`Lead counsel: Robert W. Hahl, Reg. No. 33,893
`Backup counsel: Robert Mihail, Reg. No. 66,021
`Backup counsel: John K. Pike, Reg. No. 41,253
`Neifeld IP Law, PC
`
`
`
`Paper No. __
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`Coalition For Affordable Drugs V LLC
`Petitioner
`v.
`
`Biogen MA Inc.
`Patent Owner
`____________
`
`Case Unassigned
`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
`
`
`
`DECLARATION OF STEVEN E. LINBERG PH.D.
`
`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
`
`opine only with respect to certain issues that are discussed in this declaration.
`
`II. RESOURCES CONSULTED
`2. I have reviewed the ‘514 patent (Exhibit 1001) including claims 1-20. I
`
`
`
`have also reviewed the Wakke reference (Exhibit 1002) Kappos 2006 reference
`
`(Exhibit 1003), the ICH Guideline E4 (Exhibit 1004), the Werdenberg reference
`
`(Exhibit 1016), the ClinicalTrials NCT00168701 reference (Exhibit 1022), the
`
`Begleiter reference (Exhibit 1027), the Joshi reference (Ex. 1030) and the Joshi
`
`2002 reference (Ex. 1036). 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
`
`
`
`1978. I worked for over 35 years in academic clinical research and commercial
`
`drug and biologics development, with particular attention to the overall strategy of
`
`drug development programs, to individual clinical trial design, execution, and
`
`reporting, and to regulatory interactions with the FDA. Over the course of that time
`
`
`
`2
`
`
`
`I participated in the design, conduct, reporting or oversight of more than 100
`
`clinical trials. I have held senior positions in companies which were developing
`
`drugs, developing biologics, and at contract research organizations. I am the
`
`principal editor of, and a contributing author in the text Expediting Drug and
`
`Biologics Development, now in its 3rd edition. I developed and taught graduate-
`
`level courses in Drug and Biologics Development, Clinical Trial Design, and
`
`Clinical Trial Operations for the Johns Hopkins University; and An Overview of
`
`Clinical Research, for the University of Maryland.
`
`
`
`4. From 1978 to 1984, I was a Clinical Physiology Research Associate for
`
`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
`
`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
`
`Associate Director of Clinical Research at Boehringer Mannheim Pharmaceuticals.
`
`In 1992 I was the Director of Clinical Research at Univax Biologics, Inc.. From
`
`1992 to 1995 I was a consultant at, and owner of, Linberg Research, Inc.. From
`
`1995 to 1996 I was the Vice President of Clinical Development at Collaborative
`
`Clinical Research, Inc.. From 1996 to 2001 I was the Vice President of Clinical
`
`Development at Cato Research Limited, and from 2001 to 2002 I was promoted to
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`
`
`3
`
`
`
`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
`
`Pharmaceuticals, Inc. and from 2009 to 2010 I was also Vice President and
`
`Treasurer at the same company. From 2011 to 2012 I was the founding President
`
`and CEO of Airway Therapeutics, LLC and continue as a Member of Airway
`
`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
`
`further that effort.
`
`
`
`5. I have published numerous academic papers and have served in various
`
`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 1017.
`
`
`
`6. I am being compensated for my time at my standard hourly rate for this
`
`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
`
`
`
`4
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`
`
`innovations are made; (4) sophistication of the technology; and (5) educational
`
`level of active workers in the field. I have been informed by counsel that it is from
`
`the viewpoint of a person of ordinary skill in the art that legal issues, such as claim
`
`construction and obviousness, are determined.
`
`
`
`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 (“POSITA”) at the time of the alleged
`
`invention of the ‘514 patent 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 trial designs for dose
`
`selection.
`
`
`
`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
`
`
`
`5
`
`
`
`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
`
`solve, and the education level of active professionals in the field.
`
`
`
`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
`
`patentability that were provided to me by counsel for the Petitioner.
`
`
`
`14. I understand that for purposes of this IPR the terms in the claims of the
`
`‘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
`
`
`
`6
`
`
`
`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
`
`inherently disclose that element if the missing description is necessarily present in
`
`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
`
`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
`
`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
`
`patent granted on an application for patent by another filed in the United States
`
`before the invention by the applicant for patent.
`
`B. Obviousness
`
`
`
`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
`
`
`
`7
`
`
`
`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
`
`at issue; (c) the level of ordinary skill in the art; and (d) whatever “secondary
`
`considerations” may be present, which I have been informed generally take the
`
`form of evidence showing that the invention displays a significant and unexpected
`
`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.
`
`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,
`
`“FIG. 1 demonstrates that DMF and MMF are activators of Nrf2 at concentrations
`
`within clinical exposure range (cells in culture).” Ex. 1001, col. 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. 1001, col. 5:2-5. I
`
`find nothing in the ‘514 patent which defines or explains that the therapeutic
`
`properties of MMF are different from the therapeutic properties of DMF.
`
`
`
`8
`
`
`
`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
`
`that “[t]he results shown in FIG. 1, demonstrate that DMF and MMF are potent
`
`activators of Nrf2 at concentrations within clinical exposure range.” Ex. 1001, col.
`
`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. 1001, col. 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 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
`9
`
`
`
`
`
`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. 1001, col. 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
`
`treatment group consisted of 8 animals: vehicle alone as a negative control, 5
`
`mg/kg body weight DMF twice a day, 15 mg/kg body weight DMF twice a
`
`day, 15 mg/kg body weight MMF twice a day.” Ex. 1001, col. 21:6-10.
`
`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. 1001, col. 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.”
`
`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
`10
`
`
`
`
`
`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
`
`of dimethyl fumarate”) and (claim 11: “consisting essentially of orally
`
`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
`
`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.
`
`C. “Therapeutically effective amount”
`22.1 The ‘514 patent defines “therapeutically effective amount” 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 loss, and neuronal death) or reduced inflammation of
`
`the cells of the CNS.” Ex. 1001, col. 5:53-39. In my opinion, the term
`
`
`
`11
`
`
`
`“therapeutically effective amount” means “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 loss, and
`
`neuronal death) or reduced inflammation of the cells of the CNS.”
`
`VIII.
`
`Overview of Prior Art Reviewed by Me
`
`23. I have reviewed all documents discussed in this declaration. Results of at
`
`least one Phase II clinical trial of DMF were published in 2006 (Kappos 2006).
`
`Kappos 2006 states that “BG00012 significantly reduces brain lesion activity, in a
`
`dose dependent manner, as measured by MRI in patients with RRMS over 24
`
`weeks of treatment.” Ex.1003, page 27, col. 2:52-54. In my opinion, the active
`
`ingredient of BG-12 or BG00012 is dimethyl fumarate. Ex. 1022, page 1 and Ex.
`
`1002, title.
`
`23.1 I have reviewed the document Joshi et al., (Ex. 1030). I see that Joshi
`
`et al., discloses “DIMETHYL FUMARATE FOR THE TREATMENT OF
`
`MULTIPLE SCLEROSIS” (Ex. 1030, Title), and recites in claim 1 a method of
`
`treating multiple sclerosis by administering an effective amount of DMF. The
`
`production examples include enteric-coated microtablets containing 120 mg DMF
`
`(Examples 1 and 2), microtablets in capsules containing 50 mg of DMF (Example
`
`3), and enteric coated capsules containing 110 mg DMF (Example 4). Micro-tablet
`
`
`
`12
`
`
`
`enteric coating is used to reduce gastrointestinal irritation. Ex. 1030, col. 5:29-33.
`
`The dialkyl fumarates of Joshi et al., “are not the active ingredient per se, but a so-
`
`called prodrug, which must be converted into the active ingredient in the body.”
`
`Ex. 1030, col. 5:53-58. The active agent is identified as methyl hydrogen fumarate
`
`(i.e., MMF), a metabolite of DMF. Ex. 1030, col. 3:32-34.
`
`24. In my opinion, it would have been a routine task of drug development
`
`and approval to determine the appropriate dose of DMF (or MMF) though dose-
`
`ranging studies, including determination of the minimum effective dose. This task
`
`was standard practice in drug development when the ‘514 patent was filed, as
`
`shown by the joint U.S., European and Japanese government guidance document
`
`ICH Guideline E4.
`
`25. I have also reviewed the document Wakkee (Ex. 1002). I see that Wakkee
`
`disclosed in Nov. 2007 that BG00012 contains DMF: “Drug evaluation: BG-12, an
`
`immunomodulatory dimethylfumarate.” In my opinion the “BG-12” product
`
`discussed in Wakkee contains DMF as the sole API.
`
`IX. DETAILED EXPLANATION OF THE CHALLENGES
`A. Ground 1: Claims 1-6, 8-16 and 20 are unpatentable under 35
`U.S.C. §103 as obvious over Kappos 2006 (Ex. 1003), ClinicalTrials
`NCT00168701 (Ex. 1022), Joshi (Ex. 1030), and ICH Guideline E4 (Ex.
`1004)
`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
`
`
`
`13
`
`
`
`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 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.”
`
`Kappos 2006 discloses results from “[a] randomized, double-blind, placebo-
`
`controlled clinical trial of BG00012 in patients with RRMS”. Ex. 1003, page 27,
`
`col. 2:26–27. Further, Kappos 2006 teaches “[p]atients received BG00012 capsules
`
`… by mouth…” Id. ClinicalTrials NCT00168701 is directed to a “Double-Blind,
`
`Placebo-Controlled, Dose-Ranging Study to Determine the Effacacy [sic] and
`
`Safety of BG00012 in Subjects with Relapsing-Remitting Multiple Sclerosis” and
`
`that “all investigational drug (BG00012 or placebo) will be given orally” Ex. 1022
`
`pages 1–2 . Joshi also teaches “[a] method of treating multiple sclerosis…with an
`
`amount of a pharmaceutical preparation effective for treating said multiple
`
`sclerosis, wherein the only active ingredient…is dimethyl fumarate.” Ex. 1030,
`
`claim 1, col. 8:14–19 (emphasis added). Joshi also further teaches “the
`
`pharmaceutical preparation is formulated for oral administration” (Ex. 1030 claim
`
`10 8:41-42)
`
`
`
`14
`
`
`
`27. I see the second element of claim 1 requires, “(a) a therapeutically
`
`effective amount of dimethyl fumarate, monomethyl fumarate, or a
`
`combination thereof.” Kappos 2006 discloses BG00012 as therapeutically
`
`effective stating “BG00012 significantly reduced brain lesion activity, in a dose-
`
`dependent manner… in patients with RMMS” Ex. 1003, page 27, col. 2:52-54.
`
`Kappos 2006 does not disclose BG00012 as DMF.
`
`28. ClinicalTrials NCT00168701 discloses that “DMF, [is] the active
`
`ingredient in BG00012.” Ex. 1022, page 1. In my opinion, the active ingredient of
`
`BG-12 or BG00012 is dimethyl fumarate. Ex. 1022, page 1 and Ex. 1002, title.
`
`29. Joshi also teaches “[a] method of treating multiple sclerosis … with an
`
`amount of a pharmaceutical preparation effective for treating said multiple
`
`sclerosis, wherein the only active ingredient…is dimethyl fumarate.” Ex. 1030,
`
`claim 1, col. 8:14–19 (emphasis added).
`
`30. I see the third element of claim 1 requires, “b) one or more
`
`pharmaceutically acceptable excipients.” Joshi discloses “[t]he dialkyl
`
`fumarates used according to the invention may be used alone or as a mixture of
`
`several compounds, optionally in combination with the customary carriers and
`
`excipients” (Ex. 1030, col. 4:39–42) and describes a pharmaceutical preparation
`
`containing DMF in Example 1 that is “an excipient mixture with the following
`
`composition is prepared…” (Ex. 1030, col. 6:8–28).
`
`
`
`15
`
`
`
`31. 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 2006 discloses
`
`“[p]atients were assigned to four treatment groups and received BG00012 capsules
`
`120 mg by mouth (PO) once daily (120 mg/day), 120mg three times daily (360
`
`mg/day), 240 mg three times daily (720 mg/day), or placebo for 24 weeks.” (Ex.
`
`1003, page 27, col. 2:32–35) and that an effective amount of dimethyl fumarate
`
`was found as “BG00012 (720 mg/day) significantly reduced the mean number of
`
`new Gd+lesions (the primary end point) compared with placebo” (Ex. 1003, page
`
`27, col. 2:49–51). ClinicalTrials NCT00168701 also teaches a dose-ranging study
`
`in which 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. 1022, page 2), teaching that “DMF, [is] the
`
`active ingredient in BG00012” (Ex. 1022, page 1) and 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. 1022, 2:24–25. A dose reduction of one capsule in the high dose group
`
`(going from three times 240 mg to two times 240 mg) would have resulted in a
`
`dose of 480 mg/day in 2 equal doses.
`
`
`
`16
`
`
`
`32. 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. 1004, 7:27–32. 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. 1004, 10:39–41.
`
`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. Kappos 2006 did not disclose doses between 360
`
`mg/day and 720 mg/day. However, in my opinion, Kappos 2006 does disclose that
`
`single dosage forms were readily available in 120 mg units (“120 mg by mouth
`
`once daily”), making dose ranges of 480 mg daily and 600 mg daily readily
`
`apparent intervals for further testing. Further, ClinicalTrials NCT00168701
`
`indicates that side effects such as gastrointestinal distress were known and were
`
`enough of a concern, that dosing could be reduced “for subjects who are unable to
`
`tolerate investigational drug” (Ex. 1022, page 2). Joshi also discloses unwanted
`
`
`
`17
`
`
`
`side effects from the administration of the drug (“By administration of the dialkyl
`
`fumarates in the form of micro-tablets, which is preferred, gastrointestinal
`
`irritations and side effects, which are reduced already when conventional tablets
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`are administered but is still observed, may be further reduced vis-a-vis fumaric
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`acid derivatives and salts.” Ex. 1030, col. 5:29–33.) Because side effects are
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`always a concern in drug development, as they were for DMF, and because doses
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`in multiples of 120 mg were readily available, a POSITA, in my opinion, would
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`have been motivated to develop a method of treating a subject in need of treatment
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`for multiple sclerosis by administering dimethyl fumarate at about 480 mg per day
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`(as well as 600 mg per day) in order to identify an appropriate dose of DMF that
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`minimized side effects. It would have been apparent to a POSITA that the teaching
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`of Kappos 2006 in view of at least ClinicalTrials NCT00168701, Joshi, and ICH
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`Guideline E4 would have enabled just such a development of a method such as
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`described at alternative dosing levels with a reasonable expectation of success
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`because the intervals were readily available for a standard process of drug
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`development.
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`33. Furthermore, in my opinion, a POSITA would have had reason to
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`modify the clinical trial design of Kappos 2006 in view of the ICH Guideline E4
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`with a reasonable expectation of success, as part of a group of dosing studies,
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`because the purpose of the ICH Guideline E4 was to provide instructions to help
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`18
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`
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`identify “an appropriate starting dose, the best way to adjust dosage to the needs of
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`a particular patient, and a dose beyond which increases would be unlikely to
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`provide added benefit or would produce unacceptable side effects.” Ex. 1004, 5:7–
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`10.
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`34. In sum, a POSITA, in my opinion, would have been motivated to
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`conduct routine experiments at a range of doses, including 480 mg/day, by orally
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`administering that dose of a pharmaceutical to subjects in need of treatment for
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`MS.
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`Claim 2: The method of claim 1, wherein the pharmaceutical composition is
`administered in the form of a tablet, a suspension, or a capsule.
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`35. Counsel explained to me that claim 2 depends on claim 1 and
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`
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`incorporates all its limitations. I see that claim 2 further requires, “the
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`pharmaceutical composition is administered in the form of a tablet, a
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`suspension, or a capsule.” Kappos 2006 discloses the composition is
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`administered as capsules: “patients were assigned to four treatment groups and
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`received BG00012 capsules 120 mg by mouth” Ex. 1003, page 27, col. 2:32–33.
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`Joshi also teaches “the active ingredients are used for preparing oral preparations
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`in the form of tablets, micro-tablets, pellets or granulates, optionally in capsules or
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`sachets.” Ex. 1030, col. 4:31–33. Thus, in my opinion, a POSITA would have been
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`motivated to administer DMF orally as a tablet or capsule.
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`
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`19
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`
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`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.
`
`
`36. Counsel explained to me that claim 3 depends on claim 1 and
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`incorporates all its limitations. I see that claim 3 further requires, “the
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`therapeutically effective amount is administered in separate administrations
`
`of 2, 3, 4, or 6 equal doses.” Kappos 2006 discloses the therapeutically effective
`
`amount is administered in separate administrations of 3 equal doses as: “Patients
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`were assigned to four treatment groups and received BG00012 capsules … 120 mg
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`three times daily (360 mg/day), 240 mg three times daily (720 mg/day)” (Ex. 1003,
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`page 27, col. 2:32–35). In my opinion, ClinicalTrials NCT00168701 also teaches a
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`dose-ranging study in which patients were randomized to receive BG00012...120
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`mg PO three times daily (360 mg/day), 240mg PO three times daily (720 mg/day).
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`Ex. 1022, pages 1–2. ClinicalTrials NCT00168701 discloses at least one dose or
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`three equal doses.
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`37. The ICH Guideline E4 (Ex. 1004) teaches that “[t]he choice of the size
`
`of an individual dose is often intertwined with the frequency of dosing. In general,
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`when the dose interval is long compared to the half-life of the drug, attention
`
`should be directed to the pharmacodynamic basis for the chosen dosing interval.
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`For example, there might be a comparison of the long dose-interval regimen with
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`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
`20
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`
`
`
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`associated with blood level peaks.” Ex. 1004, 7:9–15. In my opinion, attempting to
`
`find the optimal individual dose, dosing frequency and total daily dose are a
`
`normal part of drug development. 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. Furthermore, DMF is known to be metabolically converted to MMF rapidly
`
`by hydrolysis in the intestinal tissue. Ex. 1016, page 2, col. 1:6 – col. 2:1–12. In
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`my opinion, dividing the daily dose into smaller equal doses taken separately,
`
`throughout the day, would have reasonably been expected to reduce gastric
`
`distress, because smaller doses expose the G. I. tract to less DMF at one time.
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`Routine dosing experiments would have shown whether administration of 480 mg
`
`DMF in 2, 3, 4 or 6 equal doses are therapeutically effective. Further, a POSITA,
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`in my opinion, would have been motivated to use multiples of 120 mg or 240 mg
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`to perform dosing studies, since Kappos 2006 and ClinicalTrials NCT00168701
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`used both 120 mg and 240 mg dosage strengths. I would like to note that claim 3
`
`recites every dosing interval from 2 equal doses to 6 equal doses, indicating there
`
`is no critical dosing interval. Thus, a POSITA, in my opinion, would have been
`
`motivated to administer the therapeutically effective amount of 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.
`21
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`
`
`
`
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`38. Counsel explained to me that claim 4 depends on claim 3 and
`
`incorporates all its limitations. I see that claim 4 further requires, “the
`
`therapeutically effective amount is administered in separate administrations
`
`of 2 equal doses.” In my opinion, a POSITA would have been motivated to
`
`administer 480 mg/day in 2 equal doses based on the ready availability of 240 mg
`
`DMF delivered as BG00012 in Kappos 2006 as shown in claim 3 above. ICH
`
`Guideline E4 would have motivated a POSITA to administer the effective amount
`
`in two equal doses because the alternative of taking it three or four times per day
`
`would be expected to decrease patient compliance. ClinicalTrials NCT00168701
`
`states, “Dose reduction will be allowed for subjects who are unable to tolerate
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`investigational drug.” Ex. 1022, 2:24–25. In my opinion, a dose reduction of one
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`capsule in the high dose group (going from three times 240 mg to two times 240
`
`mg) would have resulted in a dose of 480 mg/day in 2 equal doses.
`
`Claim 5: The method of claim 3, wherein the therapeutically effective amount
`
`is administered in separate administrations of 3 equal doses.
`
`
`
`39. Counsel explained to me that claim 5 depends on claim 3 and
`
`incorporates all its limitations. I see that claim 5 further requires, “the
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`therapeutically effec