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 CARA LANSDEN
`
`
`
`
`
`
`
`Page 1 of 31
`
`Biogen Exhibit 2079
`Coalition v. Biogen
`IPR2015-01993
`
`
`___________
`
`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 CARA LANSDEN
`
`
`
`
`
`
`
`Page 1 of 31
`
`Biogen Exhibit 2079
`Coalition v. Biogen
`IPR2015-01993
`
`
`
`TABLE OF CONTENTS
`
`
`Personal Background and Introduction ........................................................... 1
`I.
`Biogen’s “BG-12” Program ............................................................................. 6
`II.
`III. Dr. O’Neill’s Idea of Treating MS with 480 mg/day DMF .......................... 11
`IV. Overview of BG-12 Activities ....................................................................... 13
`A. MS Phase IIb Clinical Trial (C-1900) ................................................. 13
`B.
`Planning and Preparation for MS Phase III Clinical Trials ................ 17
`V. Monthly Descriptions for BG-12 Activities: Clinical Hold Response;
`and MS Phase III Clinical Trial Preparation: May 2006 – July 2006 ........... 18
`A. May 2006 ............................................................................................. 19
`B.
`June 2006 ............................................................................................. 20
`C.
`July 2006 ............................................................................................. 21
`D. After July 2006 .................................................................................... 22
`VI. Conclusion ..................................................................................................... 23
`
`
`
`
`i
`
`Page 2 of 31
`
`
`
`TABLE OF ABBREVIATIONS/ACRONYMS
`
`Abbreviation Definition
`AAN
`American Academy of Neurology
`AC
`Advisory Committee
`ACI
`Applied Clinical Intelligence
`ADCI
`Accomplishments, Disappointments and Critical Issues
`ADME
`Absorption, Distribution, Metabolism, and Excretion
`ADS
`Application Data Sheet
`AE
`Adverse Event
`ALT
`Alanine Aminotransferase
`AOB
`Assignment of Benefit
`API
`Active Pharmaceutical Ingredient
`ARR
`Annualized Relapse Rate
`AST
`Aspartate Aminotransferase
`BID
`Twice-daily dosing
`BIIB
`Biogen Idec, Inc.
`BLA
`Biologics License Application
`BP
`Blood Pressure
`C57BL/6
`C57 Black 6
`Cdr
`Commander
`CAC
`Carcinogenicity Assessment Committee
`CAPA
`Corrective and Preventive Action
`CCLS
`Covance Central Laboratory Services SA
`CCPA
`Court of Customs and Patent Appeals
`CFR
`Code of Federal Regulations
`CDER
`Center for Drug Evaluation and Research
`CDP
`Clinical Development Plan
`CDT
`Clinical Development Team
`CEC
`Clinical Events Committee
`CIOMS
`Council for International Organizations of Medical Sciences
`CMC
`Chemistry, Manufacturing, and Controls
`CPO
`Country Pharma Organization
`CR
`Child Resistant
`CRA
`Clinical Research Associate
`CRB
`Clinical Review Board
`CRF
`Case Report Form
`
`
`
`ii
`
`Page 3 of 31
`
`
`
`CRO
`CSC
`CSR
`CSSR
`CTRB
`CTA
`DART
`DBL
`DBRPCT
`DCF
`DCSI
`DM
`DMF
`DOC
`DRG
`DSMC
`eCTD
`Ex
`EC
`ECG/EKG
`EudraCT
`EDSS
`EMA
`EN
`EOP2
`EQ-5D
`ERT
`EU
`FDA
`FDF
`FP
`FPI
`Gd
`GA
`GI
`GMP
`HBsAg
`
`Contract Research Organization
`Clinical Safety Committee
`Clinical Study Report
`Clinical Site Status Report
`Clinical Trial Review Board
`Clinical Trial Application
`Data Analysis and Review Team
`Database Lock
`Double Blind Randomized Placebo-Controlled Trial
`Data Correction Form
`Development Core Safety Information
`Data Management
`Dimethyl Fumarate
`Development Oversight Committee
`Diagnosis Related Groups
`Data Safety Monitoring Committee
`Electronic Common Technical Document
`Exhibit
`Ethics Commission
`Electrocardiogram
`European Union Drug Regulating Authorities Clinical Trials
`Expanded Disability Status Scale
`European Medicines Agency
`Examining Neurologist
`End of Phase II
`European Quality of Life - Dimensions Health Survey
`eResearch Technology
`European Union
`Food and Drug Administration
`Financial Disclosure Form
`Forward Pharma
`First Patient In
`Gadolinium
`Glatiramer Acetate
`Gastrointestinal
`Good Manufacturing Practice
`Hepatitis B Surface Antigen
`
`
`
`iii
`
`Page 4 of 31
`
`
`
`HCV
`HIV
`HV
`Hx
`IB
`ICF
`IMPD
`IND
`INEC
`IP
`ISE
`ISS
`IXRS
`kg
`LFT
`LPO
`m2
`mg
`MHRA
`MMF
`MPR
`MRI
`MS
`MSFC
`MTD
`MTR
`NDA
`NHP
`NOAEL
`ODMP
`p53
`PCT
`PD
`PIND
`PK
`PMDA
`PRA
`
`Hepatitis C Virus
`Human Immunodeficiency Virus
`Healthy Volunteers
`Medical History
`Investigator’s Brochure
`Informed Consent Form
`Investigational Medicinal Product Dossier
`Investigational New Drug Application
`Independent Neurology Evaluation Committee
`Investigational Product
`Integrated Summary of Effectiveness
`Integrated Summary of Safety
`Interactive Voice Response System
`kilogram
`Liver Function Test
`Last Patient Out
`meters squared
`milligram
`Medicines and Healthcare Products Regulatory Agency
`Monomethyl Fumarate
`Medication Possession Ratio
`Magnetic Resonance Imaging
`Multiple Sclerosis
`Multiple Sclerosis Functional Composite
`Maximum Tolerated Dose
`Magnetization Transfer Ratio
`New Drug Application
`Non-Human Primate
`No Observable Adverse Effects Level
`Ongoing Data Management Plan
`Tumor Protein p53
`Patent Cooperation Treaty
`Protocol Deviation
`Pre-Investigational New Drug Application
`Pharmacokinetics
`Pharmaceuticals and Medical Devices Agency
`Pharmaceutical Research Associates
`
`
`
`iv
`
`Page 5 of 31
`
`
`
`PS
`PSP
`PSSV
`PTAB
`PTH
`QC
`QD
`QT
`QTc
`R&D
`ROW
`SAE
`SAP
`SBU
`SF-36
`SIV
`SMT
`SOP
`SPA
`TA
`TID
`TLG
`ULN
`USC
`USPQ
`VAS
`
`Psoriasis
`Product Safety Profile
`Pre-Study Site Selection Visit
`Patent Trial and Appeal Board
`Parathyroid Hormone
`Quality Control
`Single daily dose/Once daily (Latin: Quaque Die)
`QT Interval
`QT Interval Corrected
`Research and Development
`Rest-of-world
`Serious Adverse Event
`Statistical Analysis Plan
`Strategic Business Unit
`Short Form-36 Health Survey
`Site Initiation Visit
`Study Management Team
`Standard Operating Procedure
`Special Protocol Assessment
`Therapeutic Area
`Thrice-daily dosing
`Tables, Listings, and Graphs
`Upper Limits of Normal
`United States Code
`United States Patent Quarterly
`Visual Analogue Scale
`
`
`
`v
`
`Page 6 of 31
`
`
`
`
`
`I, Cara Lansden, have personal knowledge of the facts stated herein and
`
`provide the following testimony:
`
`I.
`
`Personal Background and Introduction
`1.
`
`I am currently Associate Director for Clinical Operations at Takeda
`
`Pharmaceuticals U.S.A., Inc. I am being paid $200.00 per hour for my time
`
`associated with this matter, and being reimbursed for related out-of-pocket
`
`expenditures.
`
`2.
`
`From 1999 to 2013, I was employed by Biogen Inc. (“Biogen”).
`
`During the 14 years with Biogen, I held several positions within the company:
`
`Associate Director of Global Clinical Operations (2011 – 2013), Sr. Manager of
`
`Global Clinical Operations (2007 – 2011), Clinical Program Lead (also known as
`
`Manager, Clinical Development) (2003 – 2007), Sr. Clinical Project Manager
`
`(2002 – 2003), and Clinical Project Manager (1999 – 2002).
`
`3.
`
`I received a B.A. from Vassar College in 1991.
`
`I understand that the U.S. Patent and Trademark Office has instituted a proceeding
`
`involving of Biogen’s U.S. Patent No. 8,399,514 (“the ’514 patent,” Ex. 1001).
`
`4.
`
`I understand that Dr. Gilmore O’Neill (“Dr. O’Neill”) is a named co-
`
`inventor on the ’514 patent. By at least February 2004, Dr. O’Neill conceived of
`
`treating multiple sclerosis (“MS”) with 480 mg per day of dimethylfumarate
`
`
`
`
`
`Page 7 of 31
`
`
`
`(“DMF”), by orally administering
`
`to a human patient a pharmaceutical
`
`composition containing DMF and one or more pharmaceutically acceptable
`
`excipients. By no later than that same date, Dr. O’Neill also conceived of
`
`administering about 480 mg per day of DMF in two equal doses of 240 mg.
`
`Because MS is a chronic disease, he also conceived that such treatment would
`
`occur for at least 12 weeks.
`
`5.
`
`Dr. O’Neill’s ideas and the diligent efforts of numerous individuals at
`
`Biogen, including Dr. O’Neill and myself, eventually led to the regulatory
`
`approval of Tecfidera®, a drug product containing DMF as the sole active agent
`
`(also known as “a DMF-only product”) and one or more pharmaceutically
`
`acceptable excipients, in the United States and elsewhere. Tecfidera® is approved
`
`as an oral therapy using 480 mg per day of DMF to treat MS.
`
`6.
`
`I am familiar with Dr. O’Neill and his contributions to the subject
`
`matter claimed in the ’514 patent because I had worked closely with Dr. O’Neill on
`
`Biogen’s drug development program BG-12 at least from late 2003 to July 2006.
`
`The BG-12 program relates to the research and development of Tecfidera®, and
`
`Tecfidera® itself was previously referred to as “BG-12,” both internally and
`
`externally.
`
`7.
`
`Under the BG-12 program, Biogen researched and developed a drug
`
`product that contains DMF as the sole active agent, simultaneously in two
`
`
`
`2
`
`Page 8 of 31
`
`
`
`therapeutic areas, i.e., an MS indication and a psoriasis indication, with additional
`
`possible indications to follow. From late 2003 to July 2006, Dr. O’Neill served as
`
`the Medical Director on the BG-12 program for the MS indication. Around the
`
`same period of time, I served as the Manager, Clinical Development for both
`
`psoriasis and MS for about a year and then became more focused on the MS
`
`indication as it demanded more of my time. As the Manager, Clinical Development
`
`for MS, I reported to Dr. O’Neill.
`
`8.
`
`Through working with Dr. O’Neill directly on the BG-12 program, I
`
`witnessed Dr. O’Neill’s conceiving the idea of using 480 mg/day DMF for treating
`
`MS, by orally administering to a human patient a pharmaceutical composition
`
`containing DMF and one or more pharmaceutically acceptable excipients, by at
`
`least February 2004. I also witnessed the daily efforts, at least from late 2003 to
`
`July 2006, by numerous individuals at Biogen or contracted by Biogen, spanning
`
`clinical development, planning and operations, drug safety and risk management,
`
`regulatory affairs, data management, and other groups, to develop the MS
`
`treatment approved, marketed and patented as Tecfidera®. These intensive efforts
`
`included, among other key activities during the time period at least from late 2003
`
`to July 2006, planning, operating, and evaluating a Phase IIb clinical trial involving
`
`approximately 260 MS patients at over 40 sites, preparing and submitting Biogen’s
`
`
`
`3
`
`Page 9 of 31
`
`
`
`MS Investigational New Drug Application (“IND”) to the FDA, and planning and
`
`preparing for two pivotal MS Phase III clinical trials.
`
`9.
`
`I provide this declaration to document Dr. O’Neill’s conception of his
`
`idea to treat MS with 480 mg/day of DMF, as well as the work that I and others at
`
`Biogen1 were doing between May 2006 and July 2006.2 In my testimony below, I
`
`first provide some general overviews of the BG-12 program at Biogen (section II),
`
`Dr. O’Neill’s conception of using 480 mg/day DMF to treat MS (section III), and
`
`Biogen’s BG-12 activities (section IV). Next, in section V, I provide more detailed,
`
`month by month, descriptions of Biogen’s continuous and diligent effort with
`
`specific exemplary activities from May 2006 until July 2006, that were pertinent to
`
`the research and development of Tecfidera®. All the exhibits that I refer to in this
`
`declaration are either documents that 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 information transmitted by, me or other Biogen
`
`
`1 As used herein, activities by “Biogen” refers to activities by me, other Biogen
`
`employees, and/or Biogen’s contracted agents.
`
`2 I previously provided a declaration in Biogen’s Interference No. 106,023
`
`involving the ’514 patent to document the work that I and others at Biogen
`
`performed beginning in 2003 and continuing until July 2006.
`
`
`
`4
`
`Page 10 of 31
`
`
`
`employees having knowledge of those matters (i.e., business record) or a document
`
`that is publicly available from an official U.S. government website. It is my
`
`understanding 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. 2092, 2096, 2105, 2115, 2116, 2122, 2124, 2125, 2126,
`
`2127, 2131, 2252, 2255, 2277, 2279, 2309, 2310, 2316, and 2318 are Biogen’s
`
`business record documents. Ex. 2372 is a Clinical Review report by the U.S. Food
`
`and Drug Administration (“FDA”) (Heather Fitter, M.D.) available at the FDA’s
`
`official
`
`website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000MedR.
`
`pdf.
`
`10. All the exhibits that I refer to in this declaration are true and accurate
`
`copies of the original documents with certain redactions or a true and accurate
`
`copy of a document obtained from an official U.S. government website. I have
`
`personal knowledge of the subject matter of the exhibits and events described
`
`therein. My testimony is based on my personal knowledge through my direct
`
`involvement in the BG-12 program (Biogen’s highly organized research program
`
`relating to Tecfidera®) and, additionally, through the exhibits cited herein. For
`
`example, Exhibit Nos. 2096, 2105, 2115, 2116, 2122, 2124, 2125, 2126, 2127,
`
`2131, 2252, 2255, 2277, 2279, 2309, 2310, 2316, and 2318 are true and accurate
`
`
`
`5
`
`Page 11 of 31
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`
`
`copies of documents with certain redactions that I prepared, reviewed, and/or
`
`received at or around the time indicated in the documents. To the extent I did not
`
`prepare, review and/or receive an exhibit related to a clinical report or an FDA
`
`filing for BG-12, I was aware of the contents of those exhibits because those
`
`contents related to BG-12 were reported to and discussed by the BG-12 team. Ex.
`
`2372 is a true and accurate copy of a Clinical Review report by the FDA
`
`downloaded
`
`from
`
`the
`
`FDA’s
`
`official
`
`website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000MedR.
`
`pdf.
`
`II. Biogen’s “BG-12” Program
`11. By at least October 2003, Biogen licensed certain rights from
`
`Fumapharm, AG to develop a treatment for MS and a treatment for psoriasis using
`
`a DMF-only drug product. Ex. 2318 at 1. Biogen called this program “BG-12.” Id.
`
`Under the BG-12 program, Biogen simultaneously began working on two
`
`therapeutic areas: an MS indication and a psoriasis indication, with additional
`
`possible indications to follow. Id.
`
`12. At the outset of the BG-12 program, Biogen set forth milestones and
`
`timelines for clinical trials and regulatory submissions for both psoriasis and MS.
`
`Because drug development was a highly regulated, complex, expensive, and time
`
`consuming process, it was critical to set up research, regulatory, clinical, and
`
`
`
`6
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`Page 12 of 31
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`
`
`logistic goals to ensure that the BG-12 program met the milestones within the
`
`projected timelines. Otherwise, the BG-12 drug development program would not
`
`be viable. Due to the complexity of the BG-12 development and certain
`
`intermittent, sometimes unpredictable, requirements from various regulatory
`
`agencies, the milestones and timelines for BG-12 were constantly reevaluated, but
`
`at no time did Biogen stop or delay in pursuing the BG-12 therapy for MS, at least
`
`from late 2003 to July 2006, when I was on the BG-12 program.
`
`13. The development of Tecfidera® involved intensive, collective daily
`
`efforts of numerous individuals spanning various critical roles and responsibilities
`
`at Biogen. To manage these efforts, Biogen established a number of teams to lead
`
`the BG-12 program. Appendix I. At the program level, there was a BG-12 Program
`
`Team dedicated to the development of BG-12. The BG-12 Program Team included
`
`individuals supervising and/or directing the overall BG-12 program and also
`
`included key members, including Dr. O’Neill and myself, from each of the MS and
`
`psoriasis BG-12 teams. The BG-12 Program Team was responsible for creating
`
`and managing an integrated development plan for the BG-12 Program, accounting
`
`for all aspects of development for the MS and psoriasis indications, such as
`
`nonclinical and clinical development, operations, manufacturing, etc.
`
`14. Under the BG-12 program, there were two Clinical Development
`
`Teams (“CDTs”), i.e., MS CDT and psoriasis CDT, for the two disease indications,
`
`
`
`7
`
`Page 13 of 31
`
`
`
`respectively. For example, the MS CDT included core members such as a Medical
`
`Director, a Program Statistician, and a Manager for Clinical Development, and also
`
`lead representatives from Data Management, Planning and Operations, Regulatory
`
`Affairs, Drug Logistics, and other important groups as needed. Ex. 2096 at 6. The
`
`MS CDT was primarily responsible for developing, maintaining, and overseeing a
`
`Clinical Development Plan (“CDP”) for the MS indication, ensuring that it
`
`progressed to meet the CDP and company goals. Id. at 12.
`
`15. For each disease indication, there were also Study Management
`
`Teams (“SMTs”) dedicated to individual clinical studies. For instance, a Study
`
`Management Team, namely C-1900 SMT, was formed to plan, prepare for, and
`
`manage the Phase IIb MS clinical study (clinical study number C-1900). An SMT
`
`typically included core members such as a Clinical Trial Manager, a Project
`
`Medical Director, a Statistician, and various ad hoc members such as Manager,
`
`Clinical Development like myself. Id. at 19. The SMTs were responsible for
`
`developing the clinical study protocols, managing the day-to-day activities of the
`
`clinical studies, designing and implementing ongoing Data Review Plans, and
`
`ensuring achievement of appropriate quality and timeline goals critical to the
`
`clinical development strategy for the product. Id. at 17, 24.
`
`16. At the initiation of the BG-12 program, Dr. O’Neill became the
`
`Medical Director of the BG-12 teams on the MS side. Ex. 2318 at 1. As Medical
`
`
`
`8
`
`Page 14 of 31
`
`
`
`Director, his responsibilities included clinical trial design and assessment,
`
`development of clinical trial protocols and Investigators’ Brochures (“IBs”),
`
`monitoring clinical trials, review of clinical trial data and reporting, etc. I became
`
`the Manager, Clinical Development of the BG-12 CDTs for both MS and psoriasis
`
`in December, 2003. As Manager, Clinical Development, I worked with the
`
`Medical Directors for the MS and psoriasis teams as well as others on the BG-12
`
`program to create the clinical development plan and to ensure that the operational
`
`strategies, mainly developed at the SMT level, are aligned with the overall clinical
`
`development plan and BG-12 program strategy.
`
`17. As Medical Director for the MS indication, Dr. O’Neill played a key
`
`role on many of the BG-12 teams. For example, Dr. O’Neill and I were part of the
`
`BG-12 Program Team. Dr. O’Neill and I regularly attended BG-12 Program Team
`
`meetings, typically held on a weekly basis. Dr. O’Neill was also a core member of
`
`the MS CDT, of which I was the Manager, Clinical Development. Dr. O’Neill and
`
`I also regularly attended the MS CDT meetings, which were typically held weekly.
`
`Dr. O’Neill typically led discussions at the MS CDT meetings.
`
`18.
`
`In addition, Dr. O’Neill was a core member of the C-1900 SMT
`
`dedicated for the BG-12 MS Phase IIb clinical study, and I was as an ad hoc
`
`member of that SMT. Dr. O’Neill regularly attended BG-12 SMT meetings,
`
`
`
`9
`
`Page 15 of 31
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`
`
`typically on a weekly basis. As an ad hoc member, I attended the SMT meetings as
`
`needed, but regularly received the meeting minutes of the C-1900 SMT.
`
`19. At least during the time period when we were both on the BG-12
`
`program, Dr. O’Neill and I communicated regularly, both formally and informally,
`
`regarding BG-12 and, given our respective roles, often attended the same meetings
`
`and were copied on the same communications such as emails, meeting minutes,
`
`and summary reports. For BG-12 Program Teams meetings, CDT meetings, SMT
`
`meetings, or other meetings that Dr. O’Neill could not attend, I regularly updated
`
`him concerning discussions and developments in those meetings, and vice versa.
`
`20. The BG-12 teams, including the Program Team, the CDTs, and
`
`various SMTs for individual clinical studies, were tightly run by the respective
`
`leaders of the teams. As mentioned above, the teams typically met weekly to
`
`discuss past, current, and future BG-12 activities. Each team typically set up
`
`milestones and timelines for the coming weeks or months, which were reviewed
`
`weekly to determine if certain goals and timelines were met or needed to be
`
`adjusted. The purpose of these meeting was to facilitate quick and smooth
`
`communications within and among the teams, and to ensure that BG-12 activities
`
`tasked by various teams progressed efficiently and without delay.
`
`21. Around July 2006, Dr. Kate Dawson (“Dr. Dawson”) replaced Dr.
`
`O’Neill as the Medical Director for the BG-12 MS program. Ex. 2316 at 5. And I
`
`
`
`10
`
`Page 16 of 31
`
`
`
`transitioned out of the BG-12 program around the same time. Id. at 3. Even after I
`
`left the BG-12 program, I continued to work with Dr. O’Neill closely on other
`
`projects.
`
`22. Thus, at least from late 2003 to July 2006, Dr. O’Neill, as the Medical
`
`Director of the MS BG-12 team and a regular participant in BG-12 Program Team
`
`meetings, was kept apprised of and participated in discussions of issues and
`
`decisions relevant to the overall BG-12 program.
`
`III. Dr. O’Neill’s Idea of Treating MS with 480 mg/day DMF
`23. As mentioned above, by at least February 2004, Dr. O’Neill
`
`conceived of treating MS with an oral dose of 480 mg per day of DMF in BG-12 in
`
`preparation for a Phase IIb clinical trial on MS.
`
`24.
`
`In February 2004, I participated in a CTRB (Clinical Trial Review
`
`Board) meeting where Dr. O’Neill presented a lead dosing option for an MS Phase
`
`IIb MS clinical trial, consisting of four dosing arms of DMF: 120 mg BID (i.e., 120
`
`mg DMF twice per day, totaling 240 mg per day), 120 mg TID (i.e., 120 mg DMF
`
`three times per day, totaling 360 mg per day), 240 mg BID (i.e., 240 mg DMF
`
`twice per day, totaling 480 mg per day), and 240 mg DMF TID (i.e., 240 mg three
`
`times per day, totaling 720 mg per day). Ex. 2309 at 14, 16, 21; Ex. 2310 at 2. Dr.
`
`O’Neill also designed three alternative, secondary options: option two included
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`dosing arms of DMF of 120 mg per day, 360 mg per day, 480 mg per day, and 720
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`mg per day; option three included 120 mg per day, 360 mg per day, and 720 mg
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`per day; and option four included 720 mg per day and 1080 mg per day. Id. As
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`indicated above, the 240 mg BID (totaling 480 mg DMF per day of BG-12) dose
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`was included in Dr. O’Neill’s top two designs, and I recall his belief that the 240
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`mg BID dose would be effective to treat MS patients and should be tested in a
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`clinical trial.
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`25. Dr. O’Neill’s proposed options for the Phase IIb study confirm that he
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`had the idea to treat MS by orally administering 480 mg per day of DMF. His idea,
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`which he shared at the CTRB meeting that I and others attended, included other
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`details, such as the therapeutically effective amount of about 480 mg per day could
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`be administered in two equal doses of 240 mg (Ex. 2309 at 14, Options 1 and 2).
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`He also anticipated that such treatment should be administered for at least for 24
`
`weeks. Ex. 2309 at 16. At the time in February 2004, Biogen had available to it a
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`capsule formulation for its DMF-only product, and as a result, that is the
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`pharmaceutical formulation that Dr. O’Neill planned to use for any of his proposed
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`options in the Phase IIb study.
`
`26. At the CTRB meeting, various opinions were shared regarding Dr.
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`O’Neill’s dosing designs, and members of the CTRB offered certain scientific and
`
`pragmatic reasons in support of option 3, i.e., 120 mg/day DMF, 360 mg/day
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`DMF, and 720 mg/day DMF, for the Phase IIb trial. Id. Carmen Bozic (“Dr.
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`Bozic”), the chair of the CTRB at that time, approved option 3 for the MS Phase
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`IIb protocol shortly after the CTRB meeting.
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`27. Even though the CTRB did not approve the dosing options including
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`the 240 mg BID dose, Dr. O’Neill continued to believe in and remained a strong
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`proponent of the 240 mg BID dose. Following the approval of option 3, the BG-12
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`team started planning and preparing for the MS Phase IIb clinical study.
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`IV. Overview of BG-12 Activities
`A.
` MS Phase IIb Clinical Trial (C-1900)
`28. Planning, preparing for, operating, and evaluating the Phase IIb
`
`clinical trial (C-1900) required work on a daily basis by Biogen at least from
`
`September 2004 to March 2006 to ensure that the study proceeded as smoothly and
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`as efficiently as possible. From September 2004 to November 24, 2004 (when the
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`first dose was given to a patient), Biogen worked on a daily basis to plan and
`
`prepare for the study. After the first dose was given late November 2004, patients
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`took their respective study doses daily until early March 2006, when the last
`
`patient took the last study dose. Ex. 2092 at 1.
`
`29. Biogen’s MS Phase IIb clinical trial was a randomized, double-
`
`blinded study, which means that neither the patients nor the researchers knew
`
`which patients received the active treatment. Ex. 2372 at 27-28. The total duration
`
`of treatment was 48 weeks with the first 24 weeks constituting Part I and the
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`second 24 weeks constituting Part II. Id. The patients’ original treatment
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`assignments remained blinded for the full duration of the study, except for certain
`
`members at Biogen who were unblinded to individual results after all patients
`
`completed week 24 to evaluate efficacy data and were no longer involved in Part II
`
`of the study. Id.
`
`30. This study was comprised of 256 patients randomized at 43 sites. Id.
`
`Prior to patient enrollment, Biogen trained Investigators, Study Coordinators, and
`
`other team members on the procedures, tests, and evaluations to be used,
`
`conducted, and assessed in the study. Ex. 2092 at 2.
`
`31. Biogen’s C-1900 SMT managed the daily preparation for and
`
`operation of the trial, coordinating the efforts of Biogen’s Planning and Operations,
`
`Data Management, Medical Writing, Drug Safety and Risk Management,
`
`Biostatistics, Regulatory Affairs, and other important groups. To provide scientific
`
`and medical advice for the trial and to oversee the administrative progress of the
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`study, Biogen formed an Advisory Committee (“AC”). Id. As Medical Director,
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`Dr. O’Neill was a key member of the AC, along with the Clinical Trial Manager
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`and Project Statistician from Biogen, participating investigators, and other clinical
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`experts. Id. The AC conducted quarterly reviews of the study to monitor patient
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`accrual and compliance with the protocol at the individual investigational sites. Id.
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`Biogen also established a set of guidelines explaining the responsibilities of and
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`14
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`procedures for an independent Clinical Safety Committee (“CSC”). Id. The CSC
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`met prior to study onset in November 2004, again after 25% of the patients had 3
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`months exposure to the study drug, and subsequently thereafter every 3 months for
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`the duration of the study. Id. at 2-3. The findings and conclusions of the CSC were
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`reported to the Chairman of the AC and Dr. O’Neill. Id. at 2.
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`32. Biogen contracted with laboratories to acquire and analyze magnetic
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`resonance imaging (MRI) scans and patient samples. Id. at 3. Biogen also
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`contracted with Contract Research Organizations (“CROs”) and vendors to
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`perform numerous services, such as administrative aspects of the study (e.g., site
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`management, study initiation, monitoring, management of adverse event reports,
`
`and data management), patient randomization, patient tracking, and study drug
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`inventory. Id. Biogen also managed drug supply, contracting with companies to
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`manufacture, package, label, and distribute the BG-12 drug product and placebo.
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`Id. at 4.
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`33. Following screening and enrollment, which took place on an ongoing
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`basis, patients took their assigned doses (120 mg, 360 mg, 720 mg, or placebo)
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`daily for 48 consecutive weeks. Id. at 5. Patients who were assigned to take
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`placebo in Part I took study drug in Part II, i.e., only Part I was placebo controlled.
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`Id. at 6. Patients visited clinic for scheduled visits generally every four weeks for
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`testing/evaluation and to monitor compliance with the study protocol, with
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`additional visits occurring at the beginning and end of each part of the study. Id. at
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`23-24. Each site included a primary and backup treating neurologist, treating nurse,
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`examining neurologist, MRI technician, and a pharmacist. Id. at 16. Through their
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`respective roles, these individuals accomplished drug handling and dispersal,
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`patient safety assessments, patient efficacy assessments, and other functions
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`according to Biogen’s study protocol. Id. at 16-17.
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`34. After all patients completed week 24 of the study, the efficacy and
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`safety data thus far from Part I were evaluated by six individuals at Biogen (two
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`statisticians, three programmers, and one medical director, who was not involved
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`in the study). Id. at 20. At that time, the unblinded statisticians presented group, not
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`individual, efficacy and safety data to Dr. O’Neill, and Dr. O’Neill presented the
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`data to key Biogen employees. Id.
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`35. As the Manager, Clinical Development, I approved the directions for
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`handling and administration of the investigational new drug BG-12, along with the
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`Operations Coordinator for Pharmaceutical Science and Technology and Associate
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`Director Pharmaceutical Science and Technology for the MS Phase IIb study. Id. at
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`39.
`
`36. The C-1900 SMT typically had weekly meetings with the CROs that
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`managed the study sites during the course of the Phase IIb trial. Dr. O’Neill, the
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`clinical study manager, and others on the C-1900 SMT also had daily
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`communications with the clinical study sites, through the CROs. Key members of
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`the C-1900 SMT, including Dr. O’Neill, provided weekly updates to the BG-12
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`CDT meetings and Program Team meetings regarding the progress of the MS
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`Phase IIb trial.
`
`B.
`Planning and Preparation for MS Phase III Clinical Trials
`37. After the Phase IIb clinical trial was underway, and in addition to the
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`MS Phase IIb activities, Biogen worked daily from at least December 2004 and
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`continuing through July 2006 to advance clinical development toward its MS
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`Phase III clinical trials.
`
`38. Under the lead of Dr. O’Neill, Biogen diligently advanced toward the
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`MS Phase III trials through the coordinated efforts of its Regulatory Affairs, Drug
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`Safety and Risk Management, Planning and Operations, Data Management,
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`Clinical Communications, Drug Logistics, Medical Writing, Statistical
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`Programming, and other important groups. As explained in the monthly
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`descriptions below, Biogen worked diligently throughout this time period on the
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`following exemplary tasks:
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` extensively consider and evaluate potential options, designs, and
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`procedures for MS Phase III clinical trials;
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` prepare for and conduct a pre-IND meeting with the FDA, including
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`preparing and submitting to the FDA an extensive pre-IND meeting
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`package;
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` prepare and submit a detailed MS IND package to the FDA, including
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`designing a required Phase I QTc clinical study;
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` prepare and submit a detailed response to a temporary FDA clinical
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`hold subsequent to Biogen’s MS IND submission;
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` plan for and prepare MS Phase III clinical trial protocol concepts;
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` prepare for an End-of-Phase-2 (“EOP2”) meeting with the FDA,
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`including preparing a detailed and comprehensive EOP2 meeting
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`package; and
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` plan and conduct a Phase III feasibility study.
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`V. Monthly Descriptions for BG-12 Activities: Clinical Hold Response; and
`MS Phase III Clinical Trial Preparation: May 2006 – July 2006
`39. The f
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