`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`COALITION FOR AFFORDABLE DRUGS V LLC;
`HAYMAN CREDES MASTER FUND, L.P.;
`HAYMAN ORANGE FUND SPC – PORTFOLIO A;
`HAYMAN CAPITAL MASTER FUND, L.P.;
`HAYMAN CAPITAL MANAGEMENT, L.P.;
`HAYMAN OFFSHORE MANAGEMENT, INC.;
`HAYMAN INVESTMENTS, LLC;
`NXN PARTNERS, LLC;
`IP NAVIGATION GROUP, LLC;
`J KYLE BASS; and ERICH SPANGENBERG,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`
`____________________________________________
`
`Case: IPR2016-01993
`U.S. Patent No. 8,399,514
`____________________________________________
`
`DECLARATION OF DANIEL WYNN, M.D. FACNS FAASM
`
`
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`Page 1 of 56
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`Biogen Exhibit 2046
`Coalition v. Biogen
`IPR2015-01993
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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`PERSONAL BACKGROUND AND QUALIFICATIONS ........................... 3
`
`III. DOCUMENTS CONSIDERED ...................................................................... 5
`
`IV.
`
`ISSUES ADDRESSED ................................................................................... 6
`
`V.
`
`LEGAL PRINCIPLES ..................................................................................... 7
`
`VI. BIOGEN’S ’514 PATENT .............................................................................. 8
`
`VII. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 14
`
`VIII. OPINIONS REGARDING DR. LINBERG’S PROPOSED LEVEL
`OF ORDINARY SKILL IN THE ART ......................................................... 15
`
`IX. BIOGEN’S ’921 PROVISIONAL DESCRIBES AND ENABLES
`ALL TWENTY CLAIMS IN THE ’514 PATENT ....................................... 17
`
`A.
`
`The ’921 Provisional Provides Written Description Support for
`All of the ’514 Patent Claims .............................................................. 18
`
`B.
`
`The ’921 Provisional Enables the ’514 Patent Claims ........................ 26
`
`X.
`
`BIOGEN’S INTERNATIONAL PATENT APPLICATION NO.
`PCT/US2008/001602 DESCRIBES AND ENABLES ALL TWENTY
`CLAIMS IN THE ’514 PATENT ................................................................. 29
`
`XI. CONCLUSION .............................................................................................. 32
`
`
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`i
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`I, Daniel Wynn, provide the following testimony:
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`Case No. IPR2015-01993
`Patent 8,399,514
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`I.
`
`INTRODUCTION
`1.
`
`I have been engaged by counsel for Biogen MA Inc., Finnegan,
`
`Henderson, Farabow, Garrett & Dunner, LLP, as an expert consultant for this inter
`
`partes review proceeding. I am being compensated at a rate of $1,000 per hour,
`
`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 understand that the patent involved in this proceeding is U.S. Patent
`
`No. 8,399,514 (Ex. 1001, “the ’514 patent”), which is assigned on its face to
`
`Biogen Idec MA Inc., but is now assigned to Biogen MA Inc. (“Biogen”).
`
`3.
`
`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. 1011)
`
`’921 Provisional
` (“B1,” Ex. 1012)
`
`1
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`I understand that the ’602 Application, ’296 Application, and ’426
`
`4.
`
`Application share a substantially identical written description.
`
`5.
`
`Claim 1 of the ’514 patent states:
`
`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.
`
`Claims 11, 15, and 20 describe additional methods of treating MS by administering
`
`about 480 mg per day of dimethyl fumarate (DMF), monomethyl fumarate (MMF),
`
`or a combination thereof. Claims 6 and 12 focus on administering DMF, while
`
`claim 7 provides for administering MMF.
`
` Claim 2 specifies
`
`that
`
`the
`
`pharmaceutical composition is administered in the form of a tablet, suspension, or
`
`capsule. Dependent claims 3-5, 9, 13, 14, and 16 further specify the frequency of
`
`2
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`dosing, e.g., twice or three times a day. Claims 8 and 10 provide that the
`
`therapeutically effective dose is administered to the subject for at least 12 weeks.
`
`Claims 17-19 depend from claims 1, 11, and 15, respectively, and specify that the
`
`expression level of NQO1 is elevated after administering DMF, MMF, or a
`
`combination thereof.
`
`II.
`
`PERSONAL BACKGROUND AND QUALIFICATIONS
`6.
`
`I am the Director of Clinical Research and Director of the Multiple
`
`Sclerosis Center at Consultants in Neurology in Northbrook, Illinois. Consultants
`
`in Neurology is a large specialty practice focusing on the evaluation and treatment
`
`of multiple sclerosis and other neurological conditions. As Director of Clinical
`
`Research and Director of the Multiple Sclerosis Center, I supervise clinicians and
`
`oversee operations in the Multiple Sclerosis Center, train and manage research
`
`staff, and maintain an active clinical practice evaluating and treating patients where
`
`about 85% of my practice involves individuals with multiple sclerosis (MS). My
`
`current practice also includes continuous involvement in clinical trials, often as
`
`principal
`
`investigator, and research concerning
`
`the development of new
`
`therapeutics.
`
`7.
`
`I received my medical doctorate from The Chicago Medical School
`
`and completed residencies in internal medicine and neurology at the Mayo
`
`3
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`Graduate School of Medicine in Rochester, Minnesota, where I also received EEG
`
`and sleep disorder/polysomnography fellowships. I have expertise in a wide
`
`variety of neurological disorders with particular emphasis on MS. I have over 28
`
`years of experience as a clinician diagnosing, evaluating, and treating patients for
`
`their MS. In my clinical practice, I typically see about 1,500 to 2,000 unique MS
`
`patients per year.
`
`8.
`
`I am board certified in neurology, clinical neurophysiology (EEG,
`
`EMG and neuromuscular disease), and sleep disorders medicine. I am a fellow in
`
`the American Clinical Neurophysiology Society (FACNS) and the American
`
`Academy of Sleep Medicine (FAASM). I have affiliations with many hospitals
`
`and am a member of numerous professional organizations including Alpha Omega
`
`Alpha Honor Medical Society, National Multiple Sclerosis Society, American
`
`Academy of Neurology, American Academy of Clinical Neurophysiology, and
`
`American Medical Association. In particular, I am a Board Member and serve on
`
`the Clinical Advisory Committee of the National Multiple Sclerosis Society,
`
`Chicago-Greater Illinois Chapter.
`
`9.
`
`I have authored or co-authored many peer-reviewed articles and
`
`commentaries in addition to numerous non-reviewed works. I have been published
`
`in leading medical journals, including The New England Journal of Medicine,
`
`4
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`Neurology, Annals of Neurology, The Lancet, The Journal of the American
`
`Medical Association, Pediatrics, and Mayo Clinic Proceedings.
`
` I have
`
`additionally served as ad hoc reviewer for Headache, Journal Neuroscience,
`
`NeuroRehabilitation and Neural Repair and others. I have given hundreds of
`
`presentations and talks in my field at lectures, conferences and seminars in the U.S.
`
`and abroad.
`
`10.
`
`I have also served as principal investigator in over 160 clinical trials
`
`primarily in multiple sclerosis, and additionally in Alzheimer's disease, stroke,
`
`chronic pain and migraine, epilepsy, Parkinson's disease, sleep disorders, attention
`
`deficit hyperactivity disorder (ADHD), and others.
`
`11. My professional qualifications and experiences are described in
`
`further detail in my curriculum vitae, Exhibit 2047.
`
`III. DOCUMENTS CONSIDERED
`12.
`In forming my opinions herein, I reviewed: (1) Biogen’s ’514 patent
`
`(Ex. 1001); (2) Biogen’s ’921 Provisional (Ex. 1012); (3) Biogen’s International
`
`Patent Application No. PCT/US2008/001602 (Ex. 1011); (4) the Declaration of
`
`Steven E. Linberg, Ph.D. (Ex. 1005); (5) the Petition (Paper 1); (6) Biogen’s
`
`Preliminary Response (Paper 11); (7) Petitioner’s Reply to Biogen’s Preliminary
`
`Response (Paper 17); and (8) the Institution Decision (Paper 20). All of the
`
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`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.
`
`IV.
`
`ISSUES ADDRESSED
`13.
`
`I have been asked to provide my opinions on Petitioner’s and Dr.
`
`Linberg’s definition of the hypothetical person of ordinary skill in the art. As
`
`detailed below, I disagree with Petitioner’s and Dr. Linberg’s definition.
`
`14.
`
`I have been asked to provide my opinions on whether Biogen’s ’921
`
`Provisional (Ex. 1012) and International Application No. PCT/US2008/001602
`
`(Ex. 1011, “the ’602 Application”) describe and enable the methods of treating
`
`multiple sclerosis contained in claims 1 through 20 in the ’514 patent. As detailed
`
`below, in my opinion, the ’921 Provisional and the ’602 Application each provide
`
`written description support for all of the claims in the ’514 patent and also enable
`
`all of the ’514 patent’s claims.
`
`15.
`
`I understand that the Board has requested that Biogen address whether
`
`Biogen’s ’921 Provisional provides written description support for the limitation
`
`“about 480 mg per day” found in the claims. For the same reasons the ’921
`
`Provisional provides written description support for all of the claims in the ’514
`
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`patent, the ’921 Provisional also provides written description support for the
`
`“about 480 mg per day” element as stated in the claims.
`
`V. LEGAL PRINCIPLES
`16.
`I have been educated on the legal principles set forth below.
`
`Written Description
`
` To provide written description support for a claimed invention, an
`
`application must reasonably convey to one of ordinary skill in the art
`
`that the inventor(s) had possession of the invention as of the
`
`application’s filing date.
`
` Likewise, to provide written description support for an element of a
`
`claim, an application must reasonably convey to one of ordinary skill
`
`in the art that the inventor(s) had possession of that element within the
`
`context of the claim as of the application’s filing date.
`
`Enablement
`
` A patent 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.
`
`Claim Construction
`
`7
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` Patent claims are interpreted by giving them their broadest reasonable
`
`interpretation in view of the patent specification.
`
`Dependent Claims
`
` If Claim B is a dependent claim from Claim A, Claim B incorporates
`
`by reference all of the elements of Claim A.
`
`VI. BIOGEN’S ’514 PATENT
`17. 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 col. 27: l. 58 – col. 30: l.
`
`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, col. 1: ll. 12-52, col. 3: ll. 13-14, col. 4: ll. 29-38, col. 5: ll. 15-
`
`24 and 47-59, col. 8: ll. 35-53, col. 16: l. 66 – col. 17: l. 40, col. 18: ll. 58-64, col.
`
`20: l. 63 – col. 22, l. 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 col. 1: ll. 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 col. 1: ll. 15-52. The specification also describes an
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`animal model of MS—known as 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 col. 16: l. 66 – col. 17: l. 40),
`
`and further provides an example of administering dimethyl fumarate (“DMF”) and
`
`monomethyl fumarate (“MMF”) to mice in the EAE model, (id. at col. 20: l. 60 –
`
`col. 22: l. 13).
`
`18. 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 col. 6: ll. 18-29, 56-
`
`67; col. 7: ll. 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 col. 8:
`
`ll. 34-53, col. 18: ll. 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 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
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`loss, and neuronal death) or reduced inflammation of the
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`cells of the CNS,
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`(id. at col. 5: ll. 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 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 col. 18: ll. 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. Biogen’s disclosure in the
`
`’921 Provisional is very similar, and in many ways identical, to the disclosure of
`
`the ’514 patent. In paragraphs 28-45 below and in Appendix A, I provide a
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`detailed analysis of the written description support in Biogen’s ’921 Provisional for
`
`claims 1 through 20 of the ’514 patent.
`
`19. 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.
`4. The method of claim 3, wherein the therapeutically
`effective amount is administered in separate
`
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`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.
`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
`
`12
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`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
`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 level
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`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
`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.
`20. 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 per day.
`
`VII. LEVEL OF ORDINARY SKILL IN THE ART
`21.
`I have been informed that the hypothetical person of ordinary skill in
`
`the art is defined as a person who has at least a medical degree with at least three
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`years of training in neurology and at least three years of clinical experience treating
`
`MS. With respect to the relevant art of treatment for MS as encompassed by the
`
`claims, and based on my education, background and work experience, I agree with
`
`the definition set forth above.
`
`22.
`
`In addition, with respect to the relevant art of treatment for MS as
`
`encompassed by the claims and specification of the ’514 patent, and the
`
`applications leading to the ’514 patent, including the ’921 Provisional, and again
`
`based on my education, background and work experience, it is my opinion that the
`
`definition provided above for the hypothetical person of ordinary skill—i.e., a
`
`person who has at least a medical degree, at least three years of training in
`
`neurology, and at least three years of clinical experience treating MS—also applies
`
`to the hypothetical person of ordinary skill in the art at the time of the ’921
`
`Provisional’s filing (February 8, 2007). All of the statements and opinions herein
`
`should be read as the observation or opinion of the person of ordinary skill in the
`
`art at the relevant time.
`
`VIII. OPINIONS REGARDING DR. LINBERG’S PROPOSED LEVEL OF
`ORDINARY SKILL IN THE ART
`23.
`
` I was provided with and reviewed the Declaration of Dr. Steven E.
`
`Linberg dated September 27, 2015 (“Linberg Declaration,” Ex. 1005). In
`
`paragraph 9 of the Linberg Declaration, Dr. Linberg states that in his opinion, the
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`hypothetical person of ordinary skill in the art would “most likely have held an
`
`advanced degree, such as a Ph.D. in one of the life sciences, an M.D., a D.O., or a
`
`Pharm.D.” and “some experience with clinical trial designs for dose selection.”
`
`Ex. 1005 at ¶ 9.
`
`24.
`
`I do not agree with Dr. Linberg’s proposed definition of the
`
`hypothetical person of ordinary skill in the art. First, Dr. Linberg’s proposed
`
`person of ordinary skill does not require a physician with any experience treating
`
`patients or even a person with a medical degree, much less a clinician with a
`
`medical degree and experience treating MS patients. For example, Dr. Linberg’s
`
`person of ordinary skill might include only a researcher.
`
`25.
`
`In my opinion, Dr. Linberg’s definition is incompatible with the “art”
`
`relevant to the ’514 patent claims as interpreted in view of the specification. The
`
`’514 patent claims are directed to “treating a subject in need of treatment for
`
`multiple sclerosis,” and thus the relevant “art” in this context is the treatment of
`
`MS. In my opinion, as explained above in paragraphs 21-22, the hypothetical
`
`person of ordinary skill in this art would have at least a medical degree with at
`
`least three years of training in neurology and at least three years of clinical
`
`experience treating MS. I do not agree with Dr. Linberg’s definition, which does
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`not require a medical doctor at all, much less a physician trained in neurology with
`
`experience treating MS patients.
`
`26. Second, even in instances where Dr. Linberg’s person of ordinary skill
`
`is a medical doctor, his definition for the medical doctor does not require any
`
`training in neurology or any experience treating MS patients in particular. Ex.
`
`1005 at ¶ 9. Rather, Dr. Linberg’s defined medical doctor would have experience
`
`treating patients suffering from any disease, without requiring any particular depth
`
`of experience treating MS patients. Id. For example, many doctors have no
`
`experience treating—and are not qualified to treat—patients for MS. Again, in my
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`opinion, Dr. Linberg failed to properly consider the “art” relevant to the ’514
`
`patent claims, which is specific to treating MS.
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`IX. BIOGEN’S ’921 PROVISIONAL DESCRIBES AND ENABLES ALL
`TWENTY CLAIMS IN THE ’514 PATENT
`27.
`
`I understand that Biogen’s ’514 patent claims the benefit of priority to
`
`the ’921 Provisional, which was filed on February 8, 2007. I have been asked to
`
`provide my opinions on whether the ’921 Provisional describes and enables the
`
`methods of treating multiple sclerosis provided in claims 1 through 20 in the ’514
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`patent. As detailed below, in my opinion, the ’921 Provisional describes and
`
`enables all of the ’514 patent claims.
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`17
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`Page 19 of 56
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`A. The ’921 Provisional Provides Written Description Support for
`All of the ’514 Patent Claims
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`28.
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` It is my understanding that to provide written description support for
`
`a claimed invention, the ’921 Provisional must reasonably convey to one of
`
`ordinary skill in the art that the inventors had possession of the claimed invention
`
`as of the application’s filing date (February 8, 2007). As detailed below, it is my
`
`opinion that one of ordinary skill in the art, reading the ’921 Provisional, would
`
`understand that the inventors of the ’921 Provisional had possession of the ’514
`
`patent’s claimed inventions as of February 8, 2007 (the date the ’921 Provisional
`
`was filed). For example, a person of ordinary skill in the art, reading the ’921
`
`Provisional, would understand that the inventors of the ’921 Provisional had
`
`possession of “[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,” as recited in claim 1 of the ’514
`
`patent, as of February 8, 2007.
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`18
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`29. The ’921 Provisional describes methods of treating MS, as claimed in
`
`the ’514 patent, and repeatedly directs one of ordinary skill in the art to MS as the
`
`neurological disease particularly targeted for treatment by the disclosure. See, e.g.,
`
`Ex. 1012 at ¶¶ [0001]-[0004], [0011], [0020], [0021], [0040], [0104], [0108]-
`
`[0110], [0116] and Abstract (¶ [0126]). For example, the first paragraph of the
`
`’921 Provisional states that the invention relates to treating multiple sclerosis. Id.
`
`at ¶ [0001].
`
`30. Multiple sclerosis is also the only disease identified in the second and
`
`third paragraphs of the ’921 Provisional. Id. at ¶¶ [0002]-[0003]. The second
`
`paragraph states that multiple sclerosis is characterized by inflammation in parts of
`
`the central nervous system (CNS) and leads to the loss of the myelin sheath
`
`(protects the nerve fibers), loss of axons (the nerve fibers), and the eventual death
`
`of neurons (nerve cells), oligoden[d]rocytes, and glial cells. Id. at ¶ [0002]. The
`
`third paragraph reports that millions of people around the world suffer from
`
`multiple sclerosis and that multiple sclerosis is a progressing, disabling disease. Id.
`
`at ¶ [0003].
`
`31. The fourth paragraph of the ’921 Provisional also relates solely to
`
`multiple sclerosis. Id. at ¶ [0004]. It states that various immunotherapeutic drugs
`
`may provide relief in patients with multiple sclerosis but that none were capable of
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`reversing disease progression and that some could cause serious adverse effects.
`
`Id.
`
`32. The ’921 Provisional describes methods for screening, evaluating, and
`
`comparing the neuroprotective properties of compounds based on Nrf2 pathway
`
`upregulation, referring to these methods as methods 1-3, respectively, of the
`
`invention. Id. at ¶¶ [0010], [0041]-[0062].
`
`33. Apart from methods 1-3, the ’921 Provisional describes methods of
`
`treating a neurological disease, referring to these methods as “method 4” of the
`
`invention. See, e.g., id. at ¶¶ [0010], [0011], [0020], [0021], [0063], [0065]-
`
`[0067].
`
` The ’921 Provisional identifies certain neurological diseases as
`
`“preferable” for treatment, and further focuses the description by explaining that
`
`“[m]ore preferably, the neurological disease is MS or another demyelinating
`
`neurological disease.” Id. at ¶ [0011].
`
`34. The ’921 Provisional describes administering a therapeutically
`
`effective amount of DMF or MMF for treating MS, as claimed in the ’514 patent.
`
`The ’921 Provisional discloses that method 4 of the invention is a method of
`
`treating a mammal who has or is at risk for a neurological disease comprising
`
`administering
`
`to
`
`the mammal a “therapeutically effective amount of a
`
`neuroprotective compound,” where “therapeutically effective amount” is explicitly
`
`20
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`defined in paragraph [0040]. Id. at ¶¶ [0066], [0040]. Although other
`
`neuroprotective compounds can be administered, only DMF and MMF are
`
`specifically identified as examples. Id. at ¶ [0066]. The ’921 Provisional explains
`
`that important goals for treating MS include promoting CNS remyelination as a
`
`repair mechanism and otherwise preventing axonal loss and neuronal death. Id. at
`
`¶ [0004]. It further discloses that the invention is based, in part, on the discovery
`
`that DMF and MMF are potent activators of the Nrf2 pathway, and further based,
`
`at least in part, on the finding that DMF and MMF protect the myelin sheath,
`
`axons, and neurons in a mouse model of autoimmune neurodegenerative disease.
`
`Id. at ¶ [0029]. The ’921 Provisional explains that a compound may be assayed in
`
`a mouse model of MS known as Experimental Autoimmune Encephalomyelitis
`
`(EAE), which “provides a well established experimental model for testing agents
`
`that would be useful for the treatment of MS” because of its “many similarities to
`
`human MS in its clinical manifestations.” Id. at ¶ [0108].
`
`35. The ’921 Provisional further describes administering a therapeutically
`
`effective dose of DMF or MMF of “about 480 mg” per day for treating MS, as
`
`claimed in the ’514 patent. Specifically, paragraph [0116] of the ’921 Provisional
`
`provides the following description concerning therapeutically effective doses of
`
`DMF or MMF for treating MS:
`
`21
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`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 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 ¶ [0116] (emphasis added). The above-quoted language from paragraph
`
`[0116] is very clear on what it describes: “an effective dose of DMF or MMF,”
`
`where the term “therapeutically effective dose” is explicitly defined in paragraph
`
`[0040]. Id. at ¶¶ [0116], [0040].
`
`36. One of ordinary skill in the art—who is an MS clinician defined in
`
`paragraph 21 above—would understand from paragraph [0116] that DMF and/or
`
`MMF would be administered as a particular effective daily dose and not as a dose
`
`range. In other words, a subject would take an effective dose of DMF or MMF on
`
`a daily basis, not a range of oral doses on a daily basis. Within this context,
`
`paragraph [0116] explains that “an effective dose of DMF or MM[F] to be
`
`administered to a subject orally can be . . . from about 480 mg to about 720 mg per
`
`day.” Thus, the ’921 Provisional clearly describes that an effective dose of DMF
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`22
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`or MMF to be administered to a subject orally for the treatment of MS can be
`
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