`
`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
`____________________________________________
`
`SECOND DECLARATION OF GILMORE O’NEILL, M.D.
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`Page 1 of 58
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`Biogen Exhibit 2076
`Coalition v. Biogen
`IPR2015-01993
`
`
`
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`TABLE OF CONTENTS
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`Personal Background and Introduction ........................................................... 1
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`Biogen’s “BG-12” Program ............................................................................. 7
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`I.
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`II.
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`III. My Idea to Treat MS with 480 mg/day of DMF ...........................................12
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`IV. Biogen’s Nonclinical (Animal) Studies .........................................................17
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`V.
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`Biogen’s MS Phase IIb Clinical Trial (Study No. C-1900) ..........................19
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`VI. MS Phase III Clinical Trials (Study Nos. 109MS301 and 109MS302) ........23
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`VII. Monthly Descriptions: Nonclinical (Animal) Studies and Advancing
`Clinical Development Toward Phase III From May 2006 Until July
`2006 ...............................................................................................................27
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`A. May 2006 .............................................................................................31
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`B.
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`C.
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`June 2006 .............................................................................................33
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`July 2006 .............................................................................................35
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`VIII. Conclusion .....................................................................................................37
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`i
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`I, Gilmore O’Neill, have personal knowledge of the facts stated herein and
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`provide the following testimony:
`
`I.
`
`Personal Background and Introduction
`
`1.
`
`I am currently Senior Vice President, Drug Innovation Units at
`
`Biogen and have held this position since October 2015. In this position, I am
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`responsible for leading multi-disciplinary groups accountable for research and
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`development in Pain, Immunology, Hemophilia and Rare Diseases, and Gene and
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`Cell therapeutics. Since joining Biogen in 2003 and prior to my current title, I have
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`held several positions, including Associate Director, Medical Research from 2003
`
`to 2005; Director, Medical Research from 2005 to 2007; Senior Director,
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`Experimental Neurology from 2007 to 2010, Vice President, Experimental
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`Neurology (Early Stage) from 2010 to 2011; Vice President, Global Late Stage
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`Clinical Development from 2011 to 2013; Vice President, Global Neurology
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`Clinical Development from 2013 to 2014, and Vice President, Research and
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`Development MS Franchise from 2014 to 2015.
`
`2.
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`I received my medical degree from University College Dublin in 1988
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`and completed residencies and fellowship
`
`training
`
`in
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`internal medicine,
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`pulmonology and neuropathology in 1993 at Beaumont Hospital, Dublin. I
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`completed my residency in Neurology at Massachusetts General Hospital in 1997
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`and was Chief Resident from 1996 to 1997 during that time. I also received a
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`1
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`Master of Medical Science degree from Harvard Medical School in 1999. I am a
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`Clinical Instructor in Neurology at Harvard Medical School and a Neurologist at
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`Massachusetts General Hospital and have held those positions since 1997. I joined
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`Biogen in 2003 as Associate Director, Medical Research and, through my work at
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`the company over approximately the past 12 years, am now Senior Vice President,
`
`Drug Innovation Units. My CV is attached to this declaration as Appendix 1.
`
`3.
`
`I understand that the U.S. Patent and Trademark Office has instituted
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`a review of Biogen’s U.S. Patent No. 8,399,514 (“the ’514 patent,” Ex. 1001).
`
`4.
`
`I am a named co-inventor on the ’514 patent based on my contribution
`
`to the claimed subject matter. I am aware that the original priority application, U.S.
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`Provisional Application No. 60/888,921 (“the provisional application”) was filed
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`on February 8, 2007. I generally understand that the ’514 patent is directed to my
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`idea to treat multiple sclerosis (MS) with 480 mg/day of DMF, MMF, or a
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`combination thereof. As detailed below, by no later than February 2004, I had the
`
`idea to treat MS with 480 mg/day of DMF, specifically in two equal doses of 240
`
`mg/day. Because MS is a chronic disease, I also envisioned that a daily dose of 480
`
`mg/day of DMF would be a long-term treatment.
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`5.
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`As Medical Director from September 2003 to July 2006 of Biogen’s
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`MS drug-development program called “BG-12,” I led a team at Biogen through
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`approximately the first three years of drug development of Tecfidera®, Biogen’s
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`
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`2
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`drug product containing DMF as the sole active agent (also referred to as “a DMF-
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`only” product) and one or more pharmaceutically acceptable excipients. See Ex.
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`2373 at 5, Table 2. Tecfidera® is approved as an oral therapy using 480 mg per day
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`of DMF to treat MS patients.
`
`6.
`
`I previously provided a declaration in Biogen’s Interference No.
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`106,023 involving the ’514 patent to document my idea behind the ‘514 patent as
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`well as to document the work that I and others at Biogen1 were doing from 2003 to
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`2011 on the BG-12 program. I provide this declaration to document my idea
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`behind the ’514 patent. I also describe my work as Medical Director of the MS
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`BG-12 team, specifically in February 2004 and from May 2006 to July 2006,
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`which was the month I transitioned out of my immediate responsibilities in the
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`program.
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`7.
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`The BG-12 program was a high priority at Biogen. Biogen and its
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`employees and contractors, including me, worked diligently to develop the MS
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`treatment approved, marketed and patented as Tecfidera® through the immense,
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`collective efforts of numerous individuals within the BG-12 program, spanning
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`Clinical Development, Planning and Operations, Drug Safety and Risk
`
`
`1 As used herein, activities by “Biogen” refers to activities by me, other
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`Biogen employees, and/or Biogen’s contracted agents.
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`
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`3
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`
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`Management, Regulatory Affairs, Data Management and other important groups at
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`Biogen. Indeed, as detailed below, throughout my entire involvement on the BG-
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`12
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`team, Biogen worked diligently
`
`toward
`
`the company’s objective
`
`to
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`expeditiously obtain FDA approval and bring an oral MS treatment to market.
`
`During my time as Medical Director, these intensive efforts included, among other
`
`key activities, conducting numerous, thorough nonclinical (animal) studies,
`
`planning, operating, and evaluating a Phase IIb clinical
`
`trial
`
`involving
`
`approximately 260 MS patients at 42 sites, preparing and submitting Biogen’s MS
`
`Investigational New Drug Application (IND) to the FDA, and carefully preparing
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`for pivotal Phase III clinical trials involving well over 2000 MS patients in 28
`
`countries worldwide.2 Indeed, all of the activities described herein were directly
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`related to and in furtherance of Biogen’s development and the FDA’s approval of
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`Tecfidera® as a safe and effective drug therapy for treating MS.
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`8. More specifically, in my testimony below, I provide an overview of
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`Biogen’s BG-12 program (Section II), describe my conception of using 480 mg per
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`day of DMF to treat MS patients (Section III), and explain Biogen’s diligent
`
`activities as they relate to: nonclinical (animal) studies (Section IV), Biogen’s MS
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`Phase IIb clinical trial (Section V), and Biogen’s MS Phase III clinical trials
`
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`2 A table of abbreviations is included as Appendix 3.
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`
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`4
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`(Section VI). Next, in Section VII, I provide more detailed, month-by-month,
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`descriptions of daily exemplary activities during my time as Medical Director,
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`specifically from May 2006 to July 2006.
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`9.
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`All the exhibits that I refer to in this declaration are documents that
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`were prepared as a regular practice in the course of Biogen’s regular business
`
`activities at or near the time of the matters described in them by, or from
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`information transmitted by, me or other Biogen employees or Biogen’s contractors
`
`having knowledge of those matters (i.e., business records) or documents that are
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`publicly available at an official U.S. government website. It is my understanding
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`that it was, and continues to be, Biogen’s practice to maintain these business record
`
`documents in the course of Biogen’s regular business activities. For example,
`
`Exhibit Nos. 2082, 2083, 2092, 2105, 2115, 2122, 2125, 2126, 2130, 2131, 2252,
`
`2258, 2262, 2273-2276, 2309, 2310, 2316, 2321, 2323, 2341, 2343, 2345, 2346,
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`2350-2352, 2364-2366, 2381, and 2377 are Biogen’s business record documents.
`
`Ex. 2372 is a Clinical Review report by the FDA (Heather Fitter, M.D.) published
`
`on the FDA’s official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000MedR.
`
`pdf. Ex. 2373 is an Initial Quality Assessment relating to Biogen’s Tecfidera®
`
`product published by the FDA at the FDA’s official website:
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`
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`5
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`Page 7 of 58
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`
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000Chem
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`R.pdf. Ex. 2375 is a Statistical Review and Evaluation of Carcinogenicity Studies
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`relating to Biogen’s Tecfidera® product published by the FDA at the FDA’s
`
`official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000StatR.
`
`pdf. Ex. 2376 is a Statistical Review and Evaluation of Clinical Studies relating to
`
`Biogen’s Tecfidera® product published by the FDA at the FDA’s official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000StatR.
`
`pdf. All the exhibits that I refer to in this declaration are true and accurate copies of
`
`the original documents with certain redactions or true and accurate copies of
`
`documents obtained from an official U.S. government website. I have personal
`
`knowledge of the subject matter of the exhibits and events described therein. My
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`testimony is based on my personal knowledge through my direct involvement in
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`the BG-12 program (Biogen’s highly organized research program relating to
`
`Tecfidera®), and, additionally, through the exhibits cited herein. For example,
`
`Exhibit Nos. 2082, 2083, 2092, 2105, 2115, 2122, 2125, 2130, 2131, 2252, 2258,
`
`2262, 2309, 2310, 2316, 2321, 2323, 2341, 2343, 2345, 2346, 2350-2352, and
`
`2364-2366 are true and accurate copies of original documents that I prepared,
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`reviewed, and/or received at or around the time indicated in the documents, and
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`Exhibit Nos. 2372, 2373, 2375, and 2376 are true and accurate copies of
`
`
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`6
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`documents published by the FDA on an official government website. To the extent
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`I did not review and/or receive a final nonclinical (animal) study report for BG-12
`
`(Exhibit Nos. 2273, 2274, 2275, 2276, and 2377), I was aware of the contents of
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`those exhibits because study developments were reported to and discussed by the
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`BG-12 team during the course of those studies.
`
`II. Biogen’s “BG-12” Program
`In 2003, Biogen recognized a need for an oral therapy to treat MS, a
`10.
`
`chronic and debilitating disease. At that time, the only FDA-approved treatments
`
`were administered by injection. Not long after my hiring at Biogen in the second
`
`quarter of 2003, and subject to a confidentiality agreement, I learned of a
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`proprietary drug candidate called “FAG-201” being pursued by a company called
`
`Fumapharm AG. Under its program, Fumapharm had studied a DMF-only drug
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`product in psoriasis patients. Fumapharm had also sponsored a pilot study in which
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`a drug called Fumaderm®—a mixture of three ethyl hydrogen fumarate salts and
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`DMF—was administered to ten MS patients.
`
`11.
`
`In late September 2003, Biogen licensed certain exclusive worldwide
`
`rights from Fumapharm to develop and market a treatment for MS and a treatment
`
`for psoriasis using a DMF-only drug product. Biogen called this development
`
`program “BG-12.” Under the BG-12 program, Biogen simultaneously began
`
`working on two therapeutic areas: an MS indication (MS BG-12 team) and a
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`
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`7
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`psoriasis indication (psoriasis BG-12 team), with additional possible indications to
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`follow.
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`12. Upon initiation of the BG-12 program at Biogen, I became the
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`Medical Director of the MS BG-12 team. As Medical Director, I was primarily
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`responsible for the design of Biogen’s ongoing Clinical Development Plan (CDP)
`
`for the MS indication, which included the design of a Phase IIb proof-of-concept
`
`clinical trial of BG-12 to treat MS patients.
`
`13. As mentioned above, the development of Tecfidera® was a high
`
`priority at Biogen, involving the intensive, collective efforts of numerous
`
`individuals spanning various critical roles and responsibilities at Biogen. To
`
`manage this effort, Biogen established several teams to lead the BG-12 program.
`
`As Medical Director for the MS indication, I played a key role on many of these
`
`teams. At the program level, I was part of the BG-12 Program Team, which
`
`included individuals supervising and/or directing the overall BG-12 program and
`
`also included key members from each of the MS and psoriasis BG-12 teams. The
`
`BG-12 Program Team was responsible for creating and managing an integrated
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`development plan for the BG-12 Program, accounting for all aspects of
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`development for the MS and psoriasis indications, such as nonclinical and clinical
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`development, operations, manufacturing, financing, commercialization, etc. I
`
`regularly attended BG-12 Program Team meetings, typically held on a weekly
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`
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`8
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`basis. In addition, as Medical Director of the MS BG-12 program, I always
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`received a copy of any prepared meeting minutes, irrespective of whether I was
`
`able to attend the particular meeting.
`
`14. Under the BG-12 Program Team, Biogen established two Clinical
`
`Development Teams (CDTs): an MS CDT and psoriasis CDT for the two disease
`
`indications, respectively. As Medical Director for the MS indication, I led the MS
`
`CDT, which also included other core positions such as Manager, Clinical
`
`Development and Program Statistician. At least during my time as Medical
`
`Director, Ms. Cara Lansden served as Manager, Clinical Development, and Ms.
`
`Lansden and I communicated regularly, both formally and informally, regarding
`
`BG-12. Given our respective roles, we often attended the same meetings and
`
`received or were copied on the same communications. For CDT meetings and
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`other meetings that I could not attend, Ms. Lansden regularly updated me
`
`concerning discussions and developments in those meetings and vice versa. The
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`MS CDT also included lead representatives from Regulatory Affairs, Drug Safety
`
`and Risk Management, Planning and Operations, Data Management, Clinical
`
`Communications, Drug Logistics, and other important groups at Biogen as needed.
`
`These lead representatives coordinated the immense, critical efforts of their
`
`respective groups toward development and approval of Tecfidera®. Overall, the
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`MS CDT was responsible for developing and managing an ongoing Clinical
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`
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`Development Plan (CDP) for the MS indication and ensuring that the program met
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`company deadlines and goals. The CDP included Biogen’s clinical, scientific, and
`
`regulatory strategies for developing BG-12 and obtaining approval to market it for
`
`the treatment of MS. I regularly attended MS CDT meetings, which were typically
`
`held weekly. In addition, as Medical Director of the MS BG-12 program, I always
`
`received a copy of any prepared meeting minutes, irrespective of whether I was
`
`able to attend.
`
`15. As Medical Director, I was also part of a Study Management Team
`
`(SMT) that managed the planning and operation of the MS Phase IIb clinical trial.
`
`The SMT was led by a Clinical Trial Manager and included other core members
`
`from Planning and Operations, Data Management, Medical Writing, Drug Safety
`
`and Risk Management, Biostatistics, and other groups. The SMT also included
`
`lead members of Regulatory Affairs, Product Logistics and other groups on an as-
`
`needed basis. The SMT was responsible for developing a clinical trial protocol,
`
`managing the day-to-day activities of the clinical trial (such as managing Contract
`
`Research Organizations and other vendors, manufacturers, laboratories, etc. and
`
`communicating with regulatory agencies and committees), designing and
`
`implementing ongoing Data Review Plans, and ensuring achievement of
`
`appropriate quality, financial and timeline goals critical to the clinical development
`
`strategy for the product. I regularly attended the SMT meetings, usually held
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`weekly when planning for and carrying out the Phase IIb clinical trial. In addition,
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`as Medical Director of the MS BG-12 program, I always received a copy of any
`
`prepared meeting minutes, irrespective of whether I was able to attend.
`
`16. The MS and psoriasis BG-12 teams stayed in communication,
`
`particularly during BG-12 Program Team meetings in which key members from
`
`the MS and psoriasis teams regularly participated, as discussed above. Thus, as
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`Medical Director and a core member of and a regular participant in BG-12
`
`Program Team meetings, I participated in discussions of issues and decisions
`
`relevant to both the MS and psoriasis indications, such as the safety and tolerability
`
`of BG-12 dosing.
`
`17.
`
`In addition to the many groups and employees at Biogen who directly
`
`supported the MS BG-12 program as discussed above, there were also a number of
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`external parties contracted to work on Biogen’s behalf to carry out Biogen’s
`
`protocols for nonclinical and clinical trials. These groups included Contract
`
`Research Organizations (CROs) and other vendors, manufacturers, laboratories,
`
`investigators, medical researchers, technicians, etc. Thus, within the context of
`
`preparing for and carrying out nonclinical and clinical trials, reference to “Biogen”
`
`throughout this declaration also includes the numerous entities and individuals
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`contracted to perform trial-related services on Biogen’s behalf, such as those
`
`discussed above.
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`
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`11
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`III. My Idea to Treat MS with 480 mg/day of DMF
`18. After Biogen entered into a license agreement with Fumapharm AG,
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`Biogen initiated its BG-12 development program and I became Medical Director
`
`for the MS indication. In that position, I led the MS CDT’s efforts to design a
`
`Clinical Development Plan for the MS indication and to design a Phase IIb proof-
`
`of-concept clinical trial using BG-12 to treat MS patients. Crucial to my work was
`
`the consideration of dosing for Biogen’s oral, DMF-only MS treatment (i.e., an
`
`orally-administered pharmaceutical composition for treating MS containing DMF
`
`as the sole active agent and one or more pharmaceutically acceptable excipients,
`
`also referred to as “BG-12” 3). Ex. 2373 at 5, Table 2. While I believed at that time
`
`that orally administering BG-12 at 720 mg per day of DMF could be more
`
`efficacious for treating MS patients, I also believed that orally administering BG-
`
`12 at 480 mg per day DMF could be effective to treat MS and should be tested in
`
`Biogen’s clinical studies. As evidenced by Ex. 2309, at least by February 19, 2004,
`
`I conceived of orally administering BG-12 at a therapeutically effective amount of
`
`480 mg per day of DMF to treat MS patients. Ex. 2309 at 14, 16, 21 (Feb. 19,
`
`2004, slide presentation). In other words, by no later than February 19, 2004, I
`
`
`3 “BG-12” is also known as “BG12,” “BG’12,” or “BG00012.” The key
`
`ingredients of BG-12 did not change during the course of clinical development.
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`
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`12
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`conceived of a method of treating a subject in need of treatment for MS comprising
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`orally administering a pharmaceutical composition containing a therapeutically
`
`effective amount of DMF, MMF, or a combination thereof and one or more
`
`pharmaceutically acceptable excipients, wherein the therapeutically effective
`
`amount was 480 mg per day.
`
`19.
`
`In particular, Ex. 2309 is a slide presentation I prepared that contains
`
`my proposed protocol concept options for a Phase IIb proof-of-concept clinical
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`study4 to test BG-12 in MS patients. On February 19, 2004, I presented these
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`concepts in a meeting with Biogen’s Clinical Trial Review Board (CTRB), chaired
`
`by Dr. Carmen Bozic. The CTRB was a committee responsible for reviewing
`
`protocol concepts and providing company approval for clinical studies sponsored
`
`by Biogen. Consistent with my conviction that orally administering BG-12 at 480
`
`mg per day of DMF could be therapeutically effective to treat MS and should be
`
`tested, both my lead protocol concept (Option 1) and my first proposed alternative
`
`(Option 2) included an oral dose of 240 mg BID (i.e., 480 mg per day) of DMF for
`
`oral administration to MS patients. Ex. 2309 at 14; Ex. 2310 at 2 (Feb. 19, 2004,
`
`CTRB meeting minutes). Each of my Options 1 and 2 contained four active dosing
`
`
`4 A Phase IIb study is a controlled clinical trial to evaluate efficacy and
`
`safety of a drug in patients having the disease or condition to be treated.
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`
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`13
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`arms and contained BID (twice-per-day) dosing and TID (three times-per-day)
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`dosing. I intended the daily dose of 480 mg/day in Options 1 and 2 to be
`
`administered in two doses of 240 mg per day. Ex. 2309 at 14. MS is a chronic
`
`disease, and as result, I contemplated that all of the active doses, including the 480
`
`mg/day dose, would be administered for at least the full 24 weeks of the trial. E.g.,
`
`Ex. 2309 at 16. I also believed that the formulation of BG-12 that Biogen had at
`
`that time, a capsule, could be used in my proposed treatment methods.
`
`20. At the CTRB meeting, various opinions were shared regarding my
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`protocol design concepts. Ex. 2310 at 2 (Feb. 19, 2004, CTRB meeting minutes).
`
`For example, my 240 mg BID (480 mg/day) dose of BG-12 was met positively by
`
`the attendees. Id. Certain of the attendees believed that, of the options presented, a
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`true dose-ranging study was reflected only in Option 3, which contained three
`
`active doses: 120 mg QD (120 mg/day), 120 mg TID (360 mg/day), and 240 TID
`
`(720 mg/day). Id. In addition, it was important to Biogen to promptly commence
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`and complete the Phase IIb trial to confirm proof of concept of using BG-12 for
`
`treating MS patients. No concept was approved at the meeting in order to allow the
`
`MS BG-12 team to submit a final dosing proposal. Id. After further discussions
`
`between me and other individuals involved in the BG-12 program, the MS team
`
`proposed to test the three active doses of Option 3 in the Phase IIb trial, which
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`would fulfill proof of concept and ensure timely commencement and completion of
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`the study relative to the larger four-active-arm concepts of Options 1 and 2.
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`21. This Phase IIb proof-of-concept clinical study was an essential step
`
`toward the development and approval of Tecfidera® because Biogen was required
`
`to establish proof of concept in Phase II before it could conduct pivotal MS Phase
`
`III clinical trials. Although not included in the Phase IIb study, I understood that
`
`the 480 mg per day dose could be included in subsequent, pivotal Phase III clinical
`
`trials involving MS patients once Biogen had the benefit of assessing the results
`
`(e.g., safety, tolerability, and efficacy data) of the surrounding doses, i.e., 360 mg
`
`per day and 720 mg per day doses from the Phase IIb trial. In particular, Biogen
`
`was confident that the safety data obtained at the 720 mg per day dose in the Phase
`
`IIb trial would provide Biogen with a direct understanding of the safety of the 480
`
`mg per day dose.
`
`22.
`
`In fact, on November 23, 2004, Biogen had one of its first meetings
`
`with the FDA within the BG-12 program. Ex. 2323 at 5 (attached Nov. 23, 2004,
`
`meeting minutes). The purpose of this meeting was to discuss Biogen’s pre-IND
`
`submission for the treatment of psoriasis using BG-12. Id. Because this was one of
`
`the first meetings Biogen had with the FDA within the BG-12 program, Biogen
`
`used this opportunity to ask the FDA questions pertinent to the BG-12 program as
`
`a whole, including questions that would apply to the MS indication. Specifically,
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`
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`15
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`Biogen asked the FDA if it agreed that “exposure at 240 tid [720 mg/day] provides
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`the supportive data required to register the 240 mg bid [480 mg/day] dose?” Id. at
`
`15. The FDA provided explicit confirmation, stating that “safety data collected at
`
`the higher dose [720 mg/day] can be extrapolated downward to a lower dose [480
`
`mg/day].” Id. Thus, moving forward throughout the MS Phase IIb trial, we knew,
`
`as we had expected, that the safety data gathered from orally administering BG-12
`
`at 720 mg per day of DMF would be accepted by the FDA as evidence to establish
`
`the safety of orally administering BG-12 at 480 mg per day DMF.
`
`23. Further, as stated above, my idea to orally administer BG-12 at 240
`
`mg BID (480 mg/day) DMF to treat MS patients was positively received by those
`
`at the CTRB meeting and was an important continuing interest for the BG-12
`
`program. Moving forward, I in particular continued to believe in and remained a
`
`strong proponent of evaluating a 480 mg per day dose and recognized that the
`
`Phase IIb trial would provide relevant information to the design of the MS Phase
`
`III studies.
`
`24. After CTRB approval of the Phase IIb design concept, in the second
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`and third quarters of 2004, the MS BG-12 team continued preparing the MS
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`Clinical Development Plan, prepared and finalized the Phase IIb trial protocol,
`
`
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`16
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`Page 18 of 58
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`
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`prepared an Investigator’s Brochure5, and performed other key activities to prepare
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`for the Phase IIb clinical trial, such as evaluating and selecting sites for the trial,
`
`evaluating and contracting with vendors, laboratories, manufacturers, etc.,
`
`preparing and submitting an Investigational Medicinal Product Dossier (IMPD)6 to
`
`the regulatory agencies of participating countries, and training site personnel.
`
`IV. Biogen’s Nonclinical (Animal) Studies
`25. As discussed further in the monthly descriptions below, from at least
`
`September 2004 and continuing past the month I transitioned out of my direct
`
`responsibilities as Medical Director, i.e., July 2006, Biogen diligently conducted
`
`five, overlapping non-clinical (animal) studies under the BG-12 program. These
`
`5 An Investigator’s Brochure is a compilation of clinical and nonclinical data
`
`on an investigational product maintained by a drug developer or investigator that
`
`contains comprehensive information about the product obtained before and during
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`a drug trial.
`
`6 An IMPD is a document required by regulatory agencies of European
`
`Union member states that forms the basis of approval for performing clinical trials.
`
`The IMPD includes summaries of information related to the quality, manufacture
`
`and control of an investigational medicinal product and data from non-clinical and
`
`clinical studies.
`
`
`
`17
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`Page 19 of 58
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`
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`FDA-required studies provided critical support for the safe administration of BG-
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`12 to human patients. And they were essential steps toward the development and
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`approval of Tecfidera® because they were a necessary part of Biogen’s efforts and
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`ability to establish the safety and efficacy of BG-12 as a treatment for MS in
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`humans. See, e.g., Ex. 2262 at 1 (discussing the Sept. 1, 2005, MS pre-IND
`
`meeting that I attended in which the FDA informed Biogen that it was required to
`
`conduct additional animal studies before initiating Phase III clinical trials).
`
`26. Throughout these five overlapping nonclinical (animal) studies,
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`Biogen conducted daily administration of study drug (i.e., DMF) to animals from
`
`at least September 2004 and continuing past the month I transitioned out of my
`
`direct responsibilities as Medical Director, i.e., July 2006. See Appendix 2
`
`(showing nonclinical (animal) study and clinical (human) timelines).
`
`• Six-month rat toxicity study: animals were dosed daily from Aug. 17,
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`2004, to at least Feb. 14, 2005. Ex. 2273 at §§ 8, 9 and 10.4.4 (pages 10,
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`16);
`
`• Two-year rat carcinogenicity study: animals were dosed daily from Oct.
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`26, 2004, to at least Oct. 23, 2006. Ex. 2375 at 18;
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`• Two-year mouse carcinogenicity study: animals were dosed daily from
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`June 28, 2005, to at least June 25, 2007. Ex. 2375 at 26;
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`
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`18
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`Page 20 of 58
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`
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`• Eleven-month dog toxicity study: animals were dosed daily from Oct. 18,
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`2005, to at least Sept. 13, 2006. Ex. 2275 at §§ 5 and 6.5 (pages 9, 14-15);
`
`and
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`• One-year monkey toxicity study: animals were dosed daily from Jan. 17,
`
`2006, to at least Jan. 15, 2007. Ex. 2276 at §§ V(A) – V(D) (pages 9-11).
`
`V. Biogen’s MS Phase IIb Clinical Trial (Study No. C-1900)
`27. Biogen worked diligently every day to plan, prepare for, operate, and
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`evaluate the Phase IIb clinical trial (Study No. C-1900) from at least September
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`2004 to March 2006. This Phase IIb proof-of-concept clinical study was an
`
`essential step toward the development and approval of Tecfidera®.
`
`28. Biogen’s MS Phase IIb clinical trial was a randomized, double-
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`blinded study, which means that neither the patients nor the researchers knew
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`which patients received the active treatment. Ex. 2372 at 27. The total duration of
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`treatment was 48 weeks with the first 24 weeks constituting Part 1 and the second
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`24 weeks constituting Part 2. Id. The patients’ original treatment assignments
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`remained blinded for the full duration of the study, except for certain members at
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`Biogen who were unblinded to individual results after all patients completed week
`
`24. Id.
`
`29. Biogen commenced the trial in November 2004, when the first patient
`
`received the first study dose, and completed it in March 2006, when the last patient
`
`
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`19
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`Page 21 of 58
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`
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`study visit took place. Ex. 2092; see Appendix 2 (showing nonclinical (animal)
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`and clinical (human) study timelines). Forty-three Investigators enrolled a total of
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`256 patients into the study across 43 sites. Ex. 2372 at 27. Prior to patient
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`enrollment, Biogen trained Investigators, Study Coordinators, and other team
`
`members on the procedures, tests, and evaluations to be used, conducted, and
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`assessed in the study. Ex. 2092 at § 6.1 (page 2).
`
`30. Preparing for and carrying out the trial required a tremendous amount
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`of work. Biogen’s BG-12 MS SMT managed the daily preparation for and
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`operation of the trial, coordinating the efforts of Biogen’s Planning and Operations,
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`Data Management, Medical Writing, Drug Safety and Risk Management,
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`Biostatistics, Regulatory Affairs, and other important groups. To provide scientific
`
`and medical advice for the trial and to oversee the administrative progress of the
`
`study, Biogen formed an Advisory Committee (AC). Ex. 2092 at § 6.2.1 (page 2).
`
`As Medical Director, I was a key member of the AC, along with the Clinical Trial
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`Manager and Project Statistician from Biogen, participating investigators, and
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`other clinical experts. Id.at § 6.2.1 (page 2). The AC conducted quarterly reviews
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`of the study to monitor patient accrual and compliance with the protocol at the
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`individual investigational sites. Id. Biogen also established a set of guidelines
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`explaining the responsibilities of and procedures for an independent Clinical Safety
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`Committee (CSC). Id. at § 6.2.2 (pages 2-3). The CSC met immediately prior to
`
`
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`20
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`Page 22 of 58
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`
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`study onset in November 2004, again after 25% of the patients had 3 months
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`exposure to the study drug, and subsequently thereafter every 3 months for the
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`duration of the study. Id. The findings and conclusions of the CSC were reported to
`
`the Chairman of th
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