For the Patent Owner
`Backup counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Neifeld IP Law, PC
`
`
`
`Paper No. __
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`Coalition For Affordable Drugs V LLC
`Petitioner
`v.
`
`Biogen MA Inc.
`Patent Owner
`____________
`
`Case IPR2015-01136
`Patent 8,399,514
`Title: TREATMENT FOR MULTIPLE SCLEROSIS
`____________
`
`
`DECLARATION OF STEVEN E. LINBERG Ph. D.
`
`
`
`
`Mail Stop PATENT BOARD
`U.S. Patent Trial & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-14
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`Page 1 of 50
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`
`Backup counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Neifeld IP Law, PC
`
`
`
`Paper No. __
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`Coalition For Affordable Drugs V LLC
`Petitioner
`v.
`
`Biogen MA Inc.
`Patent Owner
`____________
`
`Case IPR2015-01136
`Patent 8,399,514
`Title: TREATMENT FOR MULTIPLE SCLEROSIS
`____________
`
`
`DECLARATION OF STEVEN E. LINBERG Ph. D.
`
`
`
`
`Mail Stop PATENT BOARD
`U.S. Patent Trial & Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-14
`
`Page 1 of 50
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`
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`DECLARATION OF STEVEN E. LINBERG PH.D.
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`I, Steven E. Linberg Ph.D., hereby declare, affirm and state the following:
`
`I.
`
`
`
`Introduction
`1. I have been retained by Neifeld IP Law, PC for this inter partes review
`
`proceeding. I understand that this Declaration is being submitted along with a
`
`Petition for inter partes review of US Patent No. 8,399,514 (“the ‘514 patent”). I
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`opine only with respect to certain issues that are discussed in this declaration.
`
`II. RESOURCES CONSULTED
`2. I have reviewed the ‘514 patent (Exhibit 1001A) including claims 1-20. I
`
`
`
`have also reviewed the Kappos 2005 reference (Exhibit 1003A), the ICH
`
`Guideline E4 (Exhibit 1004A), the Werdenberg reference (Exhibit 1016A), the
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`ClinicalTrials NCT00168701 reference (Exhibit 1022A), the Talalay reference
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`(Exhibit 1026A), and the Begleiter reference (Exhibit 1027A). I have reviewed
`
`other documentation supporting and relevant to this declaration as cited below.
`
`III. BACKGROUND, QUALFICATIONS AND COMPENSATION
`3. I received a Ph.D. in Physiology from Pennsylvania State University in
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`
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`1978. I worked for over 35 years in academic clinical research and commercial
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`drug and biologics development, with particular attention to the overall strategy of
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`drug development programs, to individual clinical trial design, execution, and
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`reporting, and to regulatory interactions with the FDA. Over the course of that time
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`I participated in the design, conduct, reporting or oversight of more than 100
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`clinical trials. I have held senior positions in companies which were developing
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`drugs, developing biologics, and at contract research organizations. I am the
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`principal editor of, and a contributing author in the text Expediting Drug and
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`Biologics Development, now in its 3rd edition. I developed and taught graduate-
`
`level courses in Drug and Biologics Development, Clinical Trial Design, and
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`Clinical Trial Operations for the Johns Hopkins University; and An Overview of
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`Clinical Research, for the University of Maryland.
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`
`
`4. From 1978 to 1984, I was a Clinical Physiology Research Associate for
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`the Shock Trauma – Maryland Institute for Emergency Medical Services Systems
`
`at the University of Maryland. From 1980 to 1984 I was an Assistant Professor of
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`Pathology, Graduate Faculty at the University of Maryland School of Medicine.
`
`From 1985 to 1986 I was a Project Leader and Clinical Research Scientist in the
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`Medical Division of Burroughs Wellcome Co. and from 1986 to 1992 I was an
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`Associate Director of Clinical Research at Boehringer Mannheim Pharmaceuticals.
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`In 1992 I was the Director of Clinical Research at Univax Biologics, Inc.. From
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`1992 to 1995 I was a consultant at, and owner of, Linberg Research, Inc.. From
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`1995 to 1996 I was the Vice President of Clinical Development at Collaborative
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`Clinical Research, Inc.. From 1996 to 2001 I was the Vice President of Clinical
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`Development at Cato Research Limited, and from 2001 to 2002 I was promoted to
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`Managing Director and Senior Vice President of Drug Development at the same
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`company. From 2002 to 2009 I was the Managing Director of Chiesi
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`Pharmaceuticals, Inc. and from 2009 to 2010 I was also Vice President and
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`Treasurer at the same company. From 2011 to 2012 I was the founding President
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`and CEO of Airway Therapeutics, LLC and continue as a Member of Airway
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`Therapeutics, LLC. From 2013 to present I have been a consultant to the
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`pharmaceutical industry, and formed S.E. Linberg Consulting, LLC in 2015 to
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`further that effort.
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`
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`5. I have published numerous academic papers and have served in various
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`advisory, board and leadership positions for research centers, universities and a
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`charitable foundation. My CV is submitted in this proceeding as Exhibit 1017A.
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`
`
`6. I am being compensated for my time at my standard hourly rate for this
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`proceeding. My compensation is in no way contingent upon my performance or the
`
`outcome of this case.
`
`IV.
`LEVEL OF ORDINARY SKILL IN THE ART
`7. I have been informed by counsel to regard a person of ordinary skill in the
`
`
`
`art as being a hypothetical person who is presumed to know all of the relevant art
`
`at the time of the invention. Factors that may be considered in determining the
`
`level of ordinary skill in the art may include: (1) type of problems encountered in
`
`the art; (2) prior art solutions to those problems; (3) rapidity with which
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`innovations are made; (4) sophistication of the technology; and (5) educational
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`level of active workers in the field. I have been informed by counsel that it is from
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`the viewpoint of a person of ordinary skill in the art that legal issues, such as claim
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`construction and obviousness, are determined.
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`
`
`8. In my opinion and based on my reading of the ‘514 patent, the field of the
`
`‘514 patent is: treating a disease with an orally administered drug.
`
`
`
`9. A person of ordinary skill in the art at the time of the alleged invention
`
`of the ‘514 patent (“POSITA”) 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.
`
`Additionally, POSITA would have had some experience with clinical trials.
`
`
`
`10. The ‘514 patent was filed on February 13, 2012. For the purposes of this
`
`Declaration, I have been asked to assume that the challenged claims may be
`
`entitled to the priority date of U.S. provisional application 60/888,921, filed Feb. 8,
`
`2007. I have been advised by counsel that because no inventor of the provisional
`
`application was named, the ‘514 patent may not be entitled to the benefit of that
`
`2007 date. At this time I have not investigated or formed any opinions about the
`
`contents of provisional application 60/888,921.
`
`
`
`11. My opinion regarding the level of ordinary skill in the art for the ‘514
`
`patent is based on my review of the patent and relevant file history, as well as my
`
`knowledge of the level of skill of individuals in this field. In forming my opinions,
`
`I have also considered the nature of problems that the ‘514 patent was intended to
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`solve, and the education level of active professionals in the field.
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`
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`12. According to the description above, I possess at least the ordinary skill in
`
`the art, and did so at the time when the inventions in the ‘514 patent were made. I
`
`am familiar with the knowledge, experience, and creativity of such a person of
`
`ordinary skill in the art of the ‘514 patent during the relevant time period.
`
`V. RELEVANT LEGAL STANDARDS
`
`
`
`13. I am not a lawyer and do not purport to offer legal opinions. In forming
`
`my opinions, however, I have been asked to apply certain standards regarding
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`patentability that were provided to me by counsel for the Petitioner.
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`
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`14. I understand that for purposes of this IPR the terms in the claims of the
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`‘514 patent are to be construed according to their broadest reasonable
`
`interpretation in light of the specification of the ‘514 patent, as those terms would
`
`have been understood by one of ordinary skill in the art, as of the priority date of
`
`the ‘514 patent.
`
`A. Anticipation
`15. I have been informed that a patent claim is “anticipated” when a single
`
`
`
`patent or printed publication describes all of the elements of a claim, either
`
`expressly or by inherent disclosure. In this context I have been informed by
`
`counsel to assume that inherency means “necessarily,” so that a prior art reference
`
`which does not expressly disclose a claim element (or “claim limitation”) may still
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`inherently disclose that element if the missing description is necessarily present in
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`the disclosure. I have been informed that for this to be true, the disclosure must be
`
`such that the natural result flowing from the operation of a system or method
`
`described in a reference necessarily results in the performance of the claim
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`limitation(s). Standards for “anticipation” as I understand them are reproduced
`
`below: (a) the invention was known or used by others in this country (United
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`States), or patented or described in a printed publication in this or a foreign
`
`country, before the invention thereof by the application for patent, (b) the invention
`
`was patented or described in a printed publication in this or a foreign country or in
`
`public use or on sale in this country, more than a year prior to the date of the
`
`application for patent in the United States, and (c) the invention was described in a
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`patent granted on an application for patent by another filed in the United States
`
`before the invention by the applicant for patent.
`
`B. Obviousness
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`
`
`16. It is my understanding that 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 claims
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`at issue; (c) the level of ordinary skill in the art; and (d) whatever “secondary
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`considerations” may be present, which I have been informed generally take the
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`form of evidence showing that the invention displays a significant and unexpected
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`property. I also understand that if all elements in a claim were known in the prior
`
`art, and a person of ordinary skill in the art could have combined the elements by
`
`known methods with no change in their respective functions, and the combination
`
`yielded no more than the expected results, then such a claim would have been
`
`obvious.
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`VI. Brief overview of the ‘514 Patent
`
` 17. In my opinion, the ‘514 patent teaches that dimethyl fumarate (DMF)
`
`and monomethyl fumarate (MMF) have essentially the same biological activity,
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`“FIG. 1 demonstrates that DMF and MMF are activators of Nrf2 at concentrations
`
`within clinical exposure range (cells in culture).” Ex. 1001A, 4:65-67. “FIG. 3
`
`shows evidence of Nrf2 activation by DMF and MMF in vivo. FIG. 4 shows
`
`evidence of Nrf2 activation by DMF and MMF in vivo.” Ex. 1001A, 5:2-5. I find
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`nothing in the ‘514 patent which defines or explains that the therapeutic properties
`
`of MMF are different from the therapeutic properties of DMF.
`
`18. In my opinion, FIG 1 of the ‘514 patent shows, the expression level of
`
`NQO1 is elevated at all concentrations of DMF tested, which expression level is
`
`proportional to DMF concentration. The specification of the ‘514 patent also states
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`8
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`that “[t]he results shown in FIG. 1, demonstrate that DMF and MMF are potent
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`activators of Nrf2 at concentrations within clinical exposure range.” Ex. 1001A,
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`2:12-14. The ‘514 specification teaches that Nrf2 controls the expression level of
`
`NQO1 at doses described in the Examples. The ‘514 patent states that “genes
`
`under the control of Nrf2 include…For example, expression levels of endogenous
`
`or exogenously introduced NQO1 may be determined as described in the
`
`Examples.” Ex. 1001A, 14:38-44.
`
`19. In my opinion, the ‘514 patent teaches that the effective amounts of
`
`DMF and MMF are the same:
`
`For DMF or MMF, an effective amount can range from 1 mg/kg to 50
`mg/kg (e.g., from 2.5 mg/kg to 20 mg/kg or from 2.5 mg/kg to 15
`mg/kg). Effective doses will also vary, as recognized by those skilled
`in the art, dependent on route of administration, excipient usage, and
`the possibility of co-usage with other therapeutic treatments including
`use of other therapeutic agents. For example, an effective dose of
`DMF or MMR [sic: MMF] to be administered to a subject orally can
`be from about 0.1 g to 1 g per pay, 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. The dosage may be determined by a
`physician and adjusted, as necessary, to suit observed effects of the
`treatment.
`
`Ex. 1001A, 18:52-67.
`
`20. In my opinion, Example 3 of the ‘514 patent tested the same dose
`
`
`
`per body weight (15 mg/kg), twice a day, for both DMF and MMF: “Each
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`treatment group consisted of 8 animals: vehicle alone as a negative control, 5
`9
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`mg/kg body weight DMF twice a day, 15 mg/kg body weight DMF twice a
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`day, 15 mg/kg body weight MMF twice a day.” Ex. 1001A, 21:6-10,
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`emphasis added.
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`VII. CLAIM CONSTRUCTION
`A.
`“Excipients”
`21. In my opinion, the ‘514 patent defines the term “excipient” or
`
`
`
`“excipients:” “As used herein, the phrase ‘pharmaceutically acceptable excipient’
`
`refers to any and all solvents, dispersion media, coatings, antibacterial and
`
`antifungal agents, isotonic and absorption delaying agents, and the like, that are
`
`compatible with pharmaceutical administration.” Ex. 1001A, 19:6-10. In my
`
`opinion, the term “excipients” means “any and all solvents, dispersion media,
`
`coatings, antibacterial and antifungal agents, isotonic and absorption delaying
`
`agents, and the like, that are compatible with pharmaceutical administration.”
`
`
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`
`
`B.
`
`“Consisting essentially of”
`
`22. I have been advised by counsel that for purposes of this declaration to
`
`assume that the term “comprising” means “including.” Except for claim 20, which
`
`uses the phrase “comprising,” all other claims in the ‘514 patent recite
`
`compositions “consisting essentially of…[active ingredient(s)]…” such as (claim
`
`1: “consisting essentially of a therapeutically effective amount of dimethyl
`
`fumarate, monomethyl fumarate, or a combination thereof”) and (claim 7:
`
`“consists essentially of monomethyl fumarate”) and (claim 6: “consists essentially
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`of dimethyl fumarate”) and (claim 11: “consisting essentially of orally
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`administering to the subject about 480 mg per day of dimethyl fumarate,
`
`monomethyl fumarate, or a combination thereof”) and (claim 15: “pharmaceutical
`
`composition consisting essentially of (a) a therapeutically effective amount of
`
`dimethyl fumarate and (b) one or more pharmaceutically acceptable excipients”). I
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`have been advised by counsel to assume for purposes of this declaration that a
`
`claim reciting a thing “consisting essentially of” specified ingredients limits the
`
`scope of the claim to the specified ingredients plus those ingredients which do not
`
`materially affect the basic and novel characteristic(s) of that thing.
`
`VIII.
`
`Overview of Prior Art Reviewed by Me
`
`23. In my opinion, once it was known that DMF is therapeutically active for
`
`treating RRMS, as taught by Kappos 2005 or ClinicalTrials NCT00168701 or ‘514
`
`Patent admission of prior art (“Fumaric acid esters, such as DMF, have been
`
`proposed for treatment of MS”), it would have been standard procedure in drug
`
`development to determine the appropriate dosing range of DMF or MMF,
`
`including its minimum effective dose, in accordance with government guidance:
`
`ICH Guideline E4.
`
`24. I have also reviewed the document “Drugs R&D, 2005, 6(4):229-30”
`
`(Ex. 1021A) cited in the ‘514 patent where it admits that fumaric acid esters, such
`
`as DMF, were known to be therapeutically active (“Fumaric acid esters, such as
`
`
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`11
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`Page 11 of 50
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`DMF, have been proposed for treatment of MS…Drugs R&D, 2005,6(4):229-30).”
`
`Ex 1001A, col. 5:6-8. Drugs R&D reports the following entry in Table II: “Nov
`
`2004 Phase II in Multiple sclerosis in Europe (PO)” Ex. 1021A, p2. In my
`
`opinion, this table entry indicates to a POSITA that a phase 2 clinical trial using
`
`the oral BG00012 composition was conducted on MS patients beginning in 2004.
`
`The fact that this was a phase 2 trial indicates that DMF was believed to have
`
`therapeutic activity against MS at that time. Also, ClinicalTrials NCT00168701
`
`titled “Effacacy [sic] and Safety of BG00012 in MS” (Ex. 1022A) disclosed in
`
`2005 that “DMF, the active ingredient in BG00012, is an immunomodulator
`
`demonstrating…possible therapeutic efficacy in MS (Schimrigk et al, 2001).” The
`
`Drug R&D 2005 (Ex. 1021A) article states that “Fumapharm AG has developed a
`
`second-generation fumarate (fumaric acid) derivative, BG 12 [BG 00012, FAG-
`
`201, BG 12/Oral Fumarate], for the oral treatment of psoriasis” (Abstract).
`
`25. I have also reviewed the document, Fumapharm AG - Galenical
`
`Development (Ex. 1023A), which is an internet archived webpage of Fumapharm
`
`(Aug 3, 2005), indicating development of “enteric coated microtablets in capsules”
`
`of a “second-generation product” identified as a fumaric acid derivative
`
`“monosubstance.” Even though the product BG00012 is not mentioned by name in
`
`Ex. 1023A, in my opinion it appears that BG00012 is the “second-generation”
`
`product discussed on the webpage.
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`
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`12
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`IX. Ground 1: Claims 1-20 would have been obvious over Kappos 2005 (Ex.
`
`1003A) or ClinicalTrials NCT00168701 (Ex. 1022A) or ‘514 Patent admission
`
`of prior art in view of ICH Guideline E4 (Ex. 1004A)
`
`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.
`
`
`
`26. I see that the first element of claim 1 requires, “[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” and defines a method of treating a subject in need of treatment for MS with an
`
`oral pharmaceutical composition. In my opinion Kappos 2005 discloses “A
`
`randomized, placebo-controlled phase II trial of a novel oral single agent fumarate
`
`therapy, BG00012, in patients with relapsing-remitting multiple sclerosis.” Ex.
`
`1003A, p2, 1:1-3. ClinicalTrials NCT00168701 discloses “Double-Blind, Placebo-
`
`Controlled, Dose-Ranging Study to Determine the Effacacy [sic] and Safety of
`
`BG00012 in Subjects with Relapsing-Remitting Multiple Sclerosis” Ex. 1022A,
`
`p1.
`
`27. I see that the second element of claim 1 requires, “(a) a therapeutically
`
`effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
`
`
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`thereof.” In my opinion, Kappos 2005 discloses a pilot study that orally
`
`administered to patients what appears to be a therapeutically effective amount of
`
`fumaric acid esters, indicated by a “significantly reduced the number of
`
`gadolinium-enhancing (Gd+) lesions in patients with RRMS.” Ex. 1003A, p2,
`
`1:13-16. ClinicalTrials NCT00168701 teaches “the efficacy data in the pilot MS
`
`study of BG00012 support a proof of concept study in MS.” Ex. 1022A, p1-2.
`
`ClinicalTrials NCT00168701 also teaches that DMF is the active ingredient in
`
`BG00012. Ex. 1022A, p1. In my opinion, DMF is an abbreviation for dimethyl
`
`fumarate and MMF is an abbreviation for monomethyfumarate. The ‘514 patent
`
`cites to prior art clinical studies on MS patients which indicated that “[f]umaric
`
`acid esters, such as DMF have been proposed for treatment of MS.” Ex. 1001A,
`
`5:6-7. In my opinion, fumaric acid esters refer principally to DMF or MMF. Thus,
`
`in my opinion, the ‘514 Patent admits that a POSITA believed that DMF and MMF
`
`were therapeutically active for MS.
`
`28. In my opinion, Kappos 2005 discloses BG00012
`
`contains a sole active ingredient. The objective is “[t]o determine the
`
`efficacy and safety of a novel single-agent oral fumarate therapy, BG00012, in
`
`patients with relapsing-remitting multiple sclerosis (RRMS).” Ex. 1003A, p2, 1:1-
`
`3. Kappos 2005 discloses that “this phase II study was designed to evaluate the
`
`efficacy of three doses of BG00012 on brain lesion activity” in MS patients.
`
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`Ex.1003A, p2, 1:17-20 Kappos 2005 also discloses that this phase II study is a
`
`“dose-ranging study.” Ex. 1003A, p2, 2:16-17. In my opinion, the Kappos 2005
`
`dose-ranging study would not have been undertaken unless BG00012 had
`
`previously been determined to be therapeutically active in treating patients with
`
`MS.
`
`29. In my opinion, ClinicalTrials NCT00168701 discloses: “Effacacy [sic]
`
`and Safety of BG00012 in MS.” and teaches “the efficacy data in the pilot MS
`
`study of BG00012 support a proof of concept study in MS.” Ex. 1022A, p1-2.
`
`30. Furthermore, DMF is known to be metabolically converted to MMF
`
`rapidly by hydrolysis in the intestinal tissue. Ex. 1016A, p2, 1:6 - 2:1-12. In my
`
`opinion, Kappos 2005 or ClinicalTrials NCT00168701 or the ‘514 patent
`
`admissions each teach a POSITA that DMF and MMF are therapeutically active on
`
`RRMS.
`
`31. I see the third element of claim 1 requires, “b) one or more
`
`pharmaceutically acceptable excipients.” In my opinion, DMF is poorly tolerated
`
`by patients (Ex. 1005A citing to Ex. 1019A, p4, 2:6-10, and p5, Table 2) and a
`
`POSITA would have been motivated to use excipients to reduce G.I. complaints.
`
`Furthermore, in my opinion, MMF is also poorly tolerated in patients and therefore
`
`a POSITA would have been motivated to use excipients to reduce G.I. complaints.
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`32. I see the fourth element of claim 1 requires, “wherein the therapeutically
`
`effective amount of dimethyl fumarate, monomethyl fumarate, or a combination
`
`thereof is about 480 mg per day.” Kappos 2005 discloses a dose-ranging study in
`
`which “[e]ligible patients were randomized to receive BG00012 120 mg PO once
`
`daily (120 mg/day), 120 mg PO three times daily (360 mg/day), 240mg PO three
`
`times daily (720 mg/day), or placebo.” Ex. 1003A, p2, 1:28 to 2:1-3. In my
`
`opinion, ClinicalTrials NCT00168701 teaches a dose-ranging study with the same
`
`doses of DMF and further acknowledges that if DMF is not well tolerated by
`
`patients, lower doses can alleviate the problem. “Dose reduction will be allowed
`
`for subjects who are unable to tolerate investigational drug.” Ex. 1022A, p2, 24-25.
`
`33. In my opinion, the ICH Guideline E4 would have instructed a POSITA
`
`as follows: “Assessment of dose-response should be an integral component of drug
`
`development with studies designed to assess dose-response an inherent part of
`
`establishing the safety and effectiveness of the drug. If development of dose-
`
`response information is built into the development process it can usually be
`
`accomplished with no loss of time and minimal extra effort compared to
`
`development plans that ignore dose-response.” Ex. 1004A, p7:27-32. ICH
`
`Guideline E4 also would have instructed that: “It is all too common to discover, at
`
`the end of a parallel dose-response study, that all doses were too high (on the
`
`plateau of the dose-response curve), or that doses did not go high enough. Ex.
`
`
`
`16
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`Page 16 of 50
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`
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`1004A, p10:39-41. In my opinion, the ICH Guideline E4 instructed a POSITA to
`
`perform dosing studies as a standard procedure in drug development in order to
`
`“allow study of the proper dose range” in phase III. In my opinion, because
`
`Kappos 2005 did not test doses between 360 mg/day and 720 mg/day, because side
`
`effects are always a concern in drug development, as they were for DMF, and
`
`because doses in multiples of 120 mg and 240 mg were readily available, a
`
`POSITA would have conducted clinical trials by administering BG00012 at a total
`
`daily dose equivalent to 480 mg/day DMF as well as 600 mg/day, as a standard
`
`process of drug development.
`
`34. In my opinion, Kappos 2005 and ClinicalTrials NCT00168701 disclose
`
`BG00012, which is a composition dosing 120 mg or 240 mg dimethyl fumarate as
`
`the sole active ingredient (“patients randomized to receive BG00012 120 mg PO
`
`once daily (120 mg/day), 120 mg PO three times daily (360 mg/day), 240mg PO
`
`three times daily (720 mg/day), Ex. 1003A, p2, 2:1-3. In my opinion, a POSITA
`
`would have designed additional dose-ranging studies using doses of 240 mg, 480
`
`mg and 600 mg in multiples of 120 mg or 240 mg, because BG00012 was already
`
`conveniently formulated to achieve such doses.
`
`35. In my opinion, a POSITA would have had reason to modify the clinical
`
`trial design of Kappos 2005 or ClinicalTrials NCT00168701 in view of the ICH
`
`Guideline E4, as part of a group of dosing studies, because the purpose of the ICH
`
`
`
`17
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`Page 17 of 50
`
`
`
`Guideline E4 is to provide instructions to help identify “an appropriate starting
`
`dose, the best way to adjust dosage to the needs of a particular patient, and a dose
`
`beyond which increases would be unlikely to provide added benefit or would
`
`produce unacceptable side effects.” Ex. 1004A, p5:7-10. In my opinion, a
`
`POSITA would have had reason to conduct dose-ranging studies due to the
`
`admittedly known therapeutic activity of DMF, in view of the ICH Guideline E4,
`
`because the purpose of the ICH Guideline E4 is to provide instructions to help
`
`identify “an appropriate starting dose, the best way to adjust dosage to the needs of
`
`a particular patient, and a dose beyond which increases would be unlikely to
`
`provide added benefit or would produce unacceptable side effects.” Ex. 1004A,
`
`p5:7-10.
`
`
`
`36. In sum, a POSITA would have been motivated to conduct routine
`
`experiments at a range of doses, including 480 mg/day, by orally administering
`
`that dose and a 600 mg/day dosage strength to subjects in need of treatment for
`
`MS. Thus, a POSITA would have been motivated by Kappos 2005 or
`
`ClinicalTrials NCT00168701 or admitted prior art, in view of ICH Guideline E4 to
`
`treat a subject in need of treatment for multiple sclerosis by 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
`
`
`
`18
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`Page 18 of 50
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`
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`excipients, wherein the therapeutically effective amount of dimethyl fumarate,
`
`monomethyl fumarate, or a combination thereof is about 480 mg per day.
`
`Claim 2: The method of claim 1, wherein the pharmaceutical composition is
`administered in the form of a tablet, a suspension, or a capsule.
`
`
`
`37. I see that claim 2 depends on claim 1 and incorporates all its limitations.
`
`Claim 2 further requires, “the pharmaceutical composition is administered in the
`
`form of a tablet, a suspension, or a capsule.” In my opinion, Kappos 2005 discloses
`
`administering BG00012 orally to MS patients using formulations with dosing
`
`strengths of 120 mg or 240 mg DMF. Ex. 1003A, p2, 2:1-3. ClinicalTrials
`
`NCT00168701 also discloses the same formulations of DMF: “Effacacy [sic] and
`
`Safety of BG00012 in MS,” wherein “the efficacy data in the pilot MS study of
`
`BG00012 support a proof of concept study in MS. Ex. 1022A, p1-2. In my
`
`opinion, a POSITA would have been motivated to administer DMF as a tablet or
`
`capsule in general, and particularly in view of Kappos 2005 or ClinicalTrials
`
`NCT00168701.
`
`
`
`38. In sum, in my opinion, a POSITA would have been motivated to, in light
`
`of Kappos 2005 or ClinicalTrials NCT00168701 or admitted prior art in view of
`
`ICH Guideline E4, to administer DMF as a tablet or capsule.
`
`Claim 3: The method of claim 1, wherein the therapeutically effective amount
`is administered in separate administrations of 2, 3, 4, or 6 equal doses.
`
`
`
`
`19
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`Page 19 of 50
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`
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`39. I see that claim 3 depends on claim 1 and incorporates all its limitations.
`
`Claim 3 further requires, “the therapeutically effective amount is administered in
`
`separate administrations of 2, 3, 4, or 6 equal doses.” In my opinion, Kappos 2005
`
`discloses a dose-ranging study in which “[e]ligible patients were randomized to
`
`receive BG00012 120 mg PO once daily (120 mg/day), 120 mg PO three times
`
`daily (360 mg/day), 240mg PO three times daily (720 mg/day), or placebo.” Ex.
`
`1003A, p2, 1:28-2:3. ClinicalTrials NCT00168701 also discloses a dose-ranging
`
`study of BG00012 with the same doses. In my opinion, both Kappos 2005 and
`
`ClinicalTrials NCT00168701 disclose at least one dose or three equal doses. In my
`
`opinion, routine dosing experiments would have shown that administration of 2, 4
`
`or 6 equal doses are therapeutically effective.
`
`40. Furthermore, in my opinion, DMF is known to cause gastrointestinal
`
`discomfort (“The gastrointestinal complaints, on the other hand, presented a real
`
`problem. More than half the patients were troubled by serious stomach complaints,
`
`involving gastralgia, but also nausea, vomiting and diarrhea.”) Ex. 1019A, p4, 2:6-
`
`10, and p5, Table 2) and so dividing the daily dose into smaller equal doses taken
`
`separately, throughout the day, would have been expected to reduce gastric distress,
`
`because smaller doses expose the G. I. tract to less DMF at one time. The ICH
`
`Guideline E4 teaches that “[t]he choice of the size of an individual dose is often
`
`intertwined with the frequency of dosing. In general, when the dose interval is long
`
`
`
`20
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`Page 20 of 50
`
`
`
`compared to the half-life of the drug, attention should be directed to the
`
`pharmacodynamic basis for the chosen dosing interval. For example, there might
`
`be a comparison of the long dose-interval regimen with the same dose in a more
`
`divided regimen, looking, where this is feasible, for persistence of desired effect
`
`throughout the dose-interval and for adverse effects associated with blood level
`
`peaks.” Ex. 1004A, p7:9-15. In my opinion, attempting to find the optimal
`
`individual dose, dosing frequency and total daily dose are a normal part of drug
`
`development.
`
`41. In my opinion, administering therapeutically effective amounts of DMF
`
`to a subject, in a number of equal doses throughout the day, would necessarily
`
`smooth out peak blood levels of the biologically active metabolite, MMF. In my
`
`opinion, a POSITA would have known that DMF is therapeutically active for MS,
`
`and thus would have been motivated to use multiples of a 120 mg or 240 mg to
`
`perform dosing studies, since BG00012 includes both 120 mg and 240 mg dosage
`
`strengths of DMF, as disclosed by Kappos 2005. Furthermore, in my opinion,
`
`since claim 3 recites every dosing interval from 2 equal doses to 6 equal doses,
`
`there is no critical dosing interval.
`
`42. In sum, a POSITA would have been motivated, in light of Kappos 2005
`
`or ClinicalTrials NCT00168701 or admitted prior art, in view of ICH Guideline
`
`
`
`21
`
`Page 21 of 50
`
`
`
`E4, to administer the therapeutically effective amount of about 480 mg/day DMF
`
`in separate administrations of 2 or 4 equal doses.
`
`Claim 4: The method of claim 3, wherein the therapeutically effective amount
`is administered in separate administrations of 2 equal doses.
`
`43. I see that claim 4 depends on claim 3 and incorporates all its limitations.
`
`
`
`Claim 4 further requires, “the therapeutically effective amount is administered in
`
`separate administrations of 2 equal doses.” As I have explained with respect to
`
`claim 3, a POSITA would have been motivated to administer 480 mg/day in 2
`
`equal doses based on the ready availability of 240 mg BG00012. In my opinion, a
`
`POSITA would have been motivated by ICH Guideline E4, to administer 480
`
`mg/day in two equal doses, because the alternative of taking 120 mg doses four
`
`times per day would be expected to decrease patient compliance. In sum, in my
`
`opinion, a POSITA would have been motivated, i
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