UNITED STATES PATENT AND TRADEMARK OFFICE
`________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2018-01403
`Patent 8,399,514 B2
`____________________________________________
`
`
`
`DECLARATION OF RICHARD C. BRUNDAGE, PHARM. D., PH.D.
`
`
`
`
`
`Biogen Exhibit 2057
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 96
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`
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`I. 
`II. 
`
`Table of Contents
`
`INTRODUCTION ........................................................................................... 1 
`QUALIFICATIONS ........................................................................................ 1 
`A. 
`Education ............................................................................................... 1 
`B. 
`Professional Experience ........................................................................ 2 
`C. 
`Publications ........................................................................................... 4 
`D.  Honors and Awards ............................................................................... 4 
`E. 
`Professional Organizations and Service Activities ............................... 5 
`PREVIOUS TESTIMONY FOR BIOGEN ..................................................... 6 
`III. 
`IV.  MATERIALS CONSIDERED ........................................................................ 6 
`V. 
`THE ASSERTED REFERENCES AND MYLAN’S ADDITIONAL
`CITATIONS .................................................................................................... 7 
`A. 
`Schimrigk 2004 (Ex. 1006) ................................................................... 7 
`B. 
`Biogen’s Phase II MS Trial ................................................................... 9 
`1. 
`January 2006 Press Release (Ex. 1005) ...................................... 9 
`2. 
`ClinicalTrials (Ex. 1010) ............................................................ 9 
`3. 
`Kappos 2006 (Ex. 1007) ........................................................... 10 
`Joshi ’999 (Ex. 1009) .......................................................................... 11 
`C. 
`ICH Guidelines (Ex. 1011) .................................................................. 12 
`D. 
`VI.  OPINIONS IN SUPPORT OF BIOGEN’S RESPONSE TO
`PETITION ..................................................................................................... 14 
`A. 
`Schimrigk 2004 and the January 2006 Press Release Do Not
`Provide Any Motivation to Go Below a Dose of 720 mg/day of
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`2. 
`
`3. 
`
`C. 
`
`DMF with a Reasonable Expectation of Success for Treating
`MS ....................................................................................................... 14 
`1.  Mylan’s Ground 1 Combination Does Not Disclose Each
`and Every Element of the Claims ............................................. 14 
`The Combined Teachings of the January 2006 Press
`Release and Schimrigk 2004 Do Not Describe an
`Effective Dose Range of DMF for Treating MS ...................... 15 
`The References Asserted in Ground 1 Do Not Provide
`Any Reason to Target a Daily Dose of 480 mg/day of
`DMF .......................................................................................... 17 
`The References of Ground 1 Do Not Provide Any
`Reasonable Expectation of Success .......................................... 21 
`B.  Mylan and Its Experts Over-simplify Any Connection Between
`Psoriasis and MS ................................................................................. 23 
`The Prior Art Did Not Define an Effective Dose Range, and the
`Dose-Response of DMF Was Not Well-Defined ................................ 25 
`1. 
`Expertise as a Clinical Pharmacologist ..................................... 26 
`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 ......... 27 
`D.  Mylan’s Scientifically Invalid After-the-Fact Calculations on
`the Results Reported in Kappos 2006 Do Not Change My
`Opinion ................................................................................................ 30 
`The ICH Guideline Is Not a Mandate to Find the Perfect Dose ......... 34 
`1. 
`Relevant Expertise .................................................................... 35 
`2. 
`The ICH Guideline Provides Only General Guidance to
`Support Drug Registration ........................................................ 35 
`A Parallel Dose-Response Study Design Is Appropriate
`for MS ....................................................................................... 37 
`
`4. 
`
`3. 
`
`E. 
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`F. 
`
`4. 
`Kappos 2006 Is Consistent With the ICH Guideline ................ 39 
`ClinicalTrials Provides No Reason to Lower the Dose of DMF
`to 480 mg/day ...................................................................................... 40 
`VII.  CONCLUSION .............................................................................................. 41 
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`I.
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
`
`
`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. Appendix A. 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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`1
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`4.
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`I was an American Society of Hospital Pharmacists fellow in Clinical
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`Pharmacokinetics at the St. Paul Ramset Medical Center in St. Paul, MD. While
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`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. I was a practicing pharmacist for about 15 years. Until
`
`about 5 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.
`
`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
`
`2
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`Pharmacokinetics
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`and Advance Disease
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`Processes
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`and
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`Clinical
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`Pharmacotherapeutics: Neurology Module. I was the course coordinator and primary
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`lecturer for both courses. In addition, I was a preceptor for the 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 Pharmacokinetics. 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
`
`3
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`courses, and workshops on
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`topics
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`including population pharmacokinetics,
`
`applications of nonlinear mixed-effects modeling in drug development, and a lecture
`
`entitled “Center for Forecasting Drug Response: The Role of Pharmacometrics” at
`
`the Institute for Therapeutics Discovery and Development.
`
`10.
`
`In my research group, I currently supervise one graduate student and
`
`one post-doctoral fellow. 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 fifty Ph.D. candidates at the University of Minnesota, nationally, and
`
`internationally.
`
`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 110 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
`
`4
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`inaugural class of the International Society of Pharmacometrics. In 2008, I received
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`the Distinguished University Teaching Professor Award for Outstanding
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`Contributions to Graduate and Professional Education. And in 1999, my paper,
`
`“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. I am presently on the Board of Regents of the American College of
`
`Clinical Pharmacology.
`
`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 reviewer for over 20 other journals, including Clinical
`
`Therapeutics, Journal of
`
`the American Pharmaceutical Association, and
`
`Pharmaceutical Research.
`
`5
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`16.
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`I have participated in professional service activities. For example, I
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`
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`took the leadership role 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
`
`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. PREVIOUS TESTIMONY FOR BIOGEN
`17.
`I previously testified on behalf of Biogen in its IPR2015-01993 relating
`
`to U.S. Patent 8,399,514 (“the ’514 patent,” Ex. 1001). That proceeding is referred
`
`to as Coalition II in this declaration. My declaration was submitted as Ex. 2042 in
`
`that proceeding and resubmitted herein as Ex. 2198. Petitioner in Coalition II did
`
`not take my deposition.
`
`IV. MATERIALS CONSIDERED
`18.
`I have been asked to consider Biogen’s ’514 patent, the Petition, and
`
`certain documents raised in the Petition.
`
`19.
`
`I understand that Petitioner has asserted in four grounds of
`
`unpatentability that the claims of the ’514 patent are obvious over various
`
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`combinations of Schimrigk 2004 (Ex. 1006), a January 2006 Press Release
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`U.S. Patent No. 8,399,514
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`(Ex. 1005), WO 2006/037342 (Ex. 1008), Kappos 2006 (Ex. 1007), Joshi ’999
`
`(Ex. 1009), ClinicalTrials (Ex. 1010), and the ICH Guideline (Ex. 1011).
`
`20.
`
`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 B. 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.
`
`V. THE ASSERTED REFERENCES AND MYLAN’S ADDITIONAL
`CITATIONS
`A.
`Schimrigk 2004 (Ex. 1006)
`21. Schimrigk 2004 is a short abstract reporting the results of an
`
`exploratory, prospective, open-label Phase II study of oral fumarate therapy for the
`
`treatment of relapsing remitting MS (“RRMS”). (Ex. 1006 at 4-5.) The objective of
`
`the study was to “evaluate the safety and efficacy of oral fumarate therapy
`
`(Fumaderm) in patients with [RRMS].” The study enrolled 10 patients, only 7 of
`
`whom completed the study by the time Schimrigk 2004 was published.
`
`22. DMF as the sole active ingredient was not tested in Schimrigk 2004.
`
`Instead, the oral fumarate therapy was administered in the form of Fumaderm®,
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`which contains a combination of DMF and monoethyl fumarate salts (Ex. 1020).
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`The oral fumarates were administered in two treatment phases at two different dose
`
`levels (6 and 3 Fumaderm® tablets, respectively) with a washout period in between
`
`the treatment phases.
`
`23. Schimrigk 2004 is not a dose ranging study, and its design precludes
`
`being able to attribute any efficacy to the 3 Fumaderm tablet dose used in the second
`
`phase. In this regard, it provides no indication that the effects of the first treatment
`
`phase (6 tablets) of oral fumarates administered had abated by the time the second
`
`treatment phase (3 tablets) began or any time during the second treatment phase.
`
`While Schimrigk 2004 explains that the first phase 6-tablet dose led to a statistically
`
`significant reduction from baseline in the number and volume of Gd+ lesions after
`
`12 weeks of treatment, it does not—and indeed it could not—attribute any effect
`
`specifically to the 3-tablet second treatment phase dose. Nor does Schimrigk 2004
`
`provide any information of efficacy relative to placebo, as Schimrigk 2004 did not
`
`include a placebo control; instead, each patient was used as his own comparator.
`
`24. The authors generally hypothesized that “oral fumarates [and not DMF
`
`only] may be a promising new treatment for RRMS,”1 without providing any
`
`
`1 Emphasis added unless otherwise indicated.
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`information regarding a dose-response relationship for Fumaderm® or DMF.
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`(Ex. 1006 at 5.)
`
`B.
`
`Biogen’s Phase II MS Trial
`1.
`January 2006 Press Release (Ex. 1005)
`25. A press release dated January 2006 made a limited statement about a
`
`Phase II study of BG-12, which is a DMF-only oral drug product. The January 2006
`
`Press Release reported that the study was designed to evaluate the efficacy and safety
`
`of BG-12 and that the study “met its primary endpoint” for RRMS. Ex. 1005 at 1. It
`
`also states that “[t]reatment with BG-12 led to a statistically significant reduction in
`
`the total number of gadolinium-enhancing brain lesions as measured by MRI with
`
`six months of treatment versus placebo.” Id. The press release does not disclose the
`
`specifics of the trial design, the doses tested, the dose or doses that led to the reported
`
`statistically significant reduction in Gd+ lesions compared to placebo, or any data.
`
`2.
`ClinicalTrials (Ex. 1010)
`26. Mylan also relies on ClinicalTrials in one of its grounds of
`
`unpatentability. DMF is identified as the active ingredient in BG00012. The
`
`document discloses four doses of BG00012 to be tested: 0 mg/day (placebo), 120
`
`mg/day, 360 mg/day, and 720 mg/day. It also indicates that the primary endpoint is
`
`the total number of Gd-enhancing lesions over four scans at weeks 12, 16, 20, and
`
`24. It does not include any results.
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`27. Although ClinicalTrials states that “[d]ose reduction will be allowed
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`for subjects who are unable to tolerate investigational drug,” (Ex. 1010 at 4), it does
`
`not provide any details about how such dose reduction will be implemented. For
`
`example, it does not clarify to what dose a patient will be reduced in any of the
`
`treatment groups. I also note that the statement about dose reduction applies equally
`
`to the placebo group and is not specific to DMF. In particular, ClinicalTrials says
`
`that dose reduction will be allowed for those patients who are unable to tolerate
`
`“investigational drug.” (Ex. 1010 at 4.) ClinicalTrials defines “investigational drug”
`
`as BG00012 or placebo. (Id. at 3)
`
`3. Kappos 2006 (Ex. 1007)
`28. Kappos 2006 is an abstract reporting certain results of Biogen’s Phase
`
`II study. It was not published until several months after the press release in January
`
`2006. It provides the objective of the study, certain details about the study design,
`
`and reports that “BG00012 (720 mg/day [of DMF]) significantly reduced the mean
`
`number of new Gd+ lesions (the primary end point) compared with placebo.”
`
`Ex. 1007 at 27. It also 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.” (Id.) It does not state, however, that any other doses of
`
`BG00012 provided an effect statistically different from placebo. Kappos 2006
`
`indicates that patients were randomized, and were permitted to be included in the
`
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`study in the absence of any baseline lesions. (Id. at 27 (“[P]atients must have had
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`U.S. Patent No. 8,399,514
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`either ≥ 1 relapse within 12 months prior to randomization or gadolinium-enhancing
`
`(Gd +) lesions on cranial MRI at screening.”)
`
`C.
`29.
`
`Joshi ’999 (Ex. 1009)
`Joshi ’999 discloses the use of certain dialkyl fumarates for the
`
`preparation of pharmaceutical preparations, such as micro-tablets or pellets. Joshi
`
`’999 does not disclose a daily dose of DMF.2 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. 1009 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. 1009 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. 1009 at 4:46-48.) Dr. Benet agrees with this
`
`characterization. (Ex. 1003 ¶ 69.)
`
`30.
`
`Joshi ’999 focuses on formulating certain dialkyl fumarates, including
`
`DMF, in dosage forms that ameliorate side effects associated with administering free
`
`
`2 Joshi ’999 does not teach a daily dosage range of DMF, as explained in my previous
`
`testimony, which I incorporate here as Ex. 2198.
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`fumaric acids. (Ex. 1009 at 3:14-15 (“The preparations according to the invention
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`do not contain any free fumaric acids per se.”).) Such dosage forms include tablets,
`
`micro-tablets, pellets or granulates, optionally in capsules or sachets. (Ex. 1009 at
`
`4:31-38.) Joshi ’999 teaches that “[b]y 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 are administered but is still
`
`observed, may be further reduced vis-à-vis fumaric acid derivatives and salts.”
`
`(Ex. 1009 at 5:29-33.)
`
`D.
`ICH Guidelines (Ex. 1011)
`31. The ICH Guidelines provide general guidance to drug developers on
`
`how to obtain dose-response information to support drug registration for a wide
`
`variety of divergent therapies for unrelated diseases. (Ex. 1011 at 5-12.) It describes
`
`four trial designs to generate dose-response information: parallel dose-response,
`
`cross-over dose-response, forced titration, and optional titration studies. (Ex. 1011
`
`at 9-12.) Parallel dose-response studies provide only population-average dose-
`
`response information whereas cross-over dose-response, forced titration, and
`
`optional titration studies also provide individual dose-response information. (Ex.
`
`1011 at 5-12.) I note that these latter types of studies do not apply to MS. (Ex. 1011
`
`at 6, 9, 11-12.)
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`32. For example, individual dose-response information may be obtained
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`
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`when the drug has an easily measurable, rapid effect that quickly dissipates when
`
`treatment is discontinued. (Ex. 1011 at 9, 11-12.) That is not the case for MS whose
`
`disease course and treatment are highly variable from one patient to another and
`
`whose lifetime disease course progresses even with no outward symptoms. As a
`
`result, 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. 1011, 9.)
`
`33. For disease-modifying treatments such as DMF for MS, I understand
`
`that individual dose titration to determine the optimal effective dose for individual
`
`patients is not possible because MS is highly variable from one patient to another
`
`and disease activity varies over time within individual patients. For these reasons,
`
`clinical trials of disease-modifying treatments in MS use large groups of patients and
`
`compare the average response of the treated group to the average response of the
`
`placebo group to determine efficacy. I further understand that physicians cannot, and
`
`do not, reduce the dose of disease-modifying therapy with an expectation of
`
`achieving the same efficacy established in a large well-controlled trial for an
`
`individual MS patient. To the extent that Mylan attempts to argue that dose-titration
`
`according to a dose-response curve for MS is possible and practical, it is not.
`
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`Case No. IPR2018-01403
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`
`VI. OPINIONS IN SUPPORT OF BIOGEN’S RESPONSE TO PETITION
`A.
`Schimrigk 2004 and the January 2006 Press Release Do Not
`Provide Any Motivation to Go Below a Dose of 720 mg/day of DMF
`with a Reasonable Expectation of Success for Treating MS
`1. Mylan’s Ground 1 Combination Does Not Disclose Each and
`Every Element of the Claims
`34. Neither the January 2006 Press Release nor Schimrigk 2004 says
`
`anything about a daily dose of 480 mg/day of DMF monotherapy.
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`35. Schimrigk 2004, as mentioned above, is limited to a very small, open-
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`label exploratory study that administered Fumaderm®, a composition of multiple
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`oral fumarates. Fumaderm® and a DMF-only product are two different drugs with
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`different active ingredients. In particular, Fumaderm® contains 120 mg of DMF and
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`95 mg of additional fumarate salts (Ex. 1020 at 2), all of which are active ingredients
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`with inseparable effects. (E.g., Ex. 1003 ¶ 36.) In contrast, a DMF-only dosage form
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`contains a single active ingredient—DMF. As such, Schimrigk 2004, which studied
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`only Fumaderm®, cannot tell a person of ordinary skill in the art anything about the
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`effectiveness of any individual fumarate by itself much less any particular dose of
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`DMF monotherapy. Thus, Schimrigk 2004 does not describe or suggest a DMF
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`monotherapy in any particular dose.
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`36. The January 2006 Press Release also fails to describe or suggest each
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`element of the claim. It does not ascribe the reported effect to any dose. It does not
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`even indicate which doses of DMF were tested. In an effort to gap-fill this
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`deficiency, Dr. Benet refers to ClinicalTrials and a 2005 Kappos presentation.
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`U.S. Patent No. 8,399,514
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`(Ex. 1003 ¶ 132 (citing Exs. 1015, 1034); Ex. 1002 ¶ 125 (same); id. at 148 (same).)
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`The January 2006 Press Release, however, never mentions the doses that were
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`tested, nor does it explain which dose met the primary endpoint. The January 2006
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`Press Release thus provides no information about any individual fumarate by itself
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`much less any particular effective dose of DMF for treating MS, and it certainly
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`never mentions or even suggests that a daily dose of 480 mg/day (a dose that was
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`not tested in Phase II) would be effective to treat MS.
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`2.
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`The Combined Teachings of the January 2006 Press Release
`and Schimrigk 2004 Do Not Describe an Effective Dose
`Range of DMF for Treating MS
`37. Dr. Benet asserts that “[t]he Schimrigk 2004 Abstract discloses that
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`Fumaderm® at doses of 360 mg/day and 720 mg/day DMF was effective in treating
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`patients with RRMS.” (Ex. 1003 ¶ 133; see also id. ¶¶ 144-145.) I disagree with this
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`statement for several reasons. First, Fumaderm® is not DMF. It includes multiple
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`active ingredients, the effects of which are inseparable in the Schimrigk study.
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`Second, Schimrigk 2004 did not show that the 3-tablet dose of Fumaderm® was
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`effective in treating patients with MS.
`
`38. Schimrigk 2004 did not use a DMF-only product. As a result,
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`Schimrigk 2004 cannot demonstrate a range of effective doses for DMF
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`monotherapy. At best, Schimrigk 2004 provides information regarding the actual
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`U.S. Patent No. 8,399,514
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`pharmaceutical drug product that was tested, in this case Fumaderm®.
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`39. Schimrigk 2004 does not, and cannot, describe any particular effect for
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`the 3-tablet dose of Fumaderm® (645 mg fumarates) because of the trial design itself.
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`In particular, the patients in the study first received a 6-tablet dose of Fumaderm®
`
`(1,290 mg fumarates). (Ex. 1006 at 5; Ex. 1020 at 2.) During this treatment phase,
`
`specifically after 12 weeks, with the 6-tablet Fumaderm® dose, Schimrigk 2004
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`reports a statistically significant reduction in Gd+ lesions and volume but without
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`providing any underlying lesion data. After a washout period, the patients were then
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`maintained on a 3-tablet daily dose of Fumaderm® (645 mg fumarates). (Ex. 1006
`
`at 5; Ex. 1020 at 2.) From this trial design, it is impossible to determine whether any
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`efficacy from the initial 6-tablet daily dose persists into the “washout” period and
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`beyond into the next 3-tablet daily dose treatment phase. As a result, one cannot
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`draw any conclusions about the possible efficacy of the 3-tablet daily dose treatment
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`phase. Any reliance on Schimrigk 2004 is further undermined by the fact that
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`reportedly only 7 patients completed the trial and the absence of any placebo control.
`
`40. Thus, Schimrigk 2004 does not teach that 3 tablets of Fumaderm®, let
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`alone 360 mg/day of DMF as monotherapy, would be effective to treat MS.
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`Consequently, it fails to provide any information about a dose-response curve for
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`Fumaderm®, and certainly not for DMF monotherapy.
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`41. The January 2006 Press Release does not attribute the reported result to
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`
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`any particular dose. Therefore, it does not demonstrate that a daily dose of 360
`
`mg/day of DMF is (or would be) effective to treat MS. Instead, as mentioned, the
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`press release simply indicates that the primary endpoint was achieved and does not
`
`provide any information about the dose that achieved that result. (See Ex. 1005.) The
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`dose of 360 mg/day of DMF is not mentioned.
`
`42. Neither the January 2006 Press Release nor Schimrigk 2004, alone or
`
`in combination, describe, teach, or suggest an effective dosage range of DMF to treat
`
`MS.
`
`3.
`
`The References Asserted in Ground 1 Do Not Provide Any
`Reason to Target a Daily Dose of 480 mg/day of DMF
`43. As mentioned above, neither the January 2006 Press Release nor
`
`Schimrigk 2004 provide information about the effectiveness of any dose of a DMF-
`
`only drug product. Instead, Schimrigk 2004 is directed to Fumaderm®, a drug
`
`product that contains various active ingredients in addition to DMF. (E.g., Ex. 1003
`
`¶ 36.) Thus, it cannot point one to any DMF monotherapy dose or dose range. The
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`January 2006 Press Release, while relating to BG-12, a DMF-only drug product,
`
`provides no information regarding which doses were actually tested or that led to the
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`reported effect. Thus, the combined references do not provide any reason to target
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`any DMF dose range or use a specific dose of DMF to treat MS, let alone the specific
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`dose of 480 mg/day. Although I have already mentioned it, I will say it again: neither
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`of these references say anything about a dose of 480 mg/day of DMF; nor, that using
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`this amount of DMF in a daily dose will treat MS.
`
`44. Schimrigk 2004 showed a certain level of efficacy (in terms of Gd+
`
`lesion volume relative to baseline, but not placebo) after 12 weeks in the initial
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`treatment phase, in which 6-tablets of Fumaderm® (containing a total dose of 1,290
`
`mg active fumarates) were administered. If anything, a person of ordinary skill in
`
`the art would have expected that a dose of at least 720 mg/day of DMF monotherapy
`
`or more would be required to reach the same level of efficacy of the combination
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`product.
`
`45.
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`In addition, the use of more than 720 mg/day of DMF monotherapy for
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`a chronic and evolving disease like MS is further supported by the relatively mild
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`side effects that Schimrigk 2004 reported for the 6-tablet dose of Fumaderm®, which
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`contains 1,290 mg/day of active fumarates. Specifically, Schimrigk 2004 states that
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`6 of the 7 patients who had completed the study at that point, had “[m]ild to moderate
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`gastrointest