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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`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 DANIEL WYNN, M.D. FACNS FAASM
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`Biogen Exhibit 2061
`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 154
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
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`Contents
`
`V.
`
`
`INTRODUCTION ........................................................................................... 4
`I.
`PROFESSIONAL BACKGROUND AND QUALIFICATIONS .................. 4
`II.
`III. MATERIALS CONSIDERED ........................................................................ 6
`IV. OVERVIEW OF MULTIPLE SCLEROSIS ................................................... 6
`A. Background on Multiple Sclerosis ........................................................... 6
`B. Clinical Measures of Multiple Sclerosis .................................................. 9
`BIOGEN’S ’514 PATENT ............................................................................ 15
`A. PERSON OF ORDINARY SKILL IN THE ART ................................ 23
`VI. THE ASSERTED REFERENCES AND MYLAN’S ADDITIONAL
`CITATIONS .................................................................................................. 24
`A. The Schimrigk 2004 Abstract (Ex. 1006) .............................................. 24
`B. Biogen’s Phase II MS Trial ................................................................... 26
`i.
`January 2006 Press Release (Ex. 1005) ....................................... 26
`ii.
`Clinical Trials (Ex. 1010) ............................................................ 26
`iii. Kappos 2006 (Ex. 1007) .............................................................. 27
`C. WO 2006/037342 (Ex. 1008) ................................................................. 28
`D. Joshi ’999 (Ex. 1009) ............................................................................. 30
`E.
`ICH Guidelines (Ex. 1011) .................................................................... 31
`VII. THE ’514 PATENT CLAIMS ARE NOT OBVIOUS ................................. 33
`A. Biogen’s Phase II Study Did Not Establish an Effective Dose
`Range of DMF to Treat MS ................................................................... 33
`B. A Person of Ordinary Skill in the Art Would Not Have
`Reanalyzed the Phase II Results ............................................................ 35
`C. Side Effects and Patient Compliance Would Not Have Pointed a
`Person of Ordinary Skill in the Art to a Daily Dose of 480
`mg/day to Treat MS ............................................................................... 41
`D. January 2006 Press Release in view of Schimrigk 2004 Abstract
`Does Not Render the ʼ514 Patent Claims Obvious ............................... 44
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`Declaration of Dr. Daniel Wynn
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`E. Kappos 2006 in View of Schimrigk 2004 Abstract Does Not
`Render the ʼ514 Patent Claims Obvious ................................................ 53
`F. Kappos 2006 in view of WO ʼ342 Does Not Render The ʼ514
`Patent Claims Obvious ........................................................................... 54
`i.
`The Disclosure of WO ’342 ........................................................ 54
`ii. WO ’342 Discloses a Long List of Wide-Ranging
`Conditions .................................................................................... 56
`iii. WO ’342 Discloses a Broad Class of Fumaric Acid Esters ........ 57
`iv. WO ’342 Discloses Indiscriminate Possible Fumaric Acid
`Ester Doses .................................................................................. 59
`v. WO ’342 Does Not Describe a Method of Treating a
`Subject in Need of Treatment for Multiple Sclerosis .................. 61
`vi. A Person of Ordinary Skill in the Art Would Not Have
`Recognized in WO ’342 the Existence of Any Particular
`Dose of Any Particular Agent for the Treatment of MS,
`Much Less Biogen’s Specific MS Treatment Claimed in
`the ’514 Patent ............................................................................. 62
`G. Kappos 2006, Clinical Trials, Joshi ʼ999 and ICH Guidelines Do
`Not Render The ʼ514 Patent Claims Obvious ....................................... 66
`VIII. Unexpected Results ....................................................................................... 71
`IX. BIOGEN’S ’921 PROVISIONAL DESCRIBES AND ENABLES
`ALL TWENTY CLAIMS IN THE ’514 PATENT ....................................... 78
`A. The ’921 Provisional Provides Written Description Support for
`All of the ’514 Patent Claims ................................................................ 79
`B. The ’921 Provisional Enables the ’514 Patent Claims .......................... 86
`BIOGEN’S INTERNATIONAL PATENT APPLICATION NO.
`PCT/US2008/001602 DESCRIBES AND ENABLES ALL TWENTY
`CLAIMS IN THE ’514 PATENT ................................................................. 89
`XI. CONCLUSION .............................................................................................. 92
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`X.
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`3
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
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`I.
`
`INTRODUCTION
`
`1.
`
`I have been engaged by counsel for Biogen MA Inc., Finnegan,
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`Henderson, Farabow, Garrett & Dunner, LLP, as an expert consultant for this inter
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`partes review proceeding. I am being compensated at a rate of $1,000 per hour, plus
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`reimbursement for related out-of-pocket expenditures. My compensation is not
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`contingent upon my opinions or the outcome of this or any other proceeding.
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`2.
`
`I understand that the patent involved in this proceeding is U.S. Patent
`
`No. 8,399,514 (Ex. 1001, “the ’514 patent”).
`
`II.
`
`PROFESSIONAL BACKGROUND AND QUALIFICATIONS
`
`3.
`
`I am the Director of Clinical Research and Director of the Multiple
`
`Sclerosis Center at Consultants in Neurology in Northbrook, Illinois. Consultants
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`in Neurology is a large specialty practice focusing on the evaluation and treatment
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`of multiple sclerosis and other neurological conditions. As Director of Clinical
`
`Research and Director of the Multiple Sclerosis Center, I supervise clinicians and
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`oversee operations in the Multiple Sclerosis Center, train and manage research staff,
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`and maintain an active clinical practice evaluating and treating patients where about
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`85% of my practice involves individuals with multiple sclerosis (MS). My current
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`practice also includes continuous involvement in clinical trials, often as principal
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`investigator, and research concerning the development of new therapeutics.
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`4
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
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`4.
`
`I received my medical doctorate from The Chicago Medical School and
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`completed residencies in internal medicine and neurology at the Mayo Graduate
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`School of Medicine in Rochester, Minnesota, where I also received EEG and sleep
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`disorder/polysomnography fellowships. I have expertise in a wide variety of
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`neurological disorders with particular emphasis on MS. I have over 31 years of
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`experience as a clinician diagnosing, evaluating, and treating patients for their MS.
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`In my clinical practice, I typically see about 1,500 unique MS patients per year.
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`5.
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`I am board certified in neurology, clinical neurophysiology (EEG,
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`EMG and neuromuscular disease), and sleep disorders medicine. I am a fellow in
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`the American Clinical Neurophysiology Society (FACNS) and the American
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`Academy of Sleep Medicine (FAASM). I have affiliations with many hospitals and
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`am a member of numerous professional organizations including Alpha Omega Alpha
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`Honor Medical Society, National Multiple Sclerosis Society, American Academy of
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`Neurology, American Academy of Clinical Neurophysiology, and American
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`Medical Association. I am also a Board Member and serve on the Clinical Advisory
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`Committee of the National Multiple Sclerosis Society, Chicago-Greater Illinois
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`Chapter.
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`6.
`
`I have authored or co-authored over 130 peer-reviewed articles and
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`commentaries in addition to numerous non-reviewed works. I have been published
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`in leading medical journals, including The New England Journal of Medicine,
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`5
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`Declaration of Dr. Daniel Wynn
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`Neurology, Annals of Neurology, The Lancet, The Journal of the American Medical
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`Association, Pediatrics, and Mayo Clinic Proceedings. I have additionally served
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`as ad hoc reviewer for Headache, Journal Neuroscience, NeuroRehabilitation and
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`Neural Repair, and others. I have given hundreds of presentations and talks in my
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`field at lectures, conferences, and seminars in the U.S. and abroad.
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`7.
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`I have also served as principal investigator in over 190 clinical trials
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`primarily in multiple sclerosis, and additionally in Alzheimer’s disease, stroke,
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`chronic pain and migraine, epilepsy, Parkinson’s disease, sleep disorders, attention
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`deficit hyperactivity disorder (ADHD), and others.
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`8. My professional qualifications and experiences are described in further
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`detail in my curriculum vitae, Appendix A.
`
`III. MATERIALS CONSIDERED
`
`9.
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`In forming my opinions herein, I reviewed the documents cited in this
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`declaration, as well as those listed in Appendix B. All of the opinions contained in
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`this declaration are based on the documents I reviewed, the legal principles of which
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`I have been advised, and my experience, knowledge, and professional judgment.
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`IV. OVERVIEW OF MULTIPLE SCLEROSIS
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`A. Background on Multiple Sclerosis
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`10. MS is a chronic, progressive, irreversible disabling disease that is
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`believed to affect over 2.5 million people worldwide. A diagnosis of MS is a life-
`
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`altering and life-long event. There is no cure for MS and its impact on individual
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`patients varies significantly. The disease manifests in a multitude of ways, but
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`almost invariably, it affects a patient’s ability to work and interact with others and
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`can cause a varied range of symptoms including fatigue, loss of balance, spasticity,
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`numbness and tingling in the extremities, weakness, visual impairments, bowel and
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`bladder dysfunction, sexual dysfunction, cognitive dysfunction, tremors, depression,
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`problems with memory and concentration, and anxiety. Ex. 2083 at 4, 6. Overall,
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`MS leads to a shortened life span, particularly more so in men than in women.
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`11. MS is viewed primarily as an inflammatory disease of central nervous
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`system (CNS) myelin, a fatty tissue that surrounds and protects nerve axons in the
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`brain, spinal cord, and optic nerves. Myelin facilitates the conduction of
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`electrochemical signals in the CNS. Myelin also preserves the health of the nerves.
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`Demyelinated nerves die prematurely, which leads to progressive, irreversible
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`disability.
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`12. MS results in the degeneration of myelin. As myelin and the nerve
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`fibers it protects are damaged or destroyed, the ability of the nerves to conduct
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`electrical impulses to and from the brain is disrupted. These injuries can cause scars,
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`or lesions, to form in the CNS, including the brain. Depending on the location of
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`the damage to the CNS, MS can cause disabling “attacks” or “relapses,” which lead
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`to one or more of the symptoms discussed above. The formation of these lesions is
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`what gave the disease its name—“multiple sclerosis”—referring to the multiple scars
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`invariably observed in the CNS of MS patients.
`
`13. What triggers the onset of MS remains unknown. It is believed that
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`both genetic and environmental factors could play a role, but there is no consensus
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`in the field regarding what triggers disease onset. The challenges associated with
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`treating MS are further magnified by the fact that its etiology is unknown, the
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`mechanism by which the disease works is poorly understood, and the biological
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`systems involved, including the CNS and immune system, are extremely
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`complicated and not fully understood.
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`14. MS can be categorized in two ways, relapsing onset MS and
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`progressive onset MS. Patients only have one form of the disease. Each form
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`appears to be caused by distinct biological (or pathological) mechanisms.
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`15. Most people with MS are diagnosed with a relapsing form of the
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`disease, which is defined by recurring attacks on the CNS and which result in a
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`magnified disability during the relapse itself. The most common form of MS is
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`relapsing-remitting MS (“RRMS”). The recurring attacks, often called “relapses,”
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`are followed by recovery periods called “remissions,” during which symptoms
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`improve partially or completely and there are no clinical manifestations of the
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`disease. Even during these remission periods, however, disability progresses. Ex.
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`2084 at 7.
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`16. Relapses result from lesions or scarring in the CNS that disrupt nerve
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`signals. Relapses vary in length, severity, and symptoms. There is currently no way
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`to predict the frequency or duration of relapses. A relapse may cause new symptoms
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`or worsening of old symptoms. After a variable number of acute relapses, patients
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`enter the progressive phase where relapses decrease in frequency, only to be
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`accompanied by a steady, inexorable loss of physical and cognitive function. There
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`is a disconnect between lesions and relapses in that many lesions do not cause overt
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`symptoms, but lead to loss of cognitive function.
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`17. While relapses are often significant clinical events resulting in at least
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`temporary disability of some kind, MS also works on a subclinical level to gradually
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`impair the CNS, resulting in a gradual and accumulating level of disability. Up to
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`40% of relapses do not completely resolve, leaving patients with permanent
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`disability. For instance, MS can cause lesions that do not result in a detectable
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`clinical relapse or attack but that do damage or destroy brain tissue, resulting in a
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`loss of brain tissue known as brain atrophy. This loss of brain tissue is believed to
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`be one of the major contributors to disability in MS patients. Ex. 2085 at 4-5.
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`B. Clinical Measures of Multiple Sclerosis
`
`18. The unpredictable nature and varied symptoms of MS make it
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`challenging for physicians to diagnose and treat. A wide variety of outcome
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`measures have been used in clinical studies and by physicians who treat MS to
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`evaluate the efficacy of drugs. Each of these outcome measures is important for
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`clinicians treating MS because they help the clinician assess whether a particular
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`drug product or dosing regimen is effective in treating MS.
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`19.
`
`In patients with relapsing forms of MS, one of the important clinical
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`outcomes commonly measured in clinical trials is the rate or frequency of relapses.
`
`Other important parameters used to evaluate whether a clinical objective has been
`
`achieved are time to first confirmed relapse and total number of relapses in a given
`
`time period. However, these parameters should not be used exclusively as a
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`surrogate for disease progression because, in many patients, the disease progresses
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`slowly over time even if the patient is not experiencing relapses. Counting relapses
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`is an underestimation of the progression of the disease, because it cannot be assessed
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`by visible symptoms alone. In order to get a complete picture of the efficacy of a
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`drug in clinical trials, additional outcome measures should be examined together
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`with relapses, including MRI-based outcome measures such as brain atrophy and
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`number and volume of lesions, and disability outcome measures such as EDSS,
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`Ambulation Index, and patient reported outcome questionnaires.
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`20. Magnetic resonance imaging, or MRI, is a tool used by clinicians to
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`diagnose MS and measure the efficacy of drugs. As discussed above, MS causes
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`inflammation and lesions in the CNS which affect brain function in discrete areas of
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`the brain. MRI provides a way of seeing the lesions. Through MRI scans, disease
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`progression and the efficacy of MS treatments can be measured.
`
`21. MRI scans are also used to monitor MS. Because not all damaged areas
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`of the CNS result in overt clinical symptoms, MRI scans detect disease activity that
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`is 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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`22. MRI methods include detecting MS lesions using T2 weighted and T1
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`weighted images.1 MS lesions detected with T2 weighted imaging appear as bright
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`spots, “hyperintense lesions,” compared with the surrounding tissue in the white
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`matter of the brain, spinal cord and optical nerves. These lesions have variable
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`underlying pathologic changes, ranging from minimal to severe tissue damage.
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`Once a T2 lesion develops, it generally persists for many years. T1 weighted
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`imaging reveals MS lesions that appear dark, “hypointense,” compared with the
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`normal surrounding tissue. MS lesions detected by T1 weighted images are more
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`severe, reflecting underlying tissue damage. An MRI contrast agent, gadolinium, is
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`used to identify very recent MS lesions. When combined with T1 weighted images,
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`1 “T1-weighted” and “T2-weighted” generally refer to images resulting from MRI
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`scans emphasizing different features in the scanned tissue.
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`after injection of gadolinium, new lesions appear as bright spots compared with
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`surrounding tissue. These gadolinium-enhancing (Gd+) lesions indicate active and
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`recent inflammation. Newly formed lesions can take up the gadolinium contrast
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`agent for a median duration of approximately 10 days after their formation. Gd+
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`lesions disappear after about ten days, because the blood brain barrier, which opens
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`at the time of new lesion formation, closes, excluding the gadolinium contrast agent
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`from the CNS tissue. Many of the contrast enhancing lesions will then appear
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`hyperintense on T2 weighted images and persist for many years.
`
`23. The FDA has approved certain medications that modify the course of
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`MS as evidenced by a reduction in the number of new lesions as seen on MRI,
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`clinical relapses and slow progression of disability. This category of medication is
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`referred to as disease-modifying therapy (DMT). DMT implies that the treatment
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`slows down the overall advance of MS, lessening the overall impact the disease has
`
`on the MS patient over time. Disease modification is the key treatment objective for
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`the MS field, because the impact of MS over time is devastating and irreversible. In
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`general, however, it is difficult to understand how to treat MS over the long-term,
`
`since it is a chronic disease, and the pathology of MS appears to change over time.
`
`Lengthening the amount of time an individual with MS can work, participate in daily
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`activities, maintain social roles, and remain independent is important to every MS
`
`patient, and to society at large, and these long-range benefits are the goals of MS
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`disease-modifying therapy. And the primary goal is to maintain these long-range
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`benefits in patients for the long-term.
`
`24. The FDA has also approved certain medications in a category of
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`treatment called “symptomatic therapy” to help patients manage some symptoms
`
`that occur commonly in MS, such as fatigue, depression, stiffness, or bladder
`
`control. These treatments are very useful for people with MS, because they can
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`lessen symptoms that lower quality of life. Symptomatic therapy is very different
`
`from disease-modifying therapies, because symptomatic therapies do not slow the
`
`underlying pathological process and do not diminish the amount of CNS damage,
`
`axonal loss, demyelination, and brain atrophy. These therapies can be tested in
`
`short-term clinical trials over two or three months, because the onset of the benefit
`
`is comparatively rapid, and the offset is rapid with the treatment benefit often being
`
`obvious for individual patients during the trial. In contrast, testing DMT generally
`
`requires years.
`
`25. As of the 2007 filing date of the ’514 patent, no safe and effective oral
`
`disease-modifying medications were approved for MS. Parenteral MS medications
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`were available, but they required regular intramuscular or subcutaneous injections
`
`or monthly intravenous infusions and had significant limitations. For most patients,
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`these injectable MS medications were associated with injection-related adverse
`
`effects, ranging from injection site necrosis to loss of underlying fatty tissue,
`
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`lipoatrophy, immediate post injection reactions, neutralizing antibodies, injection
`
`anxiety, abnormalities of liver function and others, limiting long-term adherence to
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`treatment, and leading to many patients declining to use disease-modifying therapy
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`entirely.
`
`26. 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
`
`240 mg of DMF, for a total daily dose of 480 mg of DMF. Tecfidera® falls into the
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`disease-modifying category of MS medications. The use of Tecfidera® embodies
`
`the ’514 patent claims. Indeed, claim 1 of the ’514 patent is directed to a method of
`
`treating MS by orally administering a therapeutically effective amount of DMF
`
`and/or MMF, wherein the therapeutically effective amount of DMF and/or MMF is
`
`about 480 mg per day. As an oral medication, Tecfidera® brought significant
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`convenience for patients and greatly enhanced patient acceptance and adherence,
`
`balancing therapeutic efficacy with tolerability and thus improving long-term
`
`benefits compared to injectable MS medications. I am not aware of any FDA-
`
`approved use for Tecfidera® that is not covered by the ’514 patent.
`
`27. The MS community was excited about Tecfidera® entering the market.
`
`MS patients and physicians were generally aware of two large Phase III studies
`
`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 highly effective
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`oral disease-modifying medication for MS.
`
`V. BIOGEN’S ’514 PATENT
`
`28. The ’514 patent is titled “Treatment for Multiple Sclerosis” and
`
`contains twenty claims, all of which are directed to a “method of treating a subject
`
`in need of treatment for multiple sclerosis.” Ex. 1001 at 27:58-30:28. The ’514
`
`patent describes methods of treating MS and repeatedly directs one’s attention to
`
`MS as the neurological disease particularly targeted for treatment. See, e.g., id. at
`
`Abstract, 1:12-52, 3:13-14, 4:29-38, 5:15-24, 5:47-59, 8:35-53, 16:66-17:40, 18:58-
`
`64, 20:63-22:13. For example, the ’514 patent explains that “[p]rovided are certain
`
`compounds for treating neurological diseases, including demyelinating neurological
`
`diseases, such as, e.g., multiple sclerosis.” Id. at 1:12-14. Then, among other
`
`disclosure directed to MS, the ’514 patent’s background focuses specifically on MS,
`
`including its prevalence, disease characteristics, and goals for treatment. Id. at 1:15-
`
`52. The specification also describes an MS animal model, Experimental
`
`Autoimmune Encephalomyelitis (EAE), which “provides a well established
`
`experimental model for testing agents that would be useful for the treatment of MS,”
`
`(id. at 16:66-17:40), and further provides an example of administering DMF and
`
`MMF to mice in the EAE model, (id. at 20:60-22:13).
`
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`29. The ’514 patent also describes screening, evaluating, or comparing new
`
`or existing drug candidates for the treatment of MS based on Nrf2 (nuclear factor
`
`E2-related factor) pathway upregulation. See, e.g., id. at 6:18-29, 6:56-67, 7:42-52.
`
`Apart from screening, evaluating, or comparing new or existing drug candidates, the
`
`’514 patent describes methods of treating MS using a therapeutically effective
`
`amount or dose of DMF or MMF, (see, e.g., id. at 8:34-53, 18:58-64), where the
`
`term “therapeutically effective amount [or dose]” is expressly defined as
`
`that amount of a compound which results in at least one of
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`prevention or delay of onset or amelioration of symptoms
`
`of a neurological disorder in a subject or an attainment of
`
`a desired biological outcome,
`
`such as
`
`reduced
`
`neurodegeneration (e.g., demyelination, axonal loss, and
`
`neuronal death) or reduced inflammation of the cells of the
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`CNS,
`
`(id. at 5:52-59). In particular, the ’514 patent describes effective doses of DMF or
`
`MMF for the treatment of MS as follows:
`
`For example, an effective dose of DMF or MM[F] to be
`
`administered to a subject orally can be from about 0.1 g
`
`to 1 g per [d]ay, 200 mg to about 800 mg per day (e.g.,
`
`from about 240 mg to about 720 mg per day; or from about
`
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`480 mg to about 720 mg per day; or about 720 mg per
`
`day). For example, the 720 mg per day may be
`
`administered in separate administrations of 2, 3, 4, or 6
`
`equal doses.
`
`Id. at 18:58-64 (emphasis added). Thus, the ’514 patent describes that an effective
`
`dose of DMF or MMF to be administered to a subject orally for the treatment of MS
`
`can be “about 480 mg per day.” Id.
`
`30.
`
`I have been informed that the ’514 patent issued from a series of
`
`applications as shown below:
`
`Country
`
`Patent No./
`Application No.
`
`Filing Date
`
`Abbreviation
`
`U.S.
`
`U.S.
`
`Int’l
`
`U.S.
`
`13/372,426
`
`12/526,296
`
`Feb. 13, 2012
`
`’426 Application
`
`Feb. 7, 2008
`
`’296 Application
`
`PCT/US2008/001602
`
`Feb. 7, 2008
`
`60/888,921
`
`Feb. 8, 2007
`
`’602 Application
`(“B2,” Ex. 2102)
`
`’921 Provisional
`(“B1,” Ex. 2101)
`
`31.
`
`I understand that the ’602 Application, ’296 Application, and ’426
`
`Application share a substantially identical specification.
`
`17
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
`
`32. The ’514 patent contains twenty claims. I have been advised that four
`
`of the twenty claims (claims 1, 11, 15, and 20 shown in bold) are independent claims
`
`because they do not refer back to or depend on any other claim:
`
`1.
`
`A method of treating a subject in need of
`
`treatment for multiple sclerosis comprising orally
`
`administering to the subject in need thereof a
`
`pharmaceutical composition consisting essentially of
`
`(a) a therapeutically effective amount of dimethyl
`
`fumarate, monomethyl fumarate, or a combination
`
`thereof, and (b) one or more pharmaceutically
`
`acceptable excipients, wherein the therapeutically
`
`effective amount of dimethyl fumarate, monomethyl
`
`fumarate, or a combination thereof is about 480 mg per
`
`day.
`
`2.
`
`The method of claim 1, wherein the pharmaceutical
`
`composition is administered in the form of a tablet, a
`
`suspension, or a capsule.
`
`3.
`
`The method of claim 1, wherein the therapeutically
`
`effective
`
`amount
`
`is
`
`administered
`
`in
`
`separate
`
`administrations of 2, 3, 4, or 6 equal doses.
`
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
`
`4.
`
`The method of claim 3, wherein the therapeutically
`
`administrations of 2 equal doses.
`
`5.
`
`The method of claim 3, wherein the therapeutically
`
`effective
`
`amount
`
`is
`
`administered
`
`in
`
`separate
`
`administrations of 3 equal doses.
`
`6.
`
`The method of claim 1, wherein the pharmaceutical
`
`composition consists essentially of dimethyl fumarate and
`
`one or more pharmaceutically acceptable excipients.
`
`7.
`
`The method of claim 1, wherein the pharmaceutical
`
`composition consists essentially of monomethyl fumarate
`
`and one or more pharmaceutically acceptable excipients.
`
`8.
`
`The method of claim 1, wherein the pharmaceutical
`
`composition is administered to the subject for at least 12
`
`weeks.
`
`9.
`
`The method of claim 6, wherein the therapeutically
`
`effective amount is administered to the subject in 2 equal
`
`doses.
`
`10. The method of claim 9, wherein the therapeutically
`
`effective amount is administered to the subject for at least
`
`12 weeks.
`
`19
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
`11. A method of treating a subject in need of
`
`treatment for multiple sclerosis consisting essentially
`
`of orally administering to the subject about 480 mg per
`
`day of dimethyl fumarate, monomethyl fumarate, or a
`
`combination thereof.
`
`12. The method of claim 11, wherein about 480 mg of
`
`dimethyl fumarate per day is administered to the subject.
`
`13. The method of claim 12, wherein the dimethyl
`
`fumarate is administered in separate administrations of 2
`
`equal doses.
`
`14. The method of claim 12, wherein the dimethyl
`
`fumarate is administered in separate administrations of 3
`
`equal doses.
`
`15. A method of treating a subject in need of
`
`treatment for multiple sclerosis comprising orally
`
`administering
`
`to
`
`the
`
`subject pharmaceutical
`
`composition
`
`consisting
`
`essentially
`
`of
`
`(a)
`
`a
`
`therapeutically effective amount of dimethyl fumarate
`
`and (b) one or more pharmaceutically acceptable
`
`excipients, wherein
`
`the
`
`therapeutically effective
`
`20
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
`amount of dimethyl fumarate is about 480 mg per day.
`
`16. The method of claim 15, wherein the dimethyl
`
`fumarate is administered in separate administrations of 2
`
`equal doses.
`
`17. The method of claim 1, wherein the expression level
`
`of NQO1 in the subject is elevated after administering to
`
`the subject the therapeutically effective amount of
`
`dimethyl
`
`fumarate, monomethyl
`
`fumarate, or a
`
`combination thereof.
`
`18. The method of claim 11, wherein the expression of
`
`NQO1 in the subject is elevated after administering to the
`
`subject about 480 mg per day of dimethyl fumarate,
`
`monomethyl fumarate, or a combination thereof.
`
`19. The method of claim 15, wherein the expression level
`
`of NQO1 in the subject is elevated after administering to
`
`the subject the therapeutically effective amount of
`
`dimethyl fumarate.
`
`20. A method of treating a subject in need of
`
`treatment for multiple sclerosis comprising treating
`
`the subject in need thereof with a therapeutically
`
`21
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`U.S. Patent No. 8,399,514
`Declaration of Dr. Daniel Wynn
`effective amount of dimethyl fumarate, monomethyl
`
`fumarate, or a combination thereof, wherein the
`
`therapeutically effective amount of dimethyl fumarate,
`
`monomethyl fumarate, or a combination thereof is
`
`about 480 mg per day.
`
`33. Biogen’s claimed invention in the ’514 patent includes a combination
`
`of three specific elements: (i) treating MS, (ii) by administering a therapeutically
`
`effective amount of DMF, MMF, or a combination thereof (or DMF in the case of
`
`claims 15-19), and (iii) wherein the therapeutically effective amount is about
`
`480 mg/day.
`
`34. Tecfidera® embodies the claims of the ’514 patent. Claim 1, as
`
`mentioned for example, describes a method of treating MS by orally administering
`
`a pharmaceutical composition consisting essentially of (a) a therapeutically effective
`
`amount of DMF, MMF, or a combination thereof, and (b) one or more
`
`pharmaceutically acceptable excipients, wherein the therapeutically effective
`
`amount of DMF, MMF, or a combination thereof is about 480 mg/day. Ex. 1001 at
`
`27:59-67. Claims 11, 15, and 20 describe additional methods of treating MS by
`
`administering about 480 mg/day of DMF, MMF, or a combination thereof. Ex. 1001
`
`at 29:19-22, 30:1-7, 30:22-28. Claims 6 and 12