For the Petitioner
`Lead counsel: James T. Carmichael, Reg. No. 45,306
`Backup counsel: Carol A. Spiegel, Reg. No. 68,033
`Carmichael IP, PLLC
`
`
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`COALITION FOR AFFORDABLE DRUGS V LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC – PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND, L.P.;
`HAYMAN CAPITAL MANAGEMENT FUND, L.P.;
`HAYMAN OFFSHORE MANAGEMENT, INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS, and ERICH SPANGENBERG,
`Petitioners,
`v.
`BIOGEN MA INC.,
`Patent Owner.
`____________________
`
`Case IPR2015-01993
`Patent 8,399,514 B2
`____________________
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`DECLARATION OF SAMUEL J. PLEASURE, M.D., Ph.D.
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`Page 1 of 37
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`Coalition Exhibit 1045
`Coalition v. Biogen
`IPR2015-01993
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`Lead counsel: James T. Carmichael, Reg. No. 45,306
`Backup counsel: Carol A. Spiegel, Reg. No. 68,033
`Carmichael IP, PLLC
`
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`COALITION FOR AFFORDABLE DRUGS V LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC – PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND, L.P.;
`HAYMAN CAPITAL MANAGEMENT FUND, L.P.;
`HAYMAN OFFSHORE MANAGEMENT, INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS, and ERICH SPANGENBERG,
`Petitioners,
`v.
`BIOGEN MA INC.,
`Patent Owner.
`____________________
`
`Case IPR2015-01993
`Patent 8,399,514 B2
`____________________
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`DECLARATION OF SAMUEL J. PLEASURE, M.D., Ph.D.
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`Page 1 of 37
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`Coalition Exhibit 1045
`Coalition v. Biogen
`IPR2015-01993
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`I, Samuel J. Pleasure, M.D., Ph.D., declare as follows:
`
`
`
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`Case No. IPR2015-01993
`Patent 8,399,514
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`I.
`
`Introduction
`
`1.
`
`I have been retained by Carmichael IP, PLLC on behalf of the
`
`COALITION FOR AFFORDABLE DRUGS V LLC et al. as an expert consultant
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`for this inter partes review proceeding. I am being compensated at my usual
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`hourly rate, plus reimbursement for related out-of-pocket expenditures. My
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`compensation is not contingent upon my opinions or the outcome of this or any
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`other proceeding.
`
`2.
`
`I make this declaration based on my personal knowledge,
`
`consideration of the materials I discuss herein, and my expert opinions.
`
`3.
`
`I understand that the patent involved in this proceeding is U.S. Patent
`
`No. 8,399,514 (Ex. 1001, “the ‘524 patent”).
`
`II.
`
`Professional Background and Education
`
`4.
`
`I am currently a Professor of Neurology and the Glenn W. Johnson Jr.
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`Memorial Endowed Chair of Neurology at the University of California, San
`
`Francisco School of Medicine, where I have held various positions since 1997.
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`5.
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`I have over 25 years of research experience in the field of
`
`neuroscience. My research interests include the development of the brain,
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`especially processes that regulate the number, migration and organization of
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`neurons and glial cells, including oligodendrocytes, in the brain. My work in
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`understanding the brain is directed at elucidating mechanisms that might enhance
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`Case No. IPR2015-01993
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`regeneration and repair in the injured brain as well as investigating autoimmune
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`forms of encephalitis. I have published over 110 papers and book chapters and
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`have edited a volume of DEVELOPMENTAL NEUROSCIENCE.
`
`6.
`
`I am an active member of the neuroscience community, and have been
`
`invited to present numerous lectures both nationally and abroad. I am a principle
`
`advisor to doctoral students in neuroscience at the University of California in San
`
`Francisco. I teach graduate and medical students, and have served as advisor to
`
`numerous Ph.D. graduates.
`
`7.
`
`I have served on numerous grant review panels, including several NIH
`
`review panels, was the chair of an NIH review panel for one year, and recently
`
`became a standing member of one of the National Multiple Sclerosis Society’s
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`standing grant review panels. Thus, I am quite familiar with current trends in
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`multiple sclerosis research.
`
`8.
`
`I have received research funding from numerous private foundations,
`
`the NIH, the Howard Hughes Medical Institute, and the National Multiple
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`Sclerosis Society.
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`9.
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`As part of my clinical activities, I have been an attending physician at
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`the University of California-San Francisco Multiple Sclerosis Center since 2007.
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`10.
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`I am a member of several professional organizations, including the
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`Society for Neuroscience, the American Academy of Neurology, the American
`
`Association for the Advancement of Science, and the Cajal Club. I have been a
`
`Fellow of the American Neurological Association since 2003.
`
`11.
`
`I am currently on the editorial boards of the following journals:
`
`Developmental Neuroscience, ASN Neuro, Journal of Neuroscience, Faculty of
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`1000 Research, and Brain Plasticity.
`
`12.
`
`I received a B.A. in Biology (1986), an M.D. in medicine (1993), and
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`Ph.D. in Neuroscience (1993), all from the University of Pennsylvania.
`
`13.
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`I was the Chief Resident in Neurology (1996-1997) and a Fellow in
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`Neurology (1997-2000), both at the University of California, San Francisco.
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`14.
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`I am Board Certified in Neurology by the American Board of
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`Psychiatry and Neurology (1999 and 2009).
`
`15. Additional details of my education and professional experience are
`
`provided in my curriculum vitae (Ex. 1046).
`
`III. Documents Considered
`
`16.
`
`In forming my opinions herein, I reviewed the documents listed in
`
`APPENDIX A attached to my declaration. All of the opinions contained in this
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`declaration are based on the documents I reviewed, the legal principles of which I
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`have been advised, and my experience, knowledge and professional judgment.
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`IV. Multiple Sclerosis and the EAE Animal Model
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`Patent 8,399,514
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`17. Multiple sclerosis (MS) is a disease of the human central nervous
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`system (“CNS”) characterized by inflammation, demyelination and gliosis. MS
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`lesions are typically disseminated in time and location. The course of the disease
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`can be relapsing or progressive. The manifestations of the disease vary from
`
`benign illness to a rapidly evolving and incapacitating disease. (Ex. 1047 at 3).
`
`18. MS lesions vary in size from about 1 mm to several centimeters. At
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`sites of inflammation, the blood-brain barrier (“BBB”) is disrupted, but the vessel
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`wall is usually preserved. In more than half of cases, myelin-specific
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`autoantibodies promote demyelination and stimulate macrophages and microglial
`
`cells that scavenge the myelin debris. Ultrastructural studies of MS lesions suggest
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`that fundamentally different pathologies may exist in different patients in terms of
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`(1) whether the inflammatory cell infiltrate is associated with deposition of
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`antibody and activation of complement, and (2) whether the target of the
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`immunopathologic process is the myelin sheath itself or the cell body of the
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`oligodendrocyte (the myelinating cell of the CNS). Although sparing of axons is
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`typical of MS, partial or total axonal destruction can also occur and indirect
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`evidence suggests that axonal loss is a major cause of irreversible neurologic
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`disability in MS. (Id.)
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`19. MS is approximately twice as common in women as in men. The age
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`of onset is typically between 20 and 40 years, although rarely as young as 2 years
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`and as old as 80 years. (Id.)
`
`20. Four clinical types of MS have been described – relapsing/remitting
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`MS (“RRMS”), secondary progressive MS (“SPMS”), primary progressive MS
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`(“PPMS”), and progressive/relapsing MS (“PRMS”). (Id. at 6).
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`21. RRMS accounts for about 85% of MS cases at onset and is
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`characterized by discrete attacks that generally evolve over days to weeks. Often,
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`but not invariably there is complete recovery over the ensuing weeks to months.
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`However, when ambulation is severely impaired during an attack, approximately
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`half will fail to improve. Between attacks, patients are neurologically stable. (Id.)
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`22. SPMS always begins as RRMS. At some point, the patient
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`experiences a steady deterioration in function unassociated with acute attacks.
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`SPMS produces a greater amount of fixed neurological disability than RRMS.
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`About half of patients with RRMS will develop SPMS after fifteen years, and
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`longer follow-ups indicate that the great majority of RRMS ultimately evolves into
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`SPMS. Thus, SPMS appears to be a late-stage of the same underlying illness as
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`RRMS. (Id.)
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`23. PPMS accounts for about 15% of MS cases at onset. These patients
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`do not experience attacks, but rather a steady functional decline from disease onset.
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`The disease generally begins later in life (about 40 years) and the disability
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`develops faster. Compared to RRMS, PPMS is more evenly distributed in men and
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`women. Whether PPMS is an unusual phenotype of the same underlying illness as
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`RRMS or whether these are distinct illness is unknown. (Id.)
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`24. PRMS overlaps PPMS and RRMS and accounts for about 5% of MS
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`patients. Like PPMS patients, these patients experience a steady deterioration in
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`their condition from disease onset. Unlike PPMS patients, these patients
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`occasionally experience acute attacks upon their progressive course. The early
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`stages of RPMS are indistinguishable from PPMS until the first clinical attack.
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`(Id.)
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`25. There is no definitive diagnostic test for MS. Diagnostic criteria for
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`clinically defining MS require documentation of two or more episodes of
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`symptoms and two or more signs that reflect pathology in anatomically
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`noncontiguous white matter tracts of the CNS. Symptoms must last for more than
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`24 hours and occur as distinct episodes that are separated by a month or more. At
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`least one of the two required signs must be present on neurological examination.
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`The second may be documented by certain abnormal tests, e.g., magnetic
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`resonance imaging (“MRI”) or evoked potentials (“Eps”). In patients who
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`experience gradual progression or disability for six months or more without
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`superimposed relapses, documentation of intrathecal IgG and visual EP testing
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`may be used to support the diagnosis. (Id.)
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`26. More than 95% of MS patients show characteristic abnormalities in
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`MRI. An increase in vascular permeability from a breakdown of the BBB is
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`detected by leakage of intravenous gadolinium (“Gd”) into the parenchyma. Such
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`leakage occurs early in the development of an MS lesion and is a useful marker of
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`inflammation. Gd-enhancement persists for up to 3 months. The total volume of
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`T2-weighted signal abnormality on an MRI shows a significant, albeit weak,
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`correlation with clinical disability. About one-third of T2-weighted lesions appear
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`as hypointense lesions (“black holes”) on T1-weighted imaging. Black holes may
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`be a better marker of irreversible demyelination and axonal loss than T2
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`hyperintensities. Newer MRI measures, e.g., brain atrophy, magnetization transfer
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`ratio (“MTR”) imaging and proton magnetic resonance spectroscopic imaging
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`(“MRSI”) may ultimately serve as surrogate markers for clinical disability. (Id. at
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`6-7)
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`27. Therapy for MS can be divided into several categories – (i) treatment
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`of acute attacks as they occur, (ii) treatment with disease-modifying agents that
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`reduce the biological activity of MS (thereby decreasing the attack frequency), and
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`(iii) symptomatic therapy. (Id. at 8)
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`28. Glucocorticoids provide short-term clinical benefit by reducing the
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`severity and shortening the duration of attacks, while physical and occupational
`
`therapy can help with mobility and manual dexterity. Glucocorticoids are
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`administered intravenously. (Id.)
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`29. Five disease-modifying agents have been approved in the U.S. by at
`
`least 2005 – IFN-β1a (Avonex®) (Ex. 1064 at 1), IFN-β1a (Rebif®) (Ex. 1069 at
`
`1), IFN-β1b (Betaseron®) (Ex. 1070 at 1), glatiramer acetate (Copaxone®) (Ex.
`
`1071 at 1), and natalizumab (Tysabri®) (Ex. 1072 at 1; Ex. 1062 at 1) – for
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`treatment of RRMS and SPMS patients who still experience attacks. The efficacy
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`of IFN-β and glatiramer acetate in MS probably results from immunomodulatory
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`properties (Ex. 1047 at 9-11). Thirty micrograms of Avonex® is administered
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`weekly by intramuscular injection (Ex. 1064 at 1). Forty-four micrograms of
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`Rebif® is administered three times a week by subcutaneous injection (Ex. 1069 at
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`1). Two hundred fifty micrograms of Betaseron® is administered every other day
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`by subcutaneous injection (Ex. 1070 at 1). Twenty milligrams of Copaxone® is
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`administered daily by subcutaneous injection (Ex. 1071 at 1). Three hundred
`
`milligrams of Tysabri® is infused intravenously over approximately one hour,
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`every four weeks (Ex. 1072 at 1).
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`30. Symptomatic therapy varies with the symptoms being treated. Such
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`symptoms may include weakness, ataxia/tremor, spasms, pain, bladder
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`dysfunction, urinary tract infections, constipation, depression, fatigue and heat
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`sensitivity. (Id. at 11-12)
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`31. Since MS brain and spinal cord tissue cannot be easily sampled during
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`life, animal models have been used to study the disease and to test the potential of
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`therapeutic agents to control the disease. One of these models is Experimental
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`Autoimmune Encephalomyelitis (“EAE”). EAE is primarily used as an animal
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`model of autoimmune inflammatory diseases of the CNS and can resemble many
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`of the clinical and histological features of MS. It has received the most attention as
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`a disease model of MS and is, therefore, routinely used in testing therapeutic
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`strategies for MS. Indeed, much of our current thinking about MS stems from
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`EAE. (Ex. 1048 at 1-2).
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`32. However, there are fundamental differences in the pathology and
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`immune response between MS and EAE. The artificial induction of a myelin-
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`specific immune response in EAE may by-pass key pathogenic mechanisms
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`operating in MS, since we do not even know the key target auto-antigens in MS. It
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`appears much easier to prevent, reverse or ameliorate EAE in mice than MS in
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`man. Moreover, since EAE almost always has to be induced, it cannot mimic a
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`spontaneous disease. (Ex. 1048 at 1-3 and Table 1; Ex. 1049 at 1-3 and Table 1).
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`33. Numerous therapeutic approaches that showed promising results in
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`EAE have ultimately turned out to be either inefficient or in some cases harmful in
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`human MS. It is unclear why pre-clinical EAE studies predict treatment efficacy
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`so poorly in MS. (Ex. 1048 at 4 and Table 2; Ex. 1049 at 9 and Table 2).
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`Therefore, the potential benefits of EAE as a predictor of therapeutic efficacy in
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`MS is an open question and we will probably always need carefully designed early
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`clinical trials that include imaging outcome measures and mechanistic studies to
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`assess the efficacy of treatment in patients.
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`V. Level of Ordinary Skill in the Art
`
`34.
`
`I have been asked to provide my opinion from two perspectives. First,
`
`from the perspective of a person who has at least a medical degree with at least
`
`three years of training in neurology and at least three years of clinical experience
`
`treating MS. Second, from the perspective of a person who has an advanced
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`degree, e.g., a Ph.D. in one of the life sciences, an M.D., a D.O., or a Pharm.D.,
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`with some experience with clinical trial designs for dose selection. Based on my
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`professional qualifications and experiences described above and in further detail in
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`my curriculum vitae (Ex. 1046), I am a person of ordinary skill in the art (POSA)
`
`under either definition. I myself have not provided any opinion as to the level of
`
`ordinary skill in the art.
`
`VI. Overview of Patent 8,399,514 (the ‘514 patent, Ex. 1001)
`
`35.
`
`In my opinion, the ‘514 patent suggests that the Nrf2 pathway may be
`
`activated in neurodegenerative and neuroinflammatory diseases (Ex. 1001 1:53-
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`2:22). Nrf2 is described as a protein that regulates the expression of various
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`antioxidant and detoxification enzymes, including NQO1, which protects against
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`cellular oxidative damage triggered by injury or inflammation (id.). Increased
`
`expression of NQO1 in brain tissues of Alzheimer and Parkinson patients, spinal
`
`cord of ALS patients, and brain lesions of MS patients suggest activating the Nrf2
`
`pathway as an endogenous protective process in neurodegenerative and
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`neuroinflammatory diseases, e.g., ALS, Parkinson’s, Alzheimer’s, and Huntington
`
`diseases, and demyelinating neurological diseases, e.g., MS (id.). More than 10
`
`different chemical classes of compounds are known to activate the Nrf2 pathway
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`(id. 2:39-57).
`
`36. The ‘514 patent discusses methods of screening, evaluating and
`
`comparing compounds for their ability to upregulate the Nrf2 pathway and posits
`
`using such compounds to treat neurological diseases, such as MS or other
`
`demyelinating neurological disease (id. 2:58-4:55).
`
`37. The ‘514 patent defines terms like “treatment,” “therapeutic method,”
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`and “therapeutic benefits” to refer to therapeutic as well as prophylactic/preventive
`
`measures (id. 5:47-49). Thus, those in need of treatment includes individuals
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`already having a specified disease as well as those at risk for acquiring that disease
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`(id. 5:49-51).
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`38. According to the ‘514 patent, fumaric acid esters, such as dimethyl
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`fumarate (DMF) have been proposed for treatment of MS (id. 5:6-8). DMF is said
`
`to belong to a group of anti-oxidants known for their cryoprotective and anti-
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`inflammatory properties and their ability to activate the Nrf2 pathway (id. 5:16-
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`19). This suggests DMF may be therapeutically effective for treating neurological
`
`disorders, e.g., MS (id. 5:19-24).
`
`39.
`
`In Example 1, human colon carcinoma DLD1 cells were treated with
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`DMF or MMF (monomethyl fumarate) and assayed for expression levels of
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`endogenously produced Nrf1 and NQO1 (id. 19:64-20:11). The results shown in
`
`Figure 1 apparently demonstrated that DMF and MMF activated the Nrf2 pathway
`
`(id. 20:11-13). In Example 2, DLD1 cells were transfected with Nrf2 siRNA or
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`Keap1 siRNA, treated with DMF, and assayed for expression levels of
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`endogenously produced NQO1 (id. 20:16-26). The results shown in Figure 2
`
`apparently demonstrated that DMF acts as an Nrf2 agonist (id. 20:52-58).
`
`40.
`
`In Example 3, EAE is induced in mice, which were then given 5 or 15
`
`mg/kg body weight DMF or 15 mg/kg body weight MMF twice daily by oral
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`gavage (id. 20:63-21:12). Spinal cord tissue was histologically examined with
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`anti-Nrf2 antibody and the results, shown in Figures 3 and 4, apparently
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`demonstrated DMF and MMF activated Nrf2 in vivo (id. 22:12-13).
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`41. The ‘514 patent ends with 20 claims. The four independent claims
`
`
`
`
`
`are:
`
`A method of treating a subject in need of treatment
`1.
`for multiple sclerosis comprising orally administering to
`the subject in need thereof a pharmaceutical composition
`consisting 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.
`
`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.
`
`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 amount of dimethyl fumarate is about 480 mg
`per day.
`
`20. A method of treating a subject in need of treatment
`for multiple sclerosis comprising treating the subject in
`need thereof with a therapeutically 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.
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`VII. Legal Principles
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`42.
`
`I have been educated on the legal principles as follows:
`
`43. A patent claim is entitled to the filing date of an earlier application if
`
`the earlier application adequately describes and enables the claimed invention.
`
`44. The test for whether an application provides an adequate written
`
`description of a claimed invention is whether the application reasonably conveys to
`
`one of ordinary skill in the art that the inventor(s) had possession, i.e., had made,
`
`the invention as of the application’s filing date.
`
`45. The test for whether an application enables a claimed invention is
`
`whether one of ordinary skill in the art would have understood how to make and
`
`use the full scope of the invention without “undue experimentation.” Factors to be
`
`considered in determining whether “undue experimentation” would be required
`
`include the amount of experimentation necessary to make and use the claimed
`
`invention; the amount of direction or guidance in the application, e.g., whether or
`
`not there are any working examples; the nature of the invention; the state of the
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`prior art at the time the application was filed; the relative skill of those in the art;
`
`the predictability or unpredictability of the art; and, the breadth of the claimed
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`invention.
`
`46. Patent claims are interpreted by giving them their broadest reasonable
`
`interpretation in view of the patent specification.
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`47.
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`If claim B is a dependent claim from claim A, then claim B
`
`incorporates by reference all of the elements of claim A.
`
`48. A claim is unpatentable for obviousness if two or more prior art
`
`references in combination disclose, expressly or inherently, every claim element so
`
`as to render the subject matter, as a whole, obvious to a person of ordinary skill in
`
`the art. In determining whether a claim would have been obvious at the time it was
`
`made, the following factors should be considered: (a) the scope and content of the
`
`prior art; (b) the differences between the prior art and the claim(s) at issue; (c) the
`
`level of ordinary skill in the art; and (d) whatever “secondary considerations” may
`
`be present. “Secondary considerations” generally take the form of evidence that
`
`the claimed invention produced unexpected results, satisfied a long-felt by unmet
`
`need, was met with commercial success or was copied by competitors.
`
`VIII. Provisional Application 60/888,921 (the ‘921 provisional, Ex. 1012)
`Neither Describes Nor Enables the Claims of the ‘514 Patent
`A.
`
`No written description of treating an MS patient with a
`therapeutically effective amount of about 480 mg/day DMF
`and/or MMF
`
`49.
`
`It is my understanding that to satisfy the legal criterion for written
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`descriptive support for a claimed invention, the ‘921 provisional must reasonably
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`convey to one of ordinary skill in the art that the inventors had possession, i.e., had
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`made, the claimed invention as of the application’s filing date of February 8, 2007.
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`Page 16 of 37
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`As detailed below, it is my opinion that one of ordinary skill in the art, reading the
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`Case No. IPR2015-01993
`Patent 8,399,514
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`‘921 provisional, would not understand that the inventors of the ‘921 provisional
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`had satisfied the legal criterion for written descriptive support, i.e., had possession
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`of the ‘514 patent’s claimed inventions as of February 8, 2007.
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`1.
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`the ‘921 provisional describes upregulation of endogenous
`NQO1 by DMF and MMF via the Nrf2 pathway in cancer
`cells
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`50. The ‘921 provisional is titled “Nrf2 Screening Assays and Related
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`Methods and Compositions” (Ex. 1012 at 8/49).
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`51. According to the ‘921 provisional, Nrf2 is a protein that regulates the
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`expression of various antioxidant and detoxification enzymes, including NQO1,
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`which protects against cellular oxidative damage triggered by injury or
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`inflammation (id. at 9-10/49, ¶¶[0006]-[0007]). Increased expression of NQO1 in
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`brain tissues of Alzheimer and Parkinson patients, spinal cord of ALS patients, and
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`brain lesions of MS patients suggest activating the Nrf2 pathway as an endogenous
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`protective process in neurodegenerative and neuroinflammatory diseases, e.g.,
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`ALS, Parkinson’s, Alzheimer’s, and Huntington diseases, and demyelinating
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`diseases neurological diseases, e.g., MS (id. ¶[0006]). More than 10 different
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`chemical classes of compounds are known to activate the Nrf2 pathway (id. at 10-
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`11/49, ¶[0008]).
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`Page 17 of 37
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`52. The ‘921 provisional discusses methods of screening, evaluating and
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`comparing compounds for their ability to upregulate the Nrf2 pathway and posits
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`using such compounds to treat neurological diseases, such as MS or other
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`demyelinating neurological disease (id. at 11-15/49, ¶¶[0009]-[0025]).
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`53. The ‘921 provisional defines terms like “treatment,” “therapeutic
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`method,” and “therapeutic benefits” to refer to therapeutic as well as
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`prophylactic/preventative measures (id. at 17/49, ¶0039]). Thus, those in need of
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`treatment includes individuals already having a specified disease as well as those at
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`risk for acquiring that disease (id.).
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`54. According to the ‘921 provisional, fumaric acid esters, such as
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`dimethyl fumarate (DMF) have been proposed for treatment of MS (id. at 15/49,
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`¶[0031]). DMF is said to belong to a group of anti-oxidants known for their
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`cryoprotective and anti-inflammatory properties and their ability to activate the
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`Nrf2 pathway (id. at 16/49, ¶[0033]). This suggests DMF would be expected to be
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`therapeutically effective for treating neurological disorders, e.g., MS (id.).
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`55.
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`In Example 1, human colon carcinoma DLD1 cells were treated with
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`DMF or MMF (monomethyl fumarate) and assayed for expression levels of
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`endogenously produced Nrf1 and NQO1 (id. at 41/49, ¶[0122]). The results shown
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`in Figure 1 apparently demonstrated that DMF and MMF activated the Nrf2
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`pathway (id.). In Example 2, DLD1 cells were transfected with Nrf2 siRNA or
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`Page 18 of 37
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`Keap1 siRNA, treated with DMF, and assayed for expression levels of
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`Case No. IPR2015-01993
`Patent 8,399,514
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`endogenously produced NQO1 (id. at 42/49, ¶[0123]). The results shown in Figure
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`2 apparently demonstrated that DMF acts as an Nrf2 agonist (id. ¶[0124]).
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`56. Thus, in my opinion, the ‘921 provisional describes upregulation of
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`endogenous NQO1 production by DMF and MMF via the Nrf2 pathway in DLD1
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`cancer cells, a hypothetical mechanism of action for treating MS, and plan to
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`obtain the claimed invention. The ‘921 provisional does not satisfy the legal
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`criterion for written descriptive support. There is no description of a
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`therapeutically effective method of treating an MS patient, let alone with about 480
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`mg/day of DMF and/or MMF.
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`2.
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`the ‘921 provisional does not describe a therapeutically
`effective dose of about 480 mg/day to treat MS
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`57. The only mention of a dose of about 480 mg/day in the entire ‘921
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`provisional is in paragraph [0116], which reads:
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`For example, an effective dose of DMF or MMR [sic] to
`be administered to a subject orally can be from about 0.1
`g to 1 g per day, 200 mg to about 800 mg per day (e.g.,
`from about 240 mg to about 720 mg per day; or from
`about 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.
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`In other words, any dosage between about 0.1 to 1 g per day of DMF or MMF
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`could be orally administered to a subject for some treatment. The paragraph does
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`Page 19 of 37
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`not refer to MS or to any other indication. Furthermore, if anything, the paragraph
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`Case No. IPR2015-01993
`Patent 8,399,514
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`singles out administering a dosage of about 720 mg per day, given its repeated
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`reference. Thus, in my opinion, this disclosure is insufficient to satisfy the legal
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`criterion of written descriptive support, i.e., to show possession of administering
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`about 480 mg/day as a therapeutically effective amount of DMF or MMF to treat
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`an MS subject.
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`58.
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`I was also asked if the ‘921 provisional described administering a
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`therapeutically effective dosage of about 480 mg/day DMF and/or MMF in 2, 3, 4,
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`or 6 equal doses. In my opinion, the ‘921 provisional did not. While it might have
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`been obvious to administer a dosage of about 480 mg/day DMF and/or MMF in 2,
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`3, 4, or 6 equal doses, what might be obvious does not satisfy the legal criterion for
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`written descriptive support as I understand it.
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`3.
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`the ‘921 provisional does not enable the ‘514 patent claims
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`59.
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`It is my understanding that an application enables a claimed invention
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`if a person of ordinary skill in the art, reading the application, would have
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`understood how to make and use the claimed invention without undue
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`experimentation. Factors to be considered in deciding whether “undue
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`experimentation” would be required include the amount of experimentation
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`necessary to make and use the claimed invention; the amount of direction or
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`guidance in given in the application, e.g., whether or not there are any working
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`Page 20 of 37
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`examples; the nature of the invention; the state of the prior art at the time the
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`Patent 8,399,514
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`application was filed; the relative skill of those in the art; the predictability or
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`unpredictability of the art; and, the breadth of the claimed invention.
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`60.
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` In my opinion, the ‘921 provisional does not enable one of ordinary
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`skill in the art to make and use the full scope of the ‘514 patent claims as I
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`understand the legal criteria for enablement. The ‘514 patent claims encompass
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`both therapeutic and prophylactic/preventive methods of treating MS. MS is a
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`complex autoimmune disease with no definitive diagnostic test. The key target
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`autoantigens of MS are unknown. Fundamentally different pathologies may exist
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`in different patients. The two working examples in the ‘921 provisional are limited
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`to an in vitro showing of DMF and MMF activating the Nrf2 pathway in human
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`cancer cells DLD1. There is no example of testing in any MS animal model
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`system, let alone in an MS patient. Even if an animal model, such as a mouse EAE
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`model, were treated with DMF and/or MMF, there are fundamental differences in
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`the pathology and immune response between MS and EAE. Numerous therapeutic
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`approaches that showed promising results in EAE have ultimately turned out to be
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`either inefficient or in some cases harmful in human MS. It is unclear why pre-
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`clinical EAE studies predict treatment efficacy imperfectly in MS, but the potential
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`benefits of EAE as a predictor of therapeutic efficacy in MS is an open question
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`and we will probably always need carefully designed early clinical trials that
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`Page 21 of 37
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`include imaging outcome measures and mechanistic studies to assess the efficacy
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`Patent 8,399,514
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`of treatment in patients.
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`61. Thus, in my opinion, the ‘921 provisional does not enable one of
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`ordinary skill in the art to make and use the invention of ‘514 patent claims 1-20,
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`i.e., it would require “undue experimentation” to make and use the claimed
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`invention as I understand the legal criteria for “undue experimentation.”
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`IX.
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`‘514 Patent Claims 1-20 are Obvious over the Prior Art
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`A. Overview of the prior art applied in Ground 1
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`62. Kappos 2006 discloses the results of a double-blind, phase 2 clinical
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`trial in which patients with RMMS were randomized into four treatment groups –
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`placebo, 120 mg BG00012 QD (120 mg/day), 120 mg BG00012 TID (360
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`mg/day), and 240 mg BG00012 TID (720 mg/day). The primary endpoint was the
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`total number of new Gd+ lesions over four MRI scans at weeks 12, 16, 20 and 24.
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`The 720 mg/day dosage of BG00012 (240 mg TID) significantly reduced the mean
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`number of new Gd+ lesions (the primary endpoint) compared with placebo. In
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`other words, neither 120 mg QD nor TID significantly reduced the mean number
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`of new Gd+ lesions compared to placebo (Ex. 1003A
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