partial or complete recovery (remissions). Over time, RRMS in most
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`people transitions to a pattern of progressive worsening with few or no relapses
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`(secondary progressive MS or SPMS). Some people diagnosed with MS have
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`primary progressive MS (PPMS) at disease onset. In PPMS, people demonstrate a
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`steady progression of symptoms from the time of diagnosis onward.
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`25. MS can be difficult to diagnose, so the diagnosis should be made by,
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`or confirmed by, a neurologist who is knowledgeable about MS. MRI scans are
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`generally used to detect damaged areas of the nerve (lesions or scars) to aid in the
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`diagnosis.
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`26. MRI scans are also used to monitor MS. Because not all damaged
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`areas of the nerve produce symptoms, MRI scans may detect disease activity that is
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`not otherwise apparent to the patient or the healthcare provider. MRI is an
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`important outcome measurement in MS drug research to determine the effect of a
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`drug on MS.
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`27. MRI methods include detecting MS lesions using T2 weighted and T1
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`weighted images. MS lesions detected with T2 weighted imaging appear as bright
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`spots compared with the surrounding tissue in the white matter of the brain and
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`spinal cord. These lesions have variable underlying pathology changes, ranging
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`from minimal to severe tissue damage. Once a T2 lesion develops, it generally
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`persists for many years. T1 weighted imaging reveals MS lesions that appear dark
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`compared with the normal surrounding tissue. MS lesions detected by T1 weighted
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`images are more severe, reflecting underlying tissue damage. An MRI contrast
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`agent, gadolinium, is used to identify new or very recent MS lesions. When
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`combined with T1 weighted images, after injection of gadolinium, new lesions
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`appear as bright spots compared with surrounding tissue. These gadolinium-
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`enhancing (Gd+) lesions indicate active and recent inflammation. Gd+ lesions
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`disappear about six weeks after they appear, because the blood brain barrier, which
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`opens at the time of new lesion formation, closes, excluding the gadolinium
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`contrast agent from the brain tissue. As opposed to Gd+ lesions, T2 bright lesions,
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`appearing in the same location as Gd+ lesions, persist for long periods of time.
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`28. Analysis of MS lesions has been crucial to the development of
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`treatments for MS, because when a treatment reduces new lesion formation
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`detected by MRI in a small group of MS patients, it predicts beneficial effects on
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`relapses in larger clinical studies. This is because the treatment effect on lesions is
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`linked to the treatment effect seen on relapses, but is much more sensitive,
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`meaning this benefit can be observed in far fewer patients. The magnitude of the
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`benefit on new MRI lesion formation (the MRI effect size) correlates very well
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`with the magnitude of benefit on clinical relapses (the clinical effect size). MS
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`lesions are only part of the story, however, because brain tissue that appears
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`normal using standard MRI imaging is abnormal when more advanced MRI
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`techniques are used, such as magnetization transfer ratio (MTR) or diffusion tensor
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`imaging (DTI). Also, demyelinated lesions in gray matter areas of the brain (e.g.
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`the cerebral cortex, the thalamus) are not visible using routine MRI scans, so MS
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`pathology in the gray matter requires the use of precise techniques to measure the
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`volume of the brain. Using these very precise computer programs, it has become
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`clear that the size of the brain, both the white matter and the gray matter, in MS is
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`lower than healthy people of the same gender and age, and that the brain in MS
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`shrinks much faster than it does in healthy aging people. Brain shrinkage is
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`commonly referred to as brain atrophy, and MRI techniques to measure brain
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`atrophy have become standard in MS clinical trials. The benefit of a drug in
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`slowing brain atrophy has been shown to correlate with the benefit of the same
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`drug in slowing MS-related disability worsening.
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`29. No cure exists for MS. The FDA has approved certain medications
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`that modify the course of MS by reducing the number of relapses and delaying
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`progression of disability to some degree. This category of medication is referred to
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`as disease-modifying therapy. Disease-modifying therapy implies that the
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`treatment lowers the overall advance of MS, lessening the overall impact the
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`disease has on the MS patient over time. Disease modification is the key treatment
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`objective for the MS field, because the impact of MS over time is so terrible.
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`Lengthening the amount of time an individual with MS can work, participate in
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`normal activities, maintain social roles, and remain independent is important to
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`every MS patient, and to society at large, and these long-range benefits are the
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`goals of MS disease modifying therapy.
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`30. The FDA has also approved certain medications to help patients
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`manage some symptoms that occur commonly in MS, such as fatigue, depression,
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`stiffness, or bladder control. These treatments are very useful for people with MS,
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`because they can lessen symptoms that lower quality of life. This category of
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`treatment is called “symptomatic therapy.” Symptomatic therapy is very different
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`from disease-modifying therapies, because symptomatic therapies do not change
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`the underlying pathological process, do not diminish the amount of CNS damage
`
`and deterioration, and do not interfere with the long-term consequences of the
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`neurological damage – disability related to cognitive, visual, sensory, motor,
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`autonomic, sexual, and bowel/bladder impairment. Symptomatic therapies can be
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`tested in short-term clinical trials over two or three months, because the onset of
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`the benefit is rapid, and the offset is rapid. Often, the treatment benefit is obvious
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`for individual patients within the trial of symptom therapy. In contrast, testing
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`disease-modifying therapy generally requires years.
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`31. As of the 2007 filing date of the ’514 patent, no safe and effective oral
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`disease-modifying medications were approved for MS. Injection MS medications
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`were available, but they required regular injections or monthly parenteral infusions
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`and had significant limitations. For many patients, these injectable MS medications
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`were often associated with injection anxiety or injection-related adverse effects,
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`limiting long-term adherence to treatment, and leading to many patients declining
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`to use disease-modifying therapy entirely.
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`32. On March 27, 2013, the FDA approved Tecfidera® (dimethyl fumarate
`
`(DMF)) capsules for the treatment of patients with relapsing forms of MS.
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`Tecfidera® is an oral medication administered twice a day as capsules containing
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`240 mg of DMF, for a total daily dose of 480 milligrams (mg) of DMF. Tecfidera®
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`falls into the disease-modifying category of MS medications.
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`33. Before Tecfidera® entered the market, the MS community was
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`excited. MS patients and physicians were generally aware of two Phase 3 studies
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`demonstrating that a pharmaceutical preparation of DMF (known as BG-12 or
`
`BG00012 at the time) given in a dose of 480 mg/day was a safe and effective oral
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`disease-modifying medication for MS. In July 2012, I wrote a declaration about the
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`unexpected and promising results that these clinical studies demonstrated.
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`(Ex. 2011.) That declaration was submitted to the U.S. Patent and Trademark
`
`Office as part of the application that became the ’514 patent. I was not employed
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`by Biogen when I wrote that declaration. I believed that the results shown in the
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`two Phase 3 studies were unexpected and that Tecfidera® would make a significant
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`difference in the lives of many MS patients. (Ex. 2011 at 12.) The opinions that I
`
`expressed in my 2012 declaration hold true today, as discussed further below.
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`V. The ’514 Patent and Level of Ordinary Skill in the Art
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`34. The ’514 patent claims are directed to methods for treating MS by
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`administering DMF, monomethyl fumarate (MMF), or a combination thereof in a
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`therapeutically effective amount of about 480 mg/day. As discussed above,
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`Tecfidera® is an oral medication for the treatment of MS that is administered at a
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`dose of 480 mg/day of DMF.
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`35.
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`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
`
`art. I understand that a person of ordinary skill is a hypothetical person who is
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`presumed to have known the relevant art at the time of the invention.
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`36.
`
`I understand that Biogen has taken the position that a person of
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`ordinary skill in the art in 2007 would have had at least a medical degree with at
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`least three years of training in neurology and at least three years of clinical
`
`experience treating MS. I think that this is a reasonable position because the ’514
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`patent is directed to treating MS. I am qualified to provide an opinion as to what a
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`person of ordinary skill would have known and concluded as of the 2007 filing
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`date of the ’514 patent.
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`VI. The Claimed Invention Achieved Unexpected Results
`
`37.
`
`I understand that one indicator that a claimed invention would not
`
`have been obvious to a person of ordinary skill at the time of the invention is if the
`
`claimed invention achieved unexpected results. In my opinion, the claimed
`
`invention of the ’514 patent achieved unexpected results.
`
`38.
`
`I have considered Kappos et al., 16th Meeting of the European
`
`Neurological Society (abstract to presentation May 30, 2006) (“Kappos 2006”)
`
`(Ex. 1003A) and the accompanying Kappos et al. presentation at the 16th Meeting
`
`of the European Neurological Society (May 30, 2006) (“Kappos presentation”)
`
`(Ex. 1007 at 55-77). The Kappos 2006 abstract and Kappos presentation relate to a
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`Phase 2 placebo-controlled clinical study of a pharmaceutical preparation known
`
`as BG-12 that contained DMF. (Ex. 1003A at 27.) In addition to a placebo arm,
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`three doses of DMF were tested in MS patients: 120 mg/day, 360 mg/day, and
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`720 mg/day. (Ex. 1003A at 27.)
`
`39. The primary clinical endpoint measured in the trial was the mean total
`
`number of Gd+ lesions seen on MRI scans at weeks 12, 16, 20, and 24. (Ex. 1003A
`
`at 27.) Gd+ lesions indicate new lesions, formed within the prior six weeks, and, as
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`discussed above, are a measure used to determine the inflammatory activity within
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`an individual MS patient. Secondary endpoints included the number of new and
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`Declaration of Richard A. Rudick, M.D.
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`enlarging T2 hyperintense lesions at week 24. (Ex. 1003A at 27.) New and
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`enlarging lesions represent all of the lesions that have developed or enlarged since
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`the beginning of the study.
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`40. The Phase 2 study results showed that both the 120 mg/day and
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`360 mg/day doses did not exhibit a statistically significant difference compared to
`
`placebo for either of these clinical endpoints. (Ex. 1007 at 67, 69.) For
`
`new/enlarging T2 lesions, the results with these doses were nearly identical to
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`those with placebo. (Ex. 1007 at 69.) In contrast, the 720 mg/day dose showed a
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`statistically significant effect compared to placebo for both of these clinical
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`endpoints. (Ex. 1007 at 67, 69.) The benefits of this 720 mg/day dose were not just
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`statistically significant, they demonstrated an impressive magnitude of benefit –
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`69% reduction in the number of Gd+ lesions, and 48% reduction in the number of
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`new and enlarging T2 lesions. (Ex. 1007 at 67, 69.) From a clinical perspective,
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`this is considered a very strong benefit. These Phase 2 results are depicted in
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`Figures 1 and 2 below (copied from my previous declaration, Ex. 2011 at 5).
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`Declaration of Richard A. Rudick, M.D.
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`Figure 1. Mean Total Number of Gd+ Lesions at Weeks 12, 16, 20, and 25
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`Combined in the Phase 2 Trial. (Ex. 2011 at 5.)
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`Figure 2. Mean Number of New and Emerging T2-Hyperintense Lesions
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`(Week 24) in the Phase 2 Trial. (Ex. 2011 at 5.)
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`41. The results of the Phase 2 study were not dose-proportional and there
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`was no hint of a linear dose response. A person of ordinary skill would not have
`
`known what effect, if any, a particular dose of DMF between 360 mg/day and 720
`
`mg/day might have demonstrated based on the Phase 2 results. Such person
`
`reviewing the Phase 2 results likely would have selected a dose of 720 mg/day for
`
`further investigation because only that dose was shown to be effective in the study.
`
`42. Based on the Phase 2 results, a person of ordinary skill would have
`
`had no reason to select a dose of 480 mg/day of DMF for further study. To the
`
`contrary, based on the Phase 2 results, a person of ordinary skill would have at
`
`most expected that the efficacy of a 480 mg/day dose would be more like that of
`
`the 360 mg/day dose (which was not effective) than that of the 720 mg/day dose
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`(which was effective). This is because a 480 mg/day dose is closer to a 360 mg/day
`
`dose than a 720 mg/day dose.
`
`43. The DMF pharmaceutical preparation (BG-12) was subsequently
`
`evaluated in two placebo-controlled, double-blind Phase 3 clinical studies (called
`
`DEFINE and CONFIRM). I have considered the published reports of these studies:
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`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.
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`367(12):1087-97 (2012) and Supplementary Appendix (“CONFIRM publication”)
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`(Ex. 2026). In addition to a placebo arm, these studies tested two doses of DMF in
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`MS patients: 480 mg/day (BG-12 BID) and 720 mg/day (BG-12 TID). (Ex. 2025 at
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`1; Ex. 2026 at 1.)
`
`44. The DEFINE study’s primary endpoint was the proportion of MS
`
`patients who had a relapse by two years. (Ex. 2025 at 1.) Other endpoints included
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`annualized relapse rate, the number of new and enlarging T2-weighted lesions, the
`
`number of Gd+ lesions, and confirmed progression of disability. (Ex. 2025 at 1.)
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`For each of these endpoints, the results with the 480 mg/day dose were statistically
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`significantly better than those with placebo. (Ex. 2025 at 6.) Moreover, the results
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`with the 480 mg/day dose were similar to those with the 720 mg/day dose for each
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`endpoint measured. (Ex. 2025 at 6.)
`
`45. The CONFIRM study’s primary endpoint was annualized relapse rate
`
`over two years. (Ex. 2026 at 1.) Other endpoints included the proportion of
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`patients who had a relapse by two years, the number of Gd+ lesions, the number of
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`new and enlarging T2-hyperintense lesions, the number of new T1 hypointense
`
`lesions, and progression of disability. (Ex. 2026 at 1.) For each of these endpoints
`
`except the progression of disability, the results with the 480 mg/day dose were
`
`statistically significantly better than those with placebo. (Ex. 2026 at 7.) Moreover,
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`the results with 480 mg/day were similar to those with the 720 mg/day dose for
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`each endpoint measured. (Ex. 2026 at 7.)
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`46. These DEFINE and CONFIRM Phase 3 results are summarized in
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`Figures 3, 4, and 5 below (copied from my previous declaration, Ex. 2011 at 7-8).
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`Figure 3 shows that the annualized relapse rate with 480 mg/day was similar to that
`
`with 720 mg/day. (Ex. 2011 at 7.) Figure 4 shows that the disability progression
`
`with 480 mg/day was similar to that with 720 mg/day. (Ex. 2011 at 7.)
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`Figure 3. Annualized Relapse Rate with placebo, 480 mg/day (BG-12 BID),
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`
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`and 720 mg/day (BG-12 TID). (Ex. 2011 at 7.)
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`Figure 4. Disability Progression at Two Years. The results with 480 mg/day
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`(BG-12 BID) and 720 mg/day (BG-12 TID) were only statistically
`
`significant against placebo in the DEFINE study, but they were similar to
`
`
`
`each other in both studies. (Ex. 2011 at 7.)
`
`47. Figure 5 directly compares the effects of 480 mg/day, 720 mg/day,
`
`and placebo on multiple different endpoints. It represents a pool of the results from
`
`the DEFINE and CONFIRM studies. In this figure, the dashed line indicates no
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`difference at all of the treatment compared with placebo. The distance to the left of
`
`the dashed line indicates the magnitude of the benefit on that particular outcome
`
`compared with placebo. For example, an outcome result at the 0.5 level means that
`
`the treatment is twice as good as placebo. An outcome result at the 2.0 level means
`
`that the treatment is half as good as placebo. As is evident from Figure 5, BG-12
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`Declaration of Richard A. Rudick, M.D.
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`has beneficial effects on every single outcome tested; furthermore, 480 mg/day has
`
`similar efficacy to 720 mg/day on every outcome.
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`Figure 5. Summary of Key Efficacy Endpoints (Ratio and 95% Confidence
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`Interval), DEFINE and CONFIRM (pooled). RR (rate ratio), HR (hazard
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`ratio), LMR (lesion mean ratio), OR (odds ratio). (Ex. 2011 at 8.)
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`48. A person of ordinary skill in the art would not have expected, and
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`could not have predicted, the Phase 3 results based on the Phase 2 results. The
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`Phase 2 study showed that 120 mg/day and 360 mg/day doses were ineffe
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