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`UNITED STATES PATENT AND TRADEMARK OFFICE
`________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
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`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2018-01403
`Patent 8,399,514 B2
`____________________________________________
`
`DECLARATION OF MARTIN DUDDY, M.D.
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`Biogen Exhibit 2058
`Mylan v. Biogen
`IPR 2018-01403
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`Table of Contents
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`I.
`INTRODUCTION ........................................................................................... 6
`QUALIFICATIONS ........................................................................................ 6
`II.
`SCOPE OF THE ANALYSIS ......................................................................... 8
`III.
`IV. BACKGROUND OF MULTIPLE SCLEROSIS ............................................ 9
`V.
`THE CLAIMS OF THE ’514 PATENT ........................................................14
`VI. THE ASSERTED REFERENCES AND MYLAN’S ADDITIONAL
`CITATIONS ..................................................................................................15
`A.
`Schimrigk 2004 (Ex. 1006) .................................................................15
`B.
`Biogen’s Phase II MS Trial .................................................................17
`1.
`January 2006 Press Release (Ex. 1005) ....................................17
`2.
`ClinicalTrials (Ex. 1010) ..........................................................18
`3.
`Kappos 2006 (Ex. 1007) ...........................................................19
`C. WO 2006/037342 (Ex. 1008) ..............................................................20
`D.
`Joshi ’999 (Ex. 1009) ..........................................................................22
`E.
`ICH Guidelines (Ex. 1011) ..................................................................23
`VII. OPINIONS ON THE PATENTABILITY OF THE CLAIMS OF THE
`’514 PATENT ................................................................................................25
`A.
`Schimrigk 2004 and the January 2006 Press Release Do Not
`Provide Any Motivation to Go Below a Dose of 720 mg/day of
`DMF with a Reasonable Expectation of Success for Treating
`MS .......................................................................................................25
`1. Mylan’s Ground 1 Combination Does Not Disclose Each
`and Every Element of the Claims .............................................25
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`2.
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`3.
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`4.
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`B.
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`C.
`D.
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`The Combined Teachings of the January 2006 Press
`Release and Schimrigk 2004 Do Not Describe an
`Effective Dose Range of DMF for Treating MS ......................28
`The References Asserted in Ground 1 Do Not Provide
`Any Reason to Target a Daily Dose of 480 mg/day of
`DMF ..........................................................................................32
`The References of Ground 1 Do Not Provide Any
`Reasonable Expectation of Success ..........................................35
`Any Link Between Psoriasis and MS Before Biogen Filed Its
`Application Was Speculative, at Best, and Would Not Have
`Provided Motivation or a Reasonable Expectation of Success to
`Arrive at the Claimed Methods ...........................................................37
`The Prior Art Did Not Define an Effective Dose Range ....................46
`Side Effects and/or Twice Daily Dosing Do Not Provide A
`Reason to Seek a Dose of DMF Below 720 mg/day to Treat MS ......48
`1.
`Side Effects Were Not a Motivating Factor to Reduce the
`Dose of DMF to Treat MS ........................................................48
`Twice-a-day Dosing Would Not Have Led a Skilled
`Artisan to a Dose of 480 mg/day to Treat MS. .........................51
`Kappos 2006 and WO ’342 Do Not Render the Claimed
`Subject Matter Obvious (Ground 3) ....................................................53
`The ICH Guidelines, Joshi ’999, and ClinicalTrials Do Not Fill
`the Gaps in Kappos 2006 (Ground 4) .................................................54
`G. Mylan’s Post Hoc Analyses Do Not Change What Would Have
`Been Understood From the Prior Art ..................................................56
`H. Additional Evidence Demonstrates that the Claimed Methods
`Are Not Obvious .................................................................................74
`1.
`Treatment of MS Is Replete With Failures ...............................74
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`2.
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`E.
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`F.
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`2.
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`The Phase III Effectiveness of DMF, Especially in a
`Dose of 480 mg/day, Was Unexpected Based on Its
`Relatively Modest Effect in Phase II ........................................80
`The Claimed Methods Fulfill a Long-felt But Unmet
`Need ..........................................................................................90
`VIII. CONCLUSION ..............................................................................................92
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`3.
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`I.
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`INTRODUCTION
`I, Martin Duddy, M.D., have been retained by Finnegan, Henderson,
`1.
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`Farabow, Garrett & Dunner, LLP on behalf of Biogen MA Inc. as an independent
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`expert in the field of multiple sclerosis. My qualifications in these areas are
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`established by my curriculum vitae. Appendix A. I am being compensated for the
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`time I spend on this matter, but no part of my compensation depends on the outcome
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`of this proceeding.
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`II. QUALIFICATIONS
`I received my B.Sc. in Biochemistry in 1989, my Bachelor of Medicine,
`2.
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`Surgery, and Obstetrics in 1992, and my M.D. in 2000 all from the Queen’s
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`University Belfast. I completed my higher specialist training in neurology at Royal
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`Victoria Hospital, Belfast, UK in 2003 with an intercalated fellowship at the
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`Montreal Neurological Institute, Montreal, Canada in 2001-2002. My postgraduate
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`research focused on immunological responses to multiple sclerosis (“MS”)
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`therapies. I have been a licensed medical doctor since 2002, a Member of the Royal
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`College of Physicians since 1995, and a Fellow of the Royal College of Physicians
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`since 2007.
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`3.
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` I am currently a Consultant Neurologist with a special interest in MS
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`and the Clinical Director for Neurosciences at the Royal Victoria Infirmary,
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`Newcastle upon Tyne Hospitals NHS Foundation Trust, in Newcastle, United
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`Kingdom where I have been employed since 2003. Consultants in Neurology
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`provide services to patients suffering from neurological disorders, including a large
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`population of patients suffering from MS.
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`4.
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`I have extensive experience in diagnosing and treating MS patients. I
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`currently personally see approximately 700 unique individuals with MS annually.
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`For the last sixteen years at my current employment, I have formed part of a small
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`consultant team overseeing roughly 2,000 MS patients per year, with over 1,200
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`patients in therapy. In that role, I have also gained considerable experience with the
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`adverse events associated with MS therapy—including those associated with
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`Tecfidera®—and the harm that such events have on patient treatment adherence and
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`quality of life. A considerable amount of my MS practice thus has been, and
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`remains, focused on minimizing adverse events associated with MS therapy and
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`maximizing efficacy of such therapy.
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`5.
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`I have also served as local Principal Investigator in more than 30 multi-
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`center Phase II, III, and IV clinical trials related to the treatment of MS.
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`6.
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`I served as an Associate Editor of the for the Multiple Sclerosis Journal
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`from 2012-2017 (editor of Topical Reviews section). I have co-authored more than
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`25 peer-reviewed manuscripts in the area of Neurology and specifically related to
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`diagnosis and treating MS, including in Brain; Journal of Immunology; Lancet
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`Neurology; Neurology; Multiple Sclerosis Journal; Journal of Neurology,
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`Neurosurgery & Psychiatry; Journal of Neurology; Journal of the American Medical
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`Association Neurology; Neurology Clinical Practice; Neurology, Neuroimmunology
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`& Neuroinflammation; Practical Neurology; Multiple Sclerosis and Related
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`Disorders; Nature Genetics; Movement Disorders; Frontiers of Neurology and
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`Neuroscience; Expert Review of Clinical Immunology; and others.
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`7.
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`A copy of my curriculum vitae is attached as Appendix A.
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`III. SCOPE OF THE ANALYSIS
`I have been asked to consider Biogen’s ’514 patent, the Petition,
`8.
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`Mylan’s expert declarations, and certain documents raised in the Petition.
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`9.
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`I understand that Petitioner has asserted in four grounds of
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`unpatentability that the claims of the ’514 patent are obvious over various
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`combinations of Schimrigk 2004 (Ex. 1006), a January 2006 Press Release (Ex.
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`1005), WO 2006/037342 (“WO ’342,” Ex. 1008), Kappos 2006 (Ex. 1007), Joshi
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`’999 (Ex. 1009), ClinicalTrials (Ex. 1010), and the ICH Guidelines (Ex. 1011).
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`10.
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`I have been asked to offer my opinions regarding these grounds. In
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`forming my opinions, I have considered the materials cited in this declaration and in
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`the attached Appendix B. I may consider additional documents and information in
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`forming any supplemental opinions. To the extent I consider additional documents
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`or information, including any expert declarations in this proceeding, I may offer
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`further opinions.
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`IV. BACKGROUND OF MULTIPLE SCLEROSIS
`11. MS is a unique and complex neurological autoimmune disease
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`targeting the central nervous system (“CNS”). It is chronic, unpredictable, and
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`debilitating.
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`12. Function of the CNS, which includes the brain, optic nerves, and spinal
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`cord, requires effective transmission of information within the brain and between the
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`brain and the body. This transmission of information is accomplished by neurones,
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`which are nerve cells that process and transmit information through electrical and
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`chemical signals. Each neurone consists of a cell body, an axon, and dendrites.
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`Axons are nerve fibers that are covered with a fatty substance known as myelin
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`(forming the 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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`13. The cause of MS is not fully known, but scientists believe that the
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`interaction of environmental and genetic factors are involved. It is believed that the
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`immune system attacks healthy tissue in the CNS in certain individuals, leading to
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`damaged or destroyed myelin, oligodendrocytes (the cells that produce myelin), and
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`the underlying axons. This in turn leads to damaged areas along the nerve, slowing
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`or stopping the transmission of information necessary for normal thinking and bodily
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`function. Areas of damage can be seen as scars or lesions in tissue or by magnetic
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`resonance imaging (“MRI”).
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`14. MS can adversely affect nearly every 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 an
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`increasing symptom burden. Symptoms may include walking difficulty, limb
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`weakness, spasticity, tremors, pain, loss of balance, poor coordination, numbness,
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`tingling, bladder problems, sexual dysfunction, slurred speech, blurred or double
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`vision, blindness, memory problems, concentration problems, and fatigue
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`15. The progress and severity of MS in an individual are also unpredictable.
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`Most people diagnosed with MS have relapsing-remitting MS (“RRMS”) at disease
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`onset. In RRMS, people experience clearly defined attacks of new or increasing
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`neurologic symptoms (relapses or exacerbations) followed by periods of partial or
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`complete recovery (remissions). Over time, RRMS in most people transitions to a
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`pattern of progressive worsening with few or no relapses (secondary progressive MS
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`or “SPMS”). A minority of people diagnosed with MS have primary progressive MS
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`(“PPMS”) at disease onset. In PPMS, people demonstrate a steady progression of
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`symptoms from the time of diagnosis onward.
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`16. MS can be difficult to diagnose, so the diagnosis should be made, or
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`confirmed, by a neurologist who is knowledgeable about MS. MRI scans are
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`generally used to detect damaged areas of the CNS (lesions or scars) to aid in the
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`diagnosis.
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`17. MRI scans are also used to monitor MS. Because not all damaged areas
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`of the CNS produce symptoms, MRI scans may detect disease activity that is not
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`otherwise apparent to the patient or the healthcare provider. MRI is an important
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`outcome measurement in MS drug research to determine the effect of a drug on MS,
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`but it is does not necessarily correlate with clinical symptoms. That is, it is an
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`imprecise surrogate for clinical symptoms or disease progression, particularly at the
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`individual patient level.
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`18. MRI methods include detecting MS lesions using T2 weighted and T1
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`weighted sequences. T1 imaging can be with or without gadolinium. Gadolinium is
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`a heavy metal which can cross an open blood brain barrier, as happens in MS during
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`active inflammation. The appearance of a lesion changes over time on the two
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`techniques. The life cycle of a typical lesion is to appear bright on T2 from the onset,
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`shrinking in size beyond the acute stage, but normally remaining visible. On T1
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`sequences without gadolinium, a new lesion may initially appear dark (hypointense).
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`The lesion will be gadolinium enhancing (“Gd+”) on T1 sequences for the first few
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`weeks, but this stops once the blood brain barrier closes, usually by six weeks.
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`Outside the acute phase, the lesion will persist on T2 sequences as bright against the
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`surrounding white matter of the brain or spinal cord. If there is marked tissue
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`damage, the lesion will appear hypointense on T1 imaging (a T1 black hole), or if
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`there is less damage, it may not be seen at all. An old lesion can reactivate, in which
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`case the bright area may enlarge on T2, and there will be fresh transient enhancement
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`with gadolinium on T1.
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`19. No cure exists for MS. The FDA has approved several medications that
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`modify the course of MS by reducing the number of relapses and reducing the
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`worsening of disability. This category of medication is referred to as disease-
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`modifying therapy (“DMT”). Disease-modifying therapy implies that the treatment
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`lowers the overall advance of MS, lessening the overall impact the disease has on
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`the MS patient over time. Disease modification is the key treatment objective for the
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`MS field, because the impact of MS over time can be marked. Disease modifying
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`therapies seek to reverse or at least slow down the course of MS. The pathological
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`process driving MS changes over the lifespan of an individual. Current therapies
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`target the earlier, relapsing, inflammatory stage of the disease. Lengthening the
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`amount of time an individual with MS can work, participate in normal activities,
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`maintain social roles, and remain independent is important to every MS patient, and
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`to society at large, and these long-range benefits are the goals of MS disease
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`modifying therapy.
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`20. 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 the
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`underlying pathological process, do not diminish the amount of CNS damage and
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`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 the
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`benefit is rapid, and the offset is rapid. Often, the treatment benefit is obvious for
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`individual patients within the trial of symptom therapy. In contrast, testing disease-
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`modifying therapy generally requires years. This is why Phase III trials are typically
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`much longer than Phase II trials, which often rely on MRI endpoints instead of
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`clinical endpoints. For example, a Phase II trial that relies on Gd+ lesions as a
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`primary endpoint may last a few months, whereas a Phase III trial is typically on the
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`order of two years.
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`21. As of the 2007 filing date of the ’514 patent, no oral disease-modifying
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`medications were approved for MS. Injectable MS medications were available, but
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`they required regular injections or monthly parenteral infusions and had significant
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`limitations. For many patients, these injectable MS medications were often
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`associated with injection anxiety or injection-related adverse effects, limiting long-
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`term adherence to treatment, and leading to many patients declining to use disease-
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`modifying therapy entirely.
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`22. On March 27, 2013, the FDA approved Tecfidera® (dimethyl fumarate
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`(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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`23. Before Tecfidera® entered the market, the MS community was excited.
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`MS patients and physicians were generally aware of two Phase III studies
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`demonstrating that a pharmaceutical preparation of DMF (known as BG-12 or
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`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.
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`V. THE CLAIMS OF THE ’514 PATENT
`I understand that Mylan has challenged the patentability of all of the
`24.
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`claims of the ’514 patent. Claim 1 of the ’514 patent states:
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`A method of treating a subject in need of treatment for
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`multiple sclerosis comprising orally administering to the
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`subject in need thereof a pharmaceutical composition
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`consisting essentially of (a) a therapeutically effective
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`amount of dimethyl fumarate, monomethyl fumarate, or a
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`combination
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`thereof,
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`and
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`(b)
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`one
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`or more
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`pharmaceutically acceptable excipients, wherein
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`the
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`therapeutically effective amount of dimethyl fumarate,
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`monomethyl fumarate, or a combination thereof is about
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`480 mg per day.
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`VI. THE ASSERTED REFERENCES AND MYLAN’S ADDITIONAL
`CITATIONS
`Schimrigk 2004 (Ex. 1006)
`A.
`25. Schimrigk 2004 is a short abstract reporting the results of an
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`exploratory, prospective, open-label, non-placebo-controlled Phase II study of oral
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`fumarate therapy for the treatment of relapsing remitting MS (“RRMS”). (Ex. 1006
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`at 4-5.) The stated objective of the study was to “evaluate the safety and efficacy of
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`oral fumarate therapy (Fumaderm) in patients with [RRMS].” (Id.) The study
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`enrolled 10 patients, and 3 patients discontinued the study within the first three
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`weeks.
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`26. Schimrigk 2004 identifies four phases of the study: a 6-week baseline
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`period, an 18-week treatment period (titrated up to 6 tablets of Fumaderm® a day), a
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`4-week washout period, and a 70-week treatment phase (titrated up to 3 tablets of
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`Fumaderm® a day).
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`27. The oral fumarate therapy was administered in the form of Fumaderm®,
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`which contains a combination of DMF and monoethyl fumarate (“MEF”) salts (Ex.
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`1020). The oral fumarates were administered in two treatment phases at two different
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`dose levels (6 and 3 Fumaderm® tablets, respectively) with a four-week washout
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`period in between the treatment phases.
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`28. Schimrigk 2004 explains that the first phase 6-tablet dose led to a
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`statistically significant reduction from baseline in the number and volume of Gd+
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`lesions starting after 12 weeks of treatment. Schimrigk 2004, however, provides no
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`information regarding the magnitude of that statistically significant effect that would
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`have enabled a person of ordinary skill in the art to make a judgment on its possible
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`clinical significance. It also does not (and cannot, as discussed in greater detail
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`below) attribute any effect specifically to the 3-tablet second treatment phase dose.
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`Schimrigk 2004 provides no indication that the effects of the first treatment phase of
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`oral fumarates administered had lessened by the time the second treatment phase
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`began or any time during the second treatment phase. According to Schimrigk 2004,
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`there were no statistically significant effects on any of the clinical measures
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`(Expanded Disability Status Score (“EDSS”), Ambulatory Index (“AI”), and 9-hole
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`peg test (“9-HPT”)).
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`29. Schimrigk 2004 indicates that Fumaderm® was generally tolerable:
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`“Mild to moderate gastrointestinal discomfort was initially experienced by 6 of 7
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`patients, but decreased gradually during the first 6 weeks of treatment in all
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`patients. All other side effects were generally mild and transient.” (Ex. 1006 at 5.)
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`30. DMF alone was not tested in this study. The study was not placebo-
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`controlled. Instead, each patient was used as his own comparator. The authors
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`generally hypothesized that “oral fumarates,” not DMF monotherapy, “may be a
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`promising new treatment for RRMS,”1 without providing any information regarding
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`a dose-response relationship for Fumaderm® or DMF. (Ex. 1006 at 5.) Noticeably
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`absent from Schimrigk 2004 is any information regarding relapses. Particularly at
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`this point in time, annualized relapse rates (“ARR”) were often used to demonstrate
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`clinical effectiveness of MS treatments; and, as a result, if the outcome on relapse
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`rate had been positive, I would have expected it to have been reported.
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`B.
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`Biogen’s Phase II MS Trial
`January 2006 Press Release (Ex. 1005)
`1.
`31. A press release dated January 2006 reported that BG-12 “met its
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`primary endpoint” for RRMS in a study designed to evaluate the efficacy and safety
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`of BG-12. The press release states that “[t]reatment with BG-12 led to a statistically
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`significant reduction in the total number of gadolinium-enhancing brain lesions as
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`1 Emphasis added unless otherwise indicated.
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`measured by MRI with six months of treatment versus placebo.” The press release
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`does not disclose the trial design, the doses tested, the dose or doses that led to the
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`reported statistically significant reduction in Gd+ lesions, or any data.
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`ClinicalTrials (Ex. 1010)
`2.
`32. Mylan also relies on ClinicalTrials in one of its grounds. DMF is
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`identified as the active ingredient in BG00012. The document discloses four doses
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`of BG00012 to be tested: 0 mg/day (placebo), 120 mg/day, 360 mg/day, and 720
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`mg/day. It also indicates that the primary endpoint is the total number of Gd-
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`enhancing lesions over four scans at weeks 12, 16, 20, and 24. It does not include
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`any results.
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`33. Although ClinicalTrials states that “[d]ose reduction will be allowed
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`for subjects who are unable to tolerate investigational drug,” it does not provide any
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`details about how such dose reduction will be implemented. For example, it does not
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`clarify to what dose a patient will be reduced in any of the treatment groups. I also
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`note that the statement about dose reduction applies equally to the placebo group and
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`is not specific to DMF. In particular, ClinicalTrials says that dose reduction will be
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`allowed for those patients who are unable to tolerate “investigational drug.”
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`ClinicalTrials defines “investigational drug” as BG00012 or placebo. (Ex. 1010
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`at 2.)
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`34.
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`In addition, the allowance for a dose reduction in a clinical trial protocol
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`on grounds of tolerability does not mean that such a reduction is meant to be
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`permanent or that the lower dose is itself an effective treatment dose. Instead, such
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`dose reduction allowances simply permit the study subject to lower the dose
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`(whether placebo or active) for a period of time until the intolerability subsides. I
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`would have expected the study investigators to titrate the dose up again when
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`feasible. The objective of such dose manipulation is to allow a patient to overcome
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`transient problems with tolerability and subsequently to remain in the study at the
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`dose to which they were randomized.
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`3. Kappos 2006 (Ex. 1007)
`35. Kappos 2006 is an abstract reporting certain results of Biogen’s
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`Phase II study. It provides the objective of the study, certain details about the study
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`design, and reports that “BG00012 (720 mg/day [of DMF]) significantly reduced the
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`mean number of new Gd+ lesions (the primary end point) compared with placebo.”
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`It also states that “BG00012 significantly reduces brain lesion activity, in a dose-
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`dependent manner, as measured by MRI in patients with RRMS over 24 weeks of
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`treatment.” It indicates that patients were randomized, and were permitted to be
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`included in the study either on relapse criteria or the presence of a Gd-enhancing
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`baseline lesion. In other words, the entry criteria use Gd+ lesions and relapse criteria
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`with equal weighting, and a subject could be included in the study without any Gd+
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`lesions at screening. Kappos 2006 does not report any side effects of the BG00012
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`therapy, serious or otherwise.
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`C. WO 2006/037342 (Ex. 1008)
`36. WO ʼ342 is International Publication No. WO 2006/0037342 A2, titled
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`“Controlled Release Pharmaceutical Compositions Comprising a Fumaric Acid
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`Ester.” WO ʼ342 discloses a long list of diseases, including eleven conditions listed
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`as an “autoimmune disease,” using the disclosed controlled release pharmaceutical
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`compositions but does not associate a particular disease or condition with any
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`particular dose of any active agent. (Ex. 1008 at 37-39.) WO ʼ342 provides that the
`
`active substance can be “one or more fumaric acid esters selected from di-(C1-
`
`C5)alkylesters of fumaric acid and mono-(C1-C5)alkylesters of fumaric acid, or a
`
`pharmaceutically acceptable salt thereof, which - upon oral administration and in
`
`comparison to that obtained after oral administration of Fumaderm®
`
` tablets in an
`
`equivalent range - gives a reduction in GI . . . related side-effects.” (Ex. 1008 at 3.)
`
`It further states that the “active substance” is a fumaric acid ester preferably selected
`
`from the group consisting of “dimethylfumarate, diethylfumarate, dipropylfumarate,
`
`dibutylfumarate, dipentylfumarate, methyl-ethylfumarate, methyl-propylfumarate,
`
`methyl-butylfumarate,
`
`methyl-pentylfumarate,
`
`monomethylfumarate,
`
`monoethylfumarate,
`
`monopropylfumarate,
`
`monobutylfumarate
`
`and
`
`
`
`20
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`Page 20 of 106
`
`
`
`
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`monopentylfumarate, including pharmaceutically acceptable salts thereof.” (Ex.
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`1008 at 7.)
`
`37. WO ʼ342 further discloses that “[i]n one aspect of the invention the
`
`daily dosage can be e.g. from 240 to 360 mg active substance given in one to three
`
`doses, in another aspect 360 to 480 mg active substance given in one to three doses,
`
`in another aspect 480 to 600 mg active substance given in one to three doses, in
`
`another aspect 600 to 720 mg active substance given in one to three doses, in another
`
`aspect 720 to 840 mg active substance given in one to three doses, in another aspect
`
`840 to 960 mg active substance given in one to three doses and in yet another aspect
`
`960 to 1080 mg active substance given in one to three doses.” (Ex. 1008 at 36.)
`
`WO ʼ342 also discloses an up-scale table to slowly up-titrate the active ingredient to
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`limit gastrointestinal side effects. (Ex. 1008 at 35-36.) It does not indicate that any
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`one of the intermediate titration doses is a treatment dose.
`
`38. WO ʼ342 explains that “therapy with fumarates like e.g. Fumaderm®
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`frequently gives rise to gastrointestinal side effects such as e.g. fullness, diarrhea,
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`upper abdominal cramps, flatulence and nausea. Accordingly, there is a need to
`
`develop compositions comprising one or more therapeutically or prophylactically
`
`active fumaric acid esters that provide an improved treatment with a reduction in
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`gastro-intestinal related side effects upon oral administration.” (Ex. 1008 at 2-3.)
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`
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`21
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`Page 21 of 106
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`
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`
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`The only solution WO ’342 proposes to address gastrointestinal side effects is the
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`use of a controlled release formulation. (Ex. 1008 at 2-3, 11.)
`
`D.
`39.
`
`Joshi ’999 (Ex. 1009)
`Joshi ’999 discloses the use of certain dialkyl fumarates for the
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`preparation of pharmaceutical preparations, such as micro-tablets or pellets.
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`Joshi ’999 does not disclose a daily dose of DMF. Instead, it describes the amount
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`(in mg) of DMF present in the disclosed pharmaceutical preparations. Specifically,
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`Joshi ’999 describes pharmaceutical preparations containing certain dialkyl
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`fumarates. (Ex. 1009 at Abstract.) Joshi ’999 states that the amounts to be used are
`
`selected in such a manner that the preparations contain the active ingredient in an
`
`amount corresponding to 10 to 300 mg of fumaric acid. (Ex. 1009 at 4:42-45.) It
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`therefore indicates that preferred preparations contain a total amount of 10 to 300
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`mg DMF and/or diethyl fumarate. (Ex. 1009 at 4:46-48.) Dr. Benet agrees with this
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`characterization. (Ex. 1003 ¶ 69.)
`
`40.
`
`Joshi ’999 focuses on formulating certain dialkyl fumarates, including
`
`DMF, in dosage forms that ameliorate side effects associated with administering free
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`fumaric acids. (Ex. 1009 at 3:14-15, “The preparations according to the invention
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`do not contain any free fumaric acids per se.”) Such dosage forms include tablets,
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`micro-tablets, pellets or granulates, optionally in capsules or sachets. (Ex. 1009 at
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`4:31-38.) Joshi ’999 teaches that “[b]y administration of the dialkyl fumarates in the
`
`
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`22
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`Page 22 of 106
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`
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`
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`form of micro-tablets, which is preferred, gastrointestinal irritations and side effects,
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`which are reduced already when conventional tablets are administered but is still
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`observed, may be further reduced vis-à-vis fumaric acid derivatives and salts.” (Ex.
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`1009 at 5:29-33.)
`
`ICH Guidelines (Ex. 1011)
`E.
`41. The ICH Guidelines provide general guidance to drug developers on
`
`how to obtain dose-response information to support drug registration for a wide
`
`variety of divergent therapies for unrelated diseases. (Ex. 1011 at 5-12.) It describes
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`four trial designs to generate dose-response information: parallel dose-response,
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`cross-over dose-response, forced titration, and optional titration studies. (Ex. 1011
`
`at 9-12.) The latter three study designs are appropriate in conditions where it is
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`possible to measure an individual’s response to different doses in a single study
`
`within a practical timeframe. The timescale required to measure outcomes for
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`disease-modifying therapy in MS renders these study designs (cross-over dose-
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`response, forced titration, and optional titration studies) unsuitable. (Ex. 1011 at 6,
`
`9, 11-12.)
`
`42.
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`Individual dose-response information may be obtained in a clinical
`
`study when the drug has an easily measurable, rapid effect that quickly dissipates
`
`when treatment is discontinued. (Ex. 1011 at 9, 11-12.) For example, when one is
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`dealing with “symptom therapy,” such as for psoriasis, it may be possible to obtain
`
`
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`23
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`Page 23 of 106
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`
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`
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`individual dose-response information and adjust the dose to reflect the most
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`efficacious dose for a particular patient. That is not the case for disease-modifying
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`therapy for MS, for which disease course and treatment are highly variable from one
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`patient to another. The timescale required to observe an effect also makes it
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`impractical to obtain individual dose-response information for disease-modifying
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`therapies for MS.
`
`43.
`
`In clinical practice, an MS physician would not modify the approved
`
`dose of a disease-modifying therapy to a non-approved dose for an individual
`
`patient, i.e., where a patient appears to be respondi
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