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