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 IPR2015-01993
`Patent 8,399,514 B2
`____________________________________________
`
`
`
`DECLARATION OF RICHARD C. BRUNDAGE, PHARM. D., PH.D.
`
`
`
`
`
`Page 1 of 27
`
`Biogen Exhibit 2042
`Coalition v. Biogen
`IPR2015-01993
`
`

`
`Table of Contents
`
`
`
`
`DECLARATION OF RICHARD C. BRUNDAGE, PHARM. D., PH.D. ................ 1 
`I. 
`INTRODUCTION ........................................................................................... 1 
`II.  QUALIFICATIONS ........................................................................................ 1 
`A. 
`Education ............................................................................................... 1 
`B. 
`Professional Experience ........................................................................ 2 
`C. 
`Publications ........................................................................................... 4 
`D.  Honors and Awards ............................................................................... 4 
`E. 
`Professional Organizations and Service Activities ............................... 5 
`III.  MATERIALS CONSIDERED ........................................................................ 6 
`IV.  OPINIONS IN SUPPORT OF BIOGEN’S RESPONSE TO
`PETITION ....................................................................................................... 7 
`A. 
`Joshi ’999 Does Not Disclose a Daily Dose of DMF ........................... 7 
`1. 
`Expertise as a Pharmacist ............................................................ 7 
`2. 
`Pharmaceutical Preparations Are Distinct from
`Therapeutic Regimens ................................................................ 7 
`Joshi ’999 Describes the Amount of DMF Present in a
`Pharmaceutical Preparation, Not a Daily Dose .......................... 9 
`The Dose-Response of DMF Was Not Well-Defined ........................ 11 
`1. 
`Expertise as a Clinical Pharmacologist ..................................... 11 
`2. 
`Based on the Limited Dose-Response Information
`Available for DMF in MS, No Reason Existed to Choose
`a Dose of 480 mg/day or to Expect That It Would Work ......... 12 
`The ICH Guideline Is Not a Mandate to Find the Perfect Dose ......... 15 
`1. 
`Relevant Expertise .................................................................... 16 
`
`3. 
`
`B. 
`
`C. 
`
`
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`i
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`Page 2 of 27
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`

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`
`
`2. 
`
`3. 
`
`The ICH Guideline Provides Only General Guidance to
`Support Drug Registration ........................................................ 16 
`A Parallel Dose-Response Study Design Is Appropriate
`for MS ....................................................................................... 18 
`Kappos 2006 Is Consistent With the ICH Guideline ................ 19 
`4. 
`ClinicalTrials Provides No Reason to Lower the Dose of DMF
`to 480 mg/day ...................................................................................... 21 
`CONCLUSION .............................................................................................. 22 
`
`D. 
`
`V. 
`
`
`
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`ii
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`

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`Case No. IPR2015-01993
`U.S. Patent No. 8,399,514
`
`
`
`I.
`
`INTRODUCTION
`1.
`
`I, Richard C. Brundage, Pharm. D., Ph.D., have been retained by
`
`Finnegan, Henderson, Farabow, Garrett & Dunner, LLP on behalf of Biogen MA
`
`Inc. as an independent expert in the fields of pharmacy, pharmacology,
`
`pharmacodynamics, and pharmacometrics. My qualifications in these areas are
`
`established by my curriculum vitae. Ex. 2043. I am being compensated for the time
`
`I spend on this matter, but no part of my compensation depends on the outcome of
`
`this proceeding.
`
`II. QUALIFICATIONS
`A. Education
`2.
`I received a Bachelor of Science degree with distinction in Pharmacy
`
`from the University of Minnesota – College of Pharmacy in 1977. In 1985, I
`
`obtained a Pharm. D. from the same College of Pharmacy. In addition to my
`
`bachelor degree in Pharmacy, I have a Bachelor of Arts degree in Psychology from
`
`the College of Liberal Arts at the University of Minnesota.
`
`3.
`
`From 1983 to 1984, I was a clinical post-doctoral fellow at the St.
`
`Paul Ramset Medical Center in St. Paul, MN studying neuropharmacology,
`
`specifically in the area of anti-epilepsy medications.
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`Case No. IPR2015-01993
`U.S. Patent No. 8,399,514
`I was an American Society of Hospital Pharmacists fellow in Clinical
`
`4.
`
`Pharmacokinetics at the St. Paul Ramset Medical Center in St. Paul, MN. While
`
`there from 1984-85, I continued to study clinical neuropharmacology in epilepsy.
`
`5.
`
`I also obtained a Ph.D. in Pharmaceutics from the University of
`
`Minnesota in 1996. My dissertation research involved microdialysis, studying the
`
`brain distribution of drugs used for Alzheimer’s disease.
`
`B.
`6.
`
`Professional Experience
`
`After receiving my degree in pharmacy, I worked for over 15 years as
`
`a registered pharmacist. As a pharmacist, I prepared and dispensed various types of
`
`pharmaceutical dosage
`
`forms,
`
`including
`
`tablets, capsules, suppositories,
`
`suspensions, creams, as well as many others. I was familiar with a drug’s
`
`Prescribing Information and counseled many patients on the side effects associated
`
`with the drugs that I was dispensing. Until recently (2014), I was a licensed
`
`pharmacist in Minnesota.
`
`7.
`
`I began my academic career at the College of Pharmacy, Medical
`
`University of South Carolina as an Assistant Professor of Pharmacy. In that
`
`position, I researched clinical pharmacokinetics. My instructional responsibilities
`
`included Clinical Pharmacokinetics and Advance Disease Processes and
`
`Pharmacotherapeutics: Neurology Module. I was the course coordinator and
`
`primary lecturer for both courses. In addition, I was a preceptor for the
`
`2
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`Case No. IPR2015-01993
`U.S. Patent No. 8,399,514
`undergraduate clinical practice course and the Advanced Clinical Pharmacy
`
`preceptor for the Doctor of Pharmacy Program, which included courses on clinical
`
`pharmacokinetics, neurology, and applied pharmacokinetics research.
`
`8.
`
`In 1996, after receiving my Ph.D., I joined the College of Pharmacy at
`
`the University of Minnesota as a
`
`research associate,
`
`researching
`
`the
`
`pharmacokinetics and pharmacodynamics of HIV drugs. In 2002, I was appointed
`
`to Associate Professor of Experimental and Clinical Pharmacology. In 2008, I was
`
`promoted to Professor, and I hold that same position today. My research program
`
`involves the quantitative modeling of pharmacological systems for better
`
`understanding dose-response relationships.
`
`9.
`
`During my tenure at the University of Minnesota, I have taught both
`
`professional and graduate courses,
`
`including Applied Pharmacokinetics,
`
`Pharmacometrics, and Advanced Clinical Pharmacology. I have also taught a
`
`course in Clinical Trials Simulations, which involves designing and conducting
`
`computer-based clinical trials to explore optimal design elements (e.g., sample
`
`size, timing of sample collection, timing of outcome measures). In addition to my
`
`lecturing responsibilities at the University of Minnesota, I have taught over 60
`
`lectures, short courses, and workshops on
`
`topics
`
`including population
`
`pharmacokinetics, applications of nonlinear mixed-effects modeling in drug
`
`development, and a lecture entitled “Center for Forecasting Drug Response: The
`
`3
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`U.S. Patent No. 8,399,514
`Role of Pharmacometrics” at the Institute for Therapeutics Discovery and
`
`Development.
`
`10.
`
`In my research group, I currently supervise three graduate students,
`
`one post-doctoral fellow, and many professional-level students. Over my career, I
`
`have advised over twenty-five Ph.D. students in my laboratory, and have served as
`
`a member of the examining committee for over forty Ph.D. candidates.
`
`11. My work has been supported over the years by grants and contracts,
`
`including grants from the National Institutes of Health and several pharmaceutical
`
`companies.
`
`C.
`12.
`
`Publications
`
`I have published my research in peer-reviewed journals. To date, I
`
`have published over 90 papers in refereed journals. I have also published several
`
`book chapters. In addition, I regularly present my work at conferences and as an
`
`invited speaker.
`
`D. Honors and Awards
`13.
`In 2016, I received the Bristol-Myers Squibb Mentorship Award from
`
`the American College of Clinical Pharmacology. In 2014, I became a fellow in the
`
`inaugural class of the International Society of Pharmacometrics. In 2008, I
`
`received the Distinguished University Teaching Professor Award for Outstanding
`
`Contributions to Graduate and Professional Education. And in 1999, my paper,
`
`4
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`U.S. Patent No. 8,399,514
`“Microdialysis Studies of the Distribution of Stavudine into the Central Nervous
`
`System in the Freely-Moving Rat,” received the American Association of
`
`Pharmaceutical Scientists Meritorious Manuscript Award.
`
`E.
`14.
`
`Professional Organizations and Service Activities
`
`I am a member of and have served on committees of several
`
`professional societies, including the International Society of Pharmacometrics, the
`
`American College of Clinical Pharmacology, the American Society of Clinical
`
`Pharmacology and Therapeutics, and the American Association of Pharmaceutical
`
`Scientists.
`
`15.
`
`I have sat on the editorial boards of the British Journal of
`
`Pharmacology, the Journal of Pharmacokinetics and Pharmacodynamics, and the
`
`International Journal of Clinical Pharmacology and Therapeutics. I have also
`
`been an ad hoc manuscript reviewers for over 20 other journals, including Clinical
`
`Therapeutics, Journal of
`
`the American Pharmaceutical Association, and
`
`Pharmaceutical Research.
`
`16.
`
`I have participated in professional service activities. For example, I
`
`took the leadership roll in the creation of the International Society of
`
`Pharmacometrics, which brings together bioengineers, mathematicians, physicians,
`
`economists, pharmacists, pharmacologists, and biologists
`
`interested
`
`in
`
`the
`
`application of pharmacometric principles to model-based drug development. I have
`
`5
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`U.S. Patent No. 8,399,514
`also served on the Core Committee of the University of Minnesota Adults AIDS
`
`Clinical Trials Unit. I have also served on promotion and tenure review committees
`
`at, for example, the University of Colorado, the University of Maryland, and
`
`SUNY Buffalo.
`
`III. MATERIALS CONSIDERED
`17.
`I have been asked to consider U.S. Patent 8,399,514 (“the ’514
`
`patent,” Ex. 1001), the Petition (Paper 1) and Petitioner’s Reply (Paper 17), and
`
`certain documents raised in the Petition and the Board’s Institution Decision.
`
`18.
`
`I understand that Petitioner has asserted that a combination of Kappos
`
`2006 (Ex. 1003A), Joshi ’999 (Ex. 1030), ClinicalTrials (Ex. 1022), and the ICH
`
`Guideline (Ex. 1004) renders obvious claims 1-6, 8-16, and 20 of the ’514 patent.
`
`(Petition at 7, Ground 1.)
`
`19.
`
`I have been asked to offer my opinions regarding certain aspects of
`
`these grounds. In forming my opinions, I have considered the materials cited in this
`
`declaration and in the attached Appendix A. I may consider additional documents
`
`and information in forming any supplemental opinions. To the extent I consider
`
`additional documents or information, including any expert declarations in this
`
`proceeding, I may offer further opinions.
`
`6
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`U.S. Patent No. 8,399,514
`IV. OPINIONS IN SUPPORT OF BIOGEN’S RESPONSE TO PETITION
`A.
`Joshi ’999 Does Not Disclose a Daily Dose of DMF
`20.
`
`I understand that the Board has concluded that “Joshi ’999 teaches
`
`that a dosage of range of 10 to 300 mg/day is effective.” (Paper 20 at 25, citing
`
`Ex. 1030 at claim 2.) I disagree. As discussed in detail below, Joshi ’999 does not
`
`disclose a daily dose of dimethyl fumarate (DMF), let alone a daily dose of from
`
`10 to 300 mg per day.
`
`Expertise as a Pharmacist
`
`1.
`I am well-qualified to provide an opinion regarding the disclosure of
`
`21.
`
`Joshi ’999—a patent directed, among other subject matter, to pharmaceutical
`
`preparations. (Ex. 1030 at Abstract.) In 1977, I obtained a B.S. degree in pharmacy
`
`with distinction. In 1983, I received a doctor of pharmacy degree. I was a
`
`practicing pharmacist for about 15 years. Until about two years ago, I maintained
`
`my pharmacist
`
`license
`
`in Minnesota. I have extensive experience with
`
`pharmaceutical preparations, including compounding and dispensing them. During
`
`my pharmacy studies and professional career, I have had coursework and worked
`
`with doctors on dosing and therapeutic regimens.
`
`2.
`
`Preparations Are Distinct
`Pharmaceutical
`Therapeutic Regimens
`22. A pharmaceutical preparation, also known as a pharmaceutical dosage
`
`from
`
`form, is the form in which a drug substance is given. It is a combination of drug(s)
`
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`and excipients formulated to facilitate dosing, administration, and delivery of
`
`drug(s) to the patient. Dosage forms vary in form and include creams, gels,
`
`powders, capsules, infusions, lozenges, tablets, and suppositories, among other
`
`forms.
`
`23. A dosage form contains a certain amount of drug(s), which is
`
`administered according to a therapeutic regimen. A therapeutic regimen relates to
`
`the amount and frequency of administering a given dosage form. For example, a
`
`dosage form may be a solution for intravenous injection meant to be administered
`
`at a certain flow rate over a certain period of time. Another therapeutic regimen
`
`may include applying a cream on the skin three times a day. Yet another example
`
`is taking two tablets twice a day for one week. One unit of a pharmaceutical
`
`preparation will not necessarily include the same amount of drug required to
`
`administer the daily dose of that drug.
`
`24. Medical dictionaries define a daily dose as the total amount of a
`
`therapeutic substance (drug) that is to be taken within 24 hours. (Ex. 2053,
`
`STEDMAN’S MEDICAL DICTIONARY at 581 (28th ed. 2006) (“Daily dose” is “the
`
`total amount of a therapeutic substance that is to be taken within 24 hours.”); Ex.
`
`2054, BLAKISTON’S GOULD MEDICAL DICTIONARY at 404 (Arthur Osol et al. eds.,
`
`3rd ed. 1972) (“Daily dose” is “the total amount of a medicinal to be administered
`
`in 24 hours.”); Ex. 2061, DORLAND’S ILLUSTRATED MEDICAL DICTIONARY at 402
`
`8
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`U.S. Patent No. 8,399,514
`(26th ed. 1981) (“Daily dose” is “the total amount of a drug administered in a 24-
`
`hour period.”).) These definitions comport with my understanding and experience
`
`as a pharmacist.
`
`3.
`
`Joshi ’999 Describes the Amount of DMF Present in a
`Pharmaceutical Preparation, Not a Daily Dose
`
`25.
`
`Joshi ’999 does not disclose a daily dose of DMF. Instead, it describes
`
`the amount (in mg) of DMF present in the disclosed pharmaceutical preparations.
`
`Specifically, Joshi ’999 describes pharmaceutical preparations containing certain
`
`dialkyl fumarates. (Ex. 1030 at Abstract.) Joshi ’999 states that the amounts to be
`
`used are selected in such a manner that the preparations contain the active
`
`ingredient in an amount corresponding to 10 to 300 mg of fumaric acid. (Ex. 1030
`
`at 4:42-45.) It therefore indicates that preferred preparations contain a total
`
`amount of 10 to 300 mg DMF and/or diethyl fumarate. (Ex. 1030 at 4:46-48.)
`
`Consistent with this disclosure, Joshi ’999 includes production examples to make
`
`DMF-containing capsules. Example 1 of Joshi ’999 discloses a method for
`
`preparing a pharmaceutical preparation containing 120 mg DMF. (Ex. 1030 at
`
`Example 1; see also Ex. 1005 at ¶ 23.1.) Examples 2, 3, and 4 likewise provide
`
`methods of preparing pharmaceutical preparations containing 120 mg, 50 mg, and
`
`110 mg, respectively, of DMF per pharmaceutical preparation. (Ex. 1030 at
`
`Examples 2-4.) These disclosures refer to an amount of DMF in a pharmaceutical
`
`preparation, not to a daily dose.
`
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`U.S. Patent No. 8,399,514
`26. The Board relies on the claims of Joshi ’999 in concluding that Joshi
`
`’999 discloses a daily dose of from 10 mg to 300 mg per day. Yet the claims
`
`provide no such disclosure.
`
`27. Claim 1 states:
`
`A method of treating multiple sclerosis comprising
`treating a patient in need of treatment for multiple
`sclerosis with an amount of a pharmaceutical preparation
`effective for treating said multiple sclerosis, wherein the
`only active ingredient for the treatment of multiple
`sclerosis present in said pharmaceutical preparation is
`dimethyl fumarate.
`
`(Ex. 1030 at 8:14-19.)
`
`28. Claim 1 indicates that a patient must take enough units (one or more)
`
`of a pharmaceutical preparation containing DMF to treat multiple sclerosis (MS).
`
`If the pharmaceutical preparation is a capsule, for example, one would administer
`
`one or more capsules containing DMF to the MS patient. Nothing in claim 1 refers
`
`to a daily dose of DMF.
`
`29. The Board uses claim 2 to conclude that 10 to 300 mg is an effective
`
`daily dose of DMF to treat MS. (Paper 20 at 25.) I disagree with that conclusion.
`
`Consistent with my understanding of the Joshi ’999 specification and claim 1,
`
`claim 2 simply specifies that the pharmaceutical preparation (e.g., a capsule) of
`
`claim 1 contains an amount of from 10 to 300 mg of DMF. It does not state nor
`
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`U.S. Patent No. 8,399,514
`mean that 10 to 300 mg of DMF is administered per day. In fact, neither claim 1
`
`nor claim 2 includes any time component.
`
`30. Thus, in my opinion and based on my experience and expertise, Joshi
`
`’999 refers to an amount of DMF present in a pharmaceutical preparation, not to a
`
`daily dose.
`
`B.
`The Dose-Response of DMF Was Not Well-Defined
`31. The Board has relied on available dose-response information for DMF
`
`to conclude that a person of ordinary skill in the art would have selected a dose of
`
`480 mg/day and had a reasonable expectation that such a dose would be effective
`
`in treating MS. But these conclusions are unsupported by the limited dose-response
`
`data available for DMF before the 2007 filing of Biogen’s application.
`
`Expertise as a Clinical Pharmacologist
`
`1.
` My education and research as a clinical pharmacologist make me
`
`32.
`
`well-suited to provide opinions regarding any dose-response relationship for DMF
`
`and the impact of that information on an untested daily dose (i.e., 480 mg/day).
`
`Since 1996, I have researched exposure (dose)-response relationships of
`
`therapeutic agents primarily in the area of HIV, epilepsies, transplantation, and
`
`endocrinology. The purpose of my research is to determine the appropriate dose for
`
`a given pharmaceutical agent, and to achieve that I study the dose-response
`
`relationship for that agent. As a result of my work, the FDA approved certain doses
`
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`for pediatric use of efavirenz. (Ex. 2055, Starr, S.E. et al., “Combination Therapy
`
`With Efavirenz, Nelfinavir, and Nucleoside Reverse-Transcriptase Inhibitors in
`
`Children Infected with Human Immunodeficiency Virus Type 1,” New Engl. J.
`
`Med. (1999) 341(25):1874-1881.) I have also taught graduate-level courses,
`
`including Pharmacometrics; Population Pharmacokinetics; and Advanced Topics
`
`in Pharmacometrics. In these courses, I teach the principles used to evaluate and
`
`define exposure response-relationships. I have been teaching these courses for 15
`
`years.
`
`2.
`
`Based on the Limited Dose-Response Information Available
`for DMF in MS, No Reason Existed to Choose a Dose of 480
`mg/day or to Expect That It Would Work
`33. Kappos 2006 discloses that a daily dose of 720 mg/day of DMF in MS
`
`patients showed a statistically significant reduction in brain lesions versus placebo.
`
`(Ex. 1003A.) Kappos 2006 also reported that DMF reduced brain-lesion activity in
`
`those patients in a “dose-dependent” manner. (Ex. 1003A.) A May 2006 press
`
`release regarding that same study indicates that daily doses of 120 mg/day and 360
`
`mg/day did not demonstrate statistically significant differences from placebo. (Ex.
`
`2057, May 2006 Press Release.) A daily dose of 480 mg/day was not disclosed or
`
`tested in the Phase 2 Kappos study (Ex. 1003A), and I have not seen any dose-
`
`response data for that particular dose before the February 2007 filing date.
`
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`34. The press release also reported that subjects in the Phase 2 study most
`
`commonly experienced flushing, gastrointestinal disorders, headache, and
`
`nasopharyngitis. (Ex. 2057.) Those adverse events occurred in the three active
`
`treatments groups (120 mg/day, 360 mg/day, 720 mg/day) from 2% to 8% of the
`
`time compared to 5% for placebo. (Ex. 2057; Ex. 2058, Kappos, L., et al., Lancet
`
`(2008) 372:1463-1472 at Table 3, 1471.) This means that at least one, and perhaps
`
`two, of the active arms had an adverse event rate below that observed for placebo.
`
`One cannot know which active treatment group resulted in the 8% adverse event
`
`rate, but it could have been one of the two lower tested doses.
`
`35. Despite the fact that Kappos 2006 established an effective dose (720
`
`mg/day) having side effects similar to placebo, both Petitioner and the Board
`
`maintain that a person of ordinary skill not only would have chosen a lower dose,
`
`but would have chosen a dose of about 480 mg/day. The dose-response
`
`information available for DMF, however, does not support that conclusion.
`
`36. Based on Kappos 2006 and Biogen’s press release, little or no
`
`information was available at that time about the shape of the dose-response curve
`
`for DMF in MS between the 360 mg/day and 720 mg/day doses.
`
`37.
`
`I would expect that doses closer to 360 mg/day would have responses
`
`more similar to 360 mg/day, and doses closer to 720 mg/day would behave more
`
`like the response for 720 mg/day. In other words, I would expect a dose of 480
`
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`mg/day of DMF to have a measured response more like 360 mg/day than 720
`
`mg/day because 480 mg/day is closer to 360 mg/day than it is to 720 mg/day.
`
`Similarly, I would expect doses closer to 720 mg/day, such as 600 mg/day, to be
`
`more similar to the response at 720 mg/day than 360 mg/day. These expectations
`
`are based on both basic pharmacology principles and my personal experience in
`
`this field. As a result, a person of ordinary skill in the art would not have had any
`
`reason to select a dose of 480 mg/day of DMF because the tested dose of 360
`
`mg/day possessed a response not statistically different than placebo.
`
`38.
`
`In addition, based on what was known at the time it remained possible
`
`that administering an even higher dose of DMF than 720 mg/day would have led to
`
`a greater measured response with no increase in adverse drug effects.
`
`39.
`
`In sum, I would expect that 480 mg/day of DMF to show some
`
`increase in response compared to 360 mg/day based on the statement in Kappos
`
`2006 that BG00012 (DMF) significantly reduced brain lesion activity in a dose-
`
`dependent manner. But because the art lacked a well-defined dose-response curve
`
`for DMF in MS, one could not know whether a dose of 480 mg/day of DMF would
`
`be statistically significantly different from placebo (efficacious) or not. Any such
`
`conclusion would be scientifically unsupported based on the limited scientific
`
`information available at the time. As a result, based on the limited disclosure of
`
`Kappos 2006, a person of ordinary skill would not have had a reasonable
`
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`expectation that a dose of 480 mg/day of DMF would be a therapeutically effective
`
`daily dose to treat MS, let alone as effective as the tested 720 mg/day dose.
`
`C. The ICH Guideline Is Not a Mandate to Find the Perfect Dose
`40. Petitioner contends that the ICH Guideline “instructed” a person of
`
`ordinary skill in the art to perform dosing studies as “standard procedure” to allow
`
`study of the proper dose range during Phase 3 studies. (Ex. 1005 at ¶ 32.)
`
`41.
`
`In addition, the Board excerpts quotations from the ICH Guideline
`
`regarding individual dose-response studies. Based on those selections, the Board
`
`concludes that “[t]he ICH Guideline provides convincing evidence of how a person
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`of ordinary skill in the art likely would go about determining an appropriate dosage
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`for a particular person having multiple sclerosis.” (Paper 20 at 21, emphasis
`
`added.)
`
`42.
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`I disagree with this conclusion. First, the ICH Guideline does not
`
`address individuals having MS, or any particular disease at all. Second, it
`
`acknowledges that study designs that allow estimation of individual patient dose-
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`response curves are very limited. (Ex. 1004 at 6.) It also acknowledges that when
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`the study endpoint or adverse effect is delayed, persistent, or irreversible (as is the
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`case with MS, (Ex. 2044 ¶¶ 60-62), obtaining
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`individual-dose response
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`information is typically not possible. (Ex. 1004 at 9.)
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`1.
`Relevant Expertise
`43. Here again, I am well-qualified to provide my opinion regarding the
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`ICH Guideline. The principles that I apply in my work are similar to those
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`identified in the ICH Guideline. Further, as mentioned above, I have designed and
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`executed clinical trials. (Supra at ¶¶ 9, 32.)
`
`2.
`
`The ICH Guideline Provides Only General Guidance to
`Support Drug Registration
`44. The ICH Guideline is a set of general guidelines for generating dose-
`
`response information to support drug registration. It applies to drugs and biologics
`
`with widely different mechanisms of action to treat various diseases and
`
`conditions. It was prepared by the Efficacy Expert Working Group of the ICH, and
`
`is intended to help ensure that dose-response information is generated according to
`
`sound scientific principles. (Ex. 2059, International Conference on Harmonisation;
`
`Dose-Response Information to Support Drug Registration; Guideline; Availability,
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`59 Fed. Reg. 55972 (Nov. 9, 1994).)
`
`45. The ICH Guideline does not discuss MS. It also does not provide
`
`specific recommendations regarding the magnitude of any dose adjustment for MS
`
`or any other illness.
`
`46. The ICH Guideline indicates that, ideally, exposure-response curves
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`would be characterized in each individual for a particular drug, so that the
`
`“smallest dose with a discernible useful effect or a maximum dose beyond which
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`no further beneficial effects is seen.” (Ex. 1004 at 5.) But, as noted by the ICH
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`Guideline, such “practical study designs do not exist to allow for precise
`
`determination of these doses.” (Ex. 1004 at 5, emphasis added.) In other words, the
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`ICH Guideline starts with the understanding that the ideal is impossible and then
`
`provides alternative methods to obtain sound dose-response data from which
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`informed decisions regarding a starting dose can be selected.
`
`47. According to the ICH Guideline, what is “most helpful” when
`
`determining an appropriate therapeutic dose during drug development is to
`
`understand the shape of the population average dose-response curves for both
`
`desired (efficacy) and undesired (side effects/toxicity) effects. (Ex. 1004 at 5.) But
`
`knowledge of the shape of a dose-response curve does not dictate a particular dose.
`
`Instead, as the ICH Guideline makes clear, “[v]alid dose-response data allow”
`
`judgment calls regarding an appropriate dose of a given drug. (Ex. 1004 at 5-6.)
`
`For example, different physicians and even different regulatory authorities might
`
`reach different conclusions reviewing the same data. (Ex. 1004 at 5.) The ICH
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`Guideline simply provides guidance on how to generate useful data, so that
`
`regulatory authorities can make informed, reasonable decisions regarding dosing.
`
`48. The ICH Guideline provides approaches to obtain valid dose-response
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`data from which such judgment calls can be made. While several trial designs exist
`
`to characterize dose-response curves, the ICH Guideline describes four of them:
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`parallel dose-response, cross-over dose-response, forced titration, and optional
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`titration trial designs. (Ex. 1004 at 10-12.) Each of these trial designs has
`
`advantages and disadvantages. Parallel dose-response studies provide average
`
`population exposure-response (Ex. 1004 at 10), whereas cross-over and titration
`
`studies can provide individual dose-response information (Ex. 1004 at 11-12). The
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`latter studies, however, are typically useful only where the effect is rapid and
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`where the measured effect dissipates rapidly when therapy is stopped. (Ex. 1004 at
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`9, 11-12.)
`
`3.
`
`A Parallel Dose-Response Study Design Is Appropriate for
`MS
`49. For diseases such as MS in which the study endpoint or adverse effect
`
`is delayed, persistent, or irreversible, a parallel dose-response study is usually
`
`needed. (Ex. 1004 at 9; Ex. 2044 ¶¶ 60-62.) But, as mentioned, a parallel dose-
`
`response study does not provide individual dose-response data.
`
`50. Dose-response for MS cannot be assessed by a cross-over dose-
`
`response study because the drug effect does not develop rapidly and patients do not
`
`return to baseline conditions quickly after cessation of therapy. (Ex. 2044 ¶¶ 60-
`
`62.) In fact, as the ICH Guideline states, a “critical disadvantage” of the force
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`titration study design is that it cannot distinguish response to increased dose from
`
`response to increased time on drug therapy or a cumulative dose effect. (Ex. 1004
`
`at 12.) Such a design is “unsatisfactory” when response is delayed, exactly as it is
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`in MS. (Ex. 1004 at 12; Ex. 2044 ¶¶ 60-62.) These cross-over dose-response and
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`forced titration studies (inappropriate for MS) allow for individual dose-response
`
`information, but parallel group designs (appropriate for MS) do not and only
`
`provide mean data for each dose studied. (Ex. 1004 at 11.)
`
`51. Thus, the Board’s conclusion that the ICH Guideline instructs a
`
`person of ordinary skill in the art to modify a dose for a particular MS patient is
`
`unfounded. First, the ICH Guideline is not meant to provide a treating physician
`
`with dosing guidance for a particular patient. Instead, it provides guidelines to drug
`
`developers during drug development for generating dose-response information to
`
`support regulatory approval. Second, the ICH Guideline demonstrates that for a
`
`disease such as MS, individual dose-response information is very difficult, if not
`
`impossible, to generate.
`
`4. Kappos 2006 Is Consistent With the ICH Guideline
`52. Kappos 2006 is consistent with the ICH Guideline. Kappos 2006
`
`employed a parallel dose-response trial design. (Ex. 1003A.) This was appropriate
`
`because MS is a disease in which the dose-response takes time to develop, and the
`
`effect may be cumulative where several different doses are administered. (Ex.
`
`2044 ¶ 61.)
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`53. The ICH Guideline advises that it is “prudent” to carry out dose-
`
`ranging studies early in drug development. (Ex. 1004 at 13.) Kappos 2006 reports
`
`the results of an early Phase 2 study. (Ex. 1003A.)
`
`54. The ICH Guideline indicates that the parallel, randomized dose-
`
`response study is a “widely used, successful and acceptable design.” (Ex. 1004 at
`
`13.) Kappos 2006 was just such a study. (Ex. 1003A.) The ICH Guideline states
`
`that two active treatment groups in addition to a placebo is the minimum number
`
`of doses that is desirable. (Ex. 1004 at 13.) Kappos 2006 used four doses (placebo,
`
`120 mg