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 TAMMY SARNELLI
`
`
`
`
`
`
`
`
`
`Page 1 of 49
`
`Biogen Exhibit 2080
`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 TAMMY SARNELLI
`
`
`
`
`
`
`
`
`
`Page 1 of 49
`
`Biogen Exhibit 2080
`Coalition v. Biogen
`IPR2015-01993
`
`
`
`TABLE OF CONTENTS
`
`Introduction and Personal Background ........................................................... 1
`
`A.
`
`B.
`
`Education and Work Experience ........................................................... 2
`
`Involvement With Tecfidera® Development and Biogen’s BG-
`12 Team ................................................................................................. 5
`
`
`
`
`
`I.
`
`II.
`
`Biogen Carried Out an Extensive, Well-organized Regulatory Plan for
`Its BG-12 Product to Treat MS ...................................................................... 10
`
`A.
`
`Planning and Conducting Nonclinical Safety Studies in
`Animals ............................................................................................... 12
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`P00012-04-06 (6-Month Rat BG-12 Toxicity Study) .............. 12
`
`P00012-04-11 (Two-Year Rat BG-12 Carcinogenicity
`Study) ........................................................................................ 14
`
`P00012-05-03 (Two-Year Mouse Carcinogenicity Study) ....... 15
`
`P00012-05-05 (11-Month Dog Toxicity Study) ....................... 17
`
`P00012-05-08 (1-Year Monkey Toxicity Study) ..................... 18
`
`C-1900 (Phase 2 BG-12 Dose-Ranging Study in MS Patient-
`Volunteers) .......................................................................................... 20
`
`Summary of Nonclinical and Clinical Study Activities from
`September 2004 – March 2006 ........................................................... 21
`
`Biogen’s Meetings and Communications with the FDA to
`Discuss the Filing of INDs for the Use of BG-12 to Treat
`Human Disease .................................................................................... 22
`
`1.
`
`2.
`
`IND 69,852 (for psoriasis) ........................................................ 23
`
`IND 73,061 (for MS) ................................................................ 25
`
`B.
`
`C.
`
`D.
`
`i
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`Page 2 of 49
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`
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`E.
`
`F.
`
`Biogen’s EOP2 Meeting to Discuss Phase 3 BG-12 Clinical
`Trials .................................................................................................... 29
`
`Follow Up with the FDA Following the EOP2 Meeting and
`Planning for Phase 3 ............................................................................ 33
`
`III. Conclusion ..................................................................................................... 37
`
`ii
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`Page 3 of 49
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`I, Tammy Sarnelli, have personal knowledge of the facts stated herein and
`
`provide the following testimony:
`
`I.
`
`Introduction and Personal Background
`
`1.
`
`I am currently the Senior Director, Regulatory Affairs, at Biogen Idec,
`
`Inc. (“Biogen”), and have held that position since 2014. As Senior Director,
`
`Regulatory Affairs, I serve as the regulatory lead on new drug development
`
`programs (small molecule and biologic), and in this capacity provide oversight of
`
`independent review markets and global emerging markets for Tecfidera®, Biogen’s
`
`newly-marketed multiple sclerosis product. I also serve as the regulatory
`
`representative on Biogen’s Clinical Trial Review Board, which evaluates clinical
`
`trial protocols across all therapeutic areas. My daily activities at Biogen include
`
`providing regulatory input and strategic guidance for new products, coordinating
`
`interactions with regulatory authorities on new product development, working to
`
`enhance the capabilities of Biogen’s Regulatory Affairs department, and supervising
`
`regulatory personnel (Associate Directors, Managers, and Senior Associates) within
`
`the department. I have been a Biogen employee for more than twenty-five years, the
`
`past fifteen of those as a member of Biogen’s Regulatory Affairs department.
`
`2.
`
`I understand that the U.S. Patent and Trademark Office has initiated a
`
`proceeding involving Biogen’s U.S. Patent No. 8,399,514 (the “’514 patent”).
`
`1
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`Page 4 of 49
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`3.
`
`I provide this declaration to document my work on the project that led
`
`to the regulatory approval of Tecfidera®, a multiple sclerosis (“MS”) treatment
`
`involving the daily, oral administration of 480 mg of dimethyl fumarate (“DMF”).1 I
`
`also document work done by others at Biogen, and also those contracted to do work
`
`on Biogen’s behalf, in developing Tecfidera®, from at least May 2006 up to and
`
`including February 2007.
`
`A. Education and Work Experience
`
`4.
`
`Attached hereto as Appendix A true and correct copy of my current
`
`resume is being filed herewith as Appendix A. See Appendix A (resume of Tammy
`
`Sarnelli, hereinafter the “Sarnelli Resume”).
`
`5.
`
`I am a graduate of Saint Anselm College, where I earned a Bachelor
`
`of Arts degree in biology in 1988. I later attended Suffolk University, where I was
`
`awarded a Master’s Degree in Public Administration/Health Care in 1995. See
`
`Sarnelli Resume at 1.
`
`6.
`
`From 1988 to 1989 I worked as a Research Technician at the Dana
`
`Farber Cancer Institute, where I was responsible for managing laboratory testing
`
`
`1 I previously provided a declaration in Biogen’s Interference No. 106,023, which
`
`also involves the ’514 patent.
`
`2
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`Page 5 of 49
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`
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`programs and staff technicians and coordinating testing and data analysis for studies
`
`involving monoclonal antibodies. See Sarnelli Resume at 4-5.
`
`7.
`
`I joined Biogen as a Bioassay Analyst I in 1989. As a Bioassay
`
`Analyst, my duties involved method development, laboratory analysis, and data
`
`correlation integral to quality assurance testing of research, clinical, and end-product
`
`drug samples. I also worked to prepare an SOP packet for the validation of
`
`analytical test methods and was closely involved in the development and operation
`
`of computer data tracking programs for test data correlation, statistical analysis, and
`
`summary report generation. During my time as a Bioassay Analyst at Biogen I was
`
`twice promoted to positions of increasing responsibility and accountability for
`
`laboratory projects. See Sarnelli Resume at 4.
`
`8.
`
`In 1995 I was promoted to Supervisor, QC Bioassay at Biogen, where
`
`I reviewed, approved, and released Biogen product data and coordinated with other
`
`departments to achieve project goals. In this role I was responsible for supervising
`
`analysts and assistants, coordinating the activities of the QC release testing team,
`
`and developing and maintaining a program for clinical sample receipt and inventory
`
`management. I also reviewed clinical protocols, trained Biogen employees in
`
`laboratory procedures and methods, worked to implement Good Manufacturing
`
`Practices (“GMP”s) within Biogen’s QC department, and audited Biogen contractor
`
`laboratories for GMP compliance. See id. at 3-4.
`
`3
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`Page 6 of 49
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`
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`9.
`
`In 1998 I was promoted to Regulatory Affairs Associate I, at which
`
`point I became more directly involved in interacting with various regulatory
`
`agencies on Biogen’s behalf. In this role (and later as Regulatory Affairs Associate
`
`II), my duties involved establishing generic drug names, reviewing and submitting
`
`post-marketing promotional material, and reviewing and submitting filings to the
`
`federal Food and Drug Administration (“FDA”), including Investigational New
`
`Drug Applications (“IND”s) and Orphan Drug applications for new Biogen
`
`products. I was promoted to Senior Regulatory Affairs Associate in 2001, at which
`
`point my duties expanded to include assembling, reviewing, and filing with the FDA
`
`a Biologics License Application (“BLA”) for a new biologic product, and
`
`coordinating and submitting IND amendments for that product. See Sarnelli
`
`Resume at p. 3.
`
`10.
`
`In 2002 I was promoted to Manager, Regulatory Affairs at Biogen,
`
`where my duties included construction, review and submission of BLAs for new
`
`Biogen products, and the management of new product INDs. I also served as the
`
`regulatory representative on drug development teams, providing regulatory input
`
`and strategic guidance for the development of new Biogen drug products. I also was
`
`responsible for developing and implementing regulatory training programs for other
`
`Biogen departments, particularly in the area of Chemistry, Manufacturing and
`
`Controls. While serving as Manager, Regulatory Affairs I also assisted with
`
`4
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`Page 7 of 49
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`
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`regulatory submissions
`
`for Biogen’s Amevive
`
`(alefacept) and Tysabri
`
`(natalizumab) products, both of which ultimately earned FDA approval. See id. at 2-
`
`3.
`
`11.
`
`In 2005 I was promoted to Associate Director, Regulatory Affairs at
`
`Biogen, where I continued to provide regulatory input and strategic guidance as
`
`Biogen’s regulatory representative on new drug development programs. In this role,
`
`I was responsible for interactions with various regulatory authorities, including the
`
`FDA, regarding the testing and approval of drug products in development at Biogen.
`
`It was as Associate Director, Regulatory Affairs, that I first became involved with
`
`the BG-12 project in or around February of 2006. I have remained involved with the
`
`BG-12 and Tecfidera® projects through my 2008 promotion to Director, Regulatory
`
`Affairs at Biogen and my 2014 promotion to Senior Director, Regulatory Affairs.
`
`See Sarnelli Resume at 2.
`
`B.
`
`Involvement With Tecfidera® Development and Biogen’s BG-12
`Team
`
`12.
`
`I joined the BG-12 team in or around February 2006, and was listed as
`
`a Regulatory Affairs contact in the February 22, 2006 cover letter to the FDA for
`
`Biogen’s submission of IND 73,061 (for the use of BG-12 to treat multiple
`
`sclerosis). See Ex. 2118. As Associate Director (and later, Director and Senior
`
`Director), Regulatory Affairs, I served as Biogen’s point person of contact for day-
`
`to-day communications with the FDA concerning the BG-12 project (including
`
`5
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`Page 8 of 49
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`
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`regulatory filings and other submissions), and maintained custody over all such
`
`communications and filings, including those that had taken place before I became
`
`involved with the BG-12 team.
`
`13.
`
`During my employment with Biogen, I have acquired substantial
`
`expertise regarding the communications, regulatory filings, and other submissions
`
`that are exchanged on a daily basis between Biogen and various regulatory agencies,
`
`including the FDA. Given this, I have a comprehensive working knowledge of
`
`Biogen’s policies and procedures for generating, transmitting, receiving, and storing
`
`such communications, regulatory filings, and submissions. And through my day-to-
`
`day activities as the BG-12 team’s Regulatory Affairs officer, I have personal
`
`knowledge of those communications and regulatory filings concerning the
`
`development of Tecfidera® that took place after I joined the BG-12 team. For
`
`example, as the Regulatory Affairs officer, I was one of the Biogen “subject matter
`
`experts” who was responsible for reviewing signed Clinical Study Protocols,
`
`Clinical Study Reports, and regulatory submissions for completeness, and ensuring
`
`they were submitted to the appropriate internal and external recipients, including the
`
`FDA; I also was responsible for ensuring that signed Final Study Reports from
`
`nonclinical studies were submitted to the appropriate internal and external
`
`recipients, including the FDA.
`
`6
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`Page 9 of 49
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`
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`14.
`
`Biogen maintains policies and procedures governing how Biogen
`
`employees interact with regulatory authorities. As an Associate Director (and later,
`
`Director and Senior Director), Regulatory Affairs with Biogen, I am familiar with
`
`these policies and procedures.
`
`15.
`
`In light of my knowledge and work experience, I can confidently state
`
`that all of the Exhibits discussed in my declaration are documents that were
`
`prepared (1) in the course of Biogen’s regular business activities and according to
`
`strict guidelines established by Biogen; (2) at or near the time of the matters
`
`described in them; and (3) by, or from information transmitted by, myself or other
`
`Biogen employees having knowledge of those matters. To the best of my knowledge
`
`it was, and continues to be, Biogen’s practice to maintain such documents in the
`
`course of its regular business activities. This includes Exhibit Nos. 2086, 2092,
`
`2118, 2225, 2226, 2227, 2273, 2274, 2275, 2276, 2281, 2283, 2284, 2285, 2286,
`
`2287, 2288, 2289, 2290, 2291, 2293, 2294, 2296, 2297, 2299, 2326, 2327, 2328,
`
`2330, 2331, 2332, 2333, 2377, and 2381, which are all true and correct copies (to
`
`which certain redactions have been applied) of Biogen business record documents,
`
`or true and correct copies of excerpts from Biogen business record documents.
`
`16.
`
`And in fact, the orderly maintenance of such documents has been and
`
`continues to be one of my most important responsibilities as Associate Director,
`
`Director, and finally Senior Director, Regulatory Affairs at Biogen, and as such I
`
`7
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`Page 10 of 49
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`
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`ensured that Biogen’s communications with the FDA that I refer to were
`
`documented, circulated, filed, and maintained according to Biogen’s explicit
`
`instructions for handling such communications. This includes Exhibit Nos. 2086,
`
`2092, 2118, 2225, 2226, 2227, 2273, 2274, 2275, 2276, 2281, 2283, 2284, 2285,
`
`2286, 2287, 2288, 2289, 2290, 2291, 2293, 2294, 2296, 2297, 2299, 2326, 2327,
`
`2328, 2330, 2331, 2332, 2333, 2377, and 2381, which are all true and correct copies
`
`(to which certain redactions have been applied) of Biogen’s regulatory
`
`communications, or of excerpts from Biogen’s regulatory communications. 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, including Exhibit Nos. 2086,
`
`2092, 2118, 2225, 2226, 2227, 2273, 2274, 2275, 2276, 2281, 2283, 2284, 2285,
`
`2286, 2287, 2288, 2289, 2290, 2291, 2293, 2294, 2296, 2297, 2299, 2326, 2327,
`
`2328, 2330, 2331, 2332, 2333, 2377, and 2381, which I either prepared, reviewed,
`
`and/or received at or around the time indicated in those documents, or have custody
`
`over as the BG-12 team’s regulatory officer. Finally, my declaration also discusses
`
`certain Exhibits that represent documents that are publicly available at an official
`
`U.S. government website. These include:
`
`
`
`Exhibit 2373, entitled “Initial Quality Assessment,” which
`
`relates to Biogen’s Tecfidera product and was published on the
`
`8
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`Page 11 of 49
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`
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`FDA’s
`
`official
`
`website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/20406
`
`3Orig1s000ChemR.pdf.;
`
`
`
`Exhibit 2374, entitled “Summary Review,” which relates to
`
`Biogen’s Tecfidera product and was published on the FDA’s
`
`official website:
`
`
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/20406
`
`3Orig1s000SumR.pdf,
`
`
`
`Exhibit 2375, entitled “Statistical Review and Evaluation,
`
`Carcinogenicity Studies,” which relates to Biogen’s Tecfidera
`
`product and was published on the FDA’s official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/20406
`
`3Orig1s000StatR.pdf.; and
`
`
`
`Exhibit 2085, entitled “Pharmacology Review(s),” which relates
`
`to Biogen’s Tecfidera product and was published on the FDA’s
`
`official website:
`
`
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/20406
`
`3Orig1s000PharmR.pdf;
`
`which are all true and correct copies of documents obtained from an official U.S.
`
`government website, or of excerpts from such documents.
`
`9
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`Page 12 of 49
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`17.
`
`In addition to serving as the custodian of regulatory documents related
`
`to BG-12 and Tecfidera®, I participated in the day-to-day regulatory activities for
`
`the BG-12 program. For example, I compiled and facilitated communicating
`
`nonclinical data to regulatory authorities, including the FDA. I prepared and
`
`communicated with the FDA about Biogen’s IND for the MS indication. I helped to
`
`prepare Biogen’s End of Phase 2 Meeting (“EOP2”) packet. I also prepared for and
`
`attended that EOP2 meeting. I was also directly involved in the regulatory tasks
`
`associated with Biogen’s Phase 3 studies, including communicating with the FDA
`
`and foreign regulatory agencies and reviewing clinical trial protocols. I also served
`
`as the regulatory lead for the project during Biogen’s Phase 3 studies for BG-12 in
`
`MS.
`
`II. Biogen Carried Out an Extensive, Well-organized Regulatory Plan
`for Its BG-12 Product to Treat MS
`Tecfidera® is an oral therapy marketed by Biogen to treat multiple
`18.
`
`sclerosis MS as a daily dose of 480 mg per day of dimethyl fumarate (“DMF”).
`
`Biogen referred to this product as BG-12 in internal documents and in
`
`communications with the FDA. See Ex. 2373.
`
`19.
`
`Before the approval of Tecfidera®, Biogen conducted a well-organized
`
`regulatory plan, including nonclinical animal toxicity and carcinogenicity studies, a
`
`Phase 2 proof-of-concept dose-ranging study, and two large, multicenter Phase 3
`
`10
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`Page 13 of 49
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`
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`studies. Biogen’s efforts to demonstrate safety and efficacy for its BG12 MS
`
`product took almost eight years.
`
`20.
`
`From May 2006 until February 2007, in particular, Biogen responded
`
`to an FDA clinical hold after having just submitted its IND for BG-12 in MS. See
`
`Exs. 2122, 2225, 2250 at 2, 2293, 2321, 2381. It prepared and submitted EOP2
`
`materials, as well as participated in the FDA EOP2 meeting itself. Exs. 2122, 2252,
`
`2297, 2327, 2332, 2360, 2381. Biogen also prepared and submitted to the FDA
`
`Special Protocol Assessments (“SPA”) for its Phase 3 studies. Exs. 2086, 2087,
`
`2227, 2294, 2299. At the same time, Biogen continued and initiated nonclinical
`
`animal studies and communicated the results of those studies to the FDA. Biogen
`
`also planned for a global Phase 3 campaign, including meeting with foreign
`
`regulatory agencies and coordinating with contract research organizations (“CROs”)
`
`to run the studies. E.g., Exs. 2116, 2122 at 2, 2124 at 2, 2131, 2228, and 2277. As a
`
`result, the first patient in Phase 3 received study drug in Australia in February 2007.
`
`May 2006 until February 2007 was a critical period in the development of
`
`Tecfidera®. My regulatory colleagues and I, along with other Biogen employees and
`
`departments, worked on the BG-12 project on a daily basis. I provide additional
`
`detail regarding each of these tasks below.
`
`11
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`Page 14 of 49
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`
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`A.
`21.
`
`Planning and Conducting Nonclinical Safety Studies in Animals
`
`Biogen initiated several nonclinical studies to investigate potential
`
`BG-12 toxicity and/or carcinogenicity in a variety of animal species, including mice,
`
`rats, and dogs. These studies ultimately provided essential nonclinical safety data
`
`concerning the effects of long-term, repeated BG-12 dosing. More specifically,
`
`submission of the animal toxicity studies contributed to the initial demonstration of
`
`safety that Biogen was required to make before the FDA would approve the
`
`initiation of Phase 3 human clinical trials in the United States. And submission of
`
`the animal carcinogenicity studies contributed to the ultimate demonstration of
`
`safety that Biogen was required to make before the FDA would approve Tecfidera®
`
`as a treatment for MS to be marketed in the United States.
`
`22.
`
`Biogen exchanged
`
`frequent communications with
`
`the FDA
`
`concerning these animal studies, which were initiated as early as July of 2004 and
`
`continued until the delivery of final study reports at least as late as February of
`
`2008.
`
`P00012-04-06 (6-Month Rat BG-12 Toxicity Study)
`
`1.
`Nonclinical Study No. P00012-04-06, entitled “A 6-Month Oral
`
`23.
`
`(Gavage) Toxicity Study of Dimethyl Fumarate in CD®IGS Rats,” was initiated on
`
`July 27, 2004 and completed on May 12, 2006. See Ex. 2273, at pp. 1 & 10. Biogen
`
`cited and discussed this repeat-dose, rat toxicity study in the “Nonclinical
`
`its submission for IND 73,061. See Ex. 2330, pp. 9, 21, & 34.
`
`12
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`Page 15 of 49
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`
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`And Biogen also cited and discussed this study in the “Preclinical Overview”
`
`section of materials submitted in advance of its August 30, 2006 End of Phase 2
`
`(“EOP2”) meeting with the FDA to discuss Phase 3 clinical trials to investigate BG-
`
`12 as a treatment for MS. See Ex. 2281, pp. 30 & 34–42. As custodian of Biogen’s
`
`BG-12 related filings to the FDA, I can confirm that a true and accurate copy of an
`
`excerpt from the final report for Study No. P00012-04-06 (to which certain
`
`redactions have been made) is attached hereto as Exhibit 2273.
`
`24.
`
`According to the final report for Study No. P00012-04-06, study
`
`animals were separated into two groups, the “main study” animals, and the
`
`“recovery Phase” animals, and received daily oral doses of either BG-12 or placebo
`
`for six consecutive months. See Ex. 2273, pp. 1 & 10. The “main study was initiated
`
`with test article [BG-12] administration on August 17, 2004,” which was designated
`
`“Study Day 0.” See id. Following this, either “test article or vehicle control material
`
`was administered daily via oral gavage for 26 consecutive weeks.” See id. at 10 &
`
`16. Daily administration of BG-12 thus began on August 17, 2004 (Study Day 0)
`
`and, with the exception of two days upon which no study animals were dosed
`
`because of inclement weather, continued through at least February 14, 2005 (Study
`
`Day 181). See id.
`
`13
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`Page 16 of 49
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`
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`P00012-04-11 (Two-Year Rat BG-12 Carcinogenicity Study)
`
`2.
`On October 12, 2004, Biogen initiated nonclinical Study No. P00012-
`
`25.
`
`04-11, which was entitled “A Two Year Oral (Gavage) Carcinogenicity Study in
`
`Rats with BG00012.” See Ex. 2274, p. 1. Biogen cited and discussed this mouse
`
`carcinogenicity study in the “Nonclinical Overview” section of its February 22,
`
`2006 submission of IND 73,061 (for multiple sclerosis), observing that it was
`
`intended “to support registration of BG00012.” See Ex. 2330, pp. 28 & 37. And
`
`Biogen also cited and discussed this study in the “Preclinical Overview” section of
`
`materials submitted in advance of its August 30, 2006 End of Phase 2 (“EOP2”)
`
`meeting with the FDA to discuss Phase 3 clinical trials to investigate BG-12 as a
`
`treatment for MS. See Ex. 2281, pp. 34 & 50–52. Biogen filed the final report for
`
`Study No. P00012-04-11 with the FDA on March 11, 2008, and the submission
`
`letter indicated that I was Biogen’s designated contact for the submission. See Ex.
`
`2283. Given this, and as the custodian of Biogen’s BG-12 related filings with the
`
`FDA, I can confirm that a true and accurate copy of an excerpt from the final report
`
`for Study No. P00012-04-11 that was filed with the FDA on February 12, 2009 (to
`
`which certain redactions have been made) is attached hereto as Exhibit 2274.
`
`26.
`
`In Study No. P00012-04-11, BG-12 was administered once-daily to
`
`rats for a varying number of weeks. See, e.g., Ex. 2375, p. 18 (Study duration: 104
`
`weeks (two male dose groups terminated early)); Ex. 2085 at 128–152. Daily dosing
`
`14
`
`Page 17 of 49
`
`
`
`began on October 26, 2004 (the in-life Phase). See Ex. 2274 at § 5. But for two days
`
`when dosing was impossible due to inclement weather, daily dosing continued until
`
`October 23, 2006. Id. § 6.6 (drug administered daily to animals for 80, 82, or 104
`
`weeks; dosing was not possible on Feb. 14, 2007). Animals were checked twice
`
`daily throughout the study, with detailed clinical observations being conducted once
`
`a week. See id. at §§ 7.1.1, 7.1.2.
`
`P00012-05-03 (Two-Year Mouse Carcinogenicity Study)
`
`3.
`On June 7, 2005, Biogen initiated nonclinical Study No. P00012-05-
`
`27.
`
`03, which was entitled “Two-Year Oral (Gavage) Carcinogenicity Study in Mice
`
`with BG00012.” See Ex. 2377. Biogen cited and discussed Study No. P00012-05-03
`
`in the “Nonclinical Overview” section in its February 22, 2006 submission of IND
`
`73,061 (for multiple sclerosis), describing it as “[a] two-year carcinogenicity study
`
`with DMF in mice [that] is currently in the 7th month of dosing,” and stating that a
`
`final report would be available by June of 2008, which would “be used to support
`
`registration of BG00012.” See Ex. 2330, pp. 28 & 37. And Biogen also cited and
`
`discussed this study in the “Preclinical Overview” section of materials submitted in
`
`advance of its August 30, 2006 End of Phase 2 (“EOP2”) meeting with the FDA to
`
`discuss Phase 3 clinical trials to investigate BG-12 as a treatment for MS. See Ex.
`
`2281, pp. 34 & 50–52. Biogen filed the final report for Study No. P00012-05-03
`
`with the FDA on February 12, 2009, and the submission letter indicated that I was
`
`15
`
`Page 18 of 49
`
`
`
`Biogen’s designated contact for the submission. See Ex. 2284. Given this, and as the
`
`custodian of Biogen’s BG-12 related filings to the FDA, I can confirm that a true
`
`and accurate copy of an excerpt from the final report for Study No. P00012-05-03
`
`that was filed with the FDA on February 12, 2009 (to which certain redactions have
`
`been made) is attached hereto as Exhibit 2377.
`
`28.
`
`In Study No. P00012-05-03, BG-12 was administered once-daily to
`
`mice for a varying number of weeks. See Ex. 2375 at 26 (Group 1-4 males and
`
`females dosed for 104 weeks, Group 5 males dosed for 72 weeks, Group 5 females
`
`dose for 82 weeks); Ex. 2085 at 153–179. Daily dosing began on June 28, 2005 (the
`
`in-life Phase). See Ex. 2377 at § 5. But for one day during which dosing was
`
`impossible due to inclement weather, daily dosing continued until June 25, 2007. Id.
`
`at § 6.5 (drug administered to animals for 72, 82, or 104 weeks; dosing was not
`
`possible on Feb. 14, 2007). Animals were checked twice daily throughout the study,
`
`with detailed clinical observations being conducted once a week. See id. at §§ 7.1.2,
`
`7.1.3.
`
`29.
`
`On September 25, 2006, Biogen provided the FDA with a “2-Year
`
`mouse carcinogenicity study update” regarding P00012-5-03, which requested that
`
`the FDA “contact Tammy Sarnelli, Associate Director, Regulatory Affairs” if it
`
`required any additional information. See Ex. 2226.
`
`16
`
`Page 19 of 49
`
`
`
`P00012-05-05 (11-Month Dog Toxicity Study)
`
`4.
`On September 15, 2005, Biogen initiated nonclinical Study No.
`
`30.
`
`P00012-05-05, which was entitled “An 11-Month Toxicity Study of BG00012
`
`Administered by the Oral (Capsule) Route to Dogs with a 1-Month Recovery
`
`Period.” See Ex. 2275. Biogen cited and discussed this repeat-dose, rat toxicity
`
`study in the “Nonclinical Overview” and “Toxicology” Sections in Module 2 of its
`
`submission for IND 73,061. See Ex. 2330, pp. 6–8 & 35 (observing that “in
`
`response to input by the Agency at our Pre-IND meeting,” Biogen had initiated “[a]
`
`one year chronic dog study with DMF”). Biogen also cited and discussed this study
`
`in the “Preclinical Overview” section of materials submitted in advance of its
`
`August 30, 2006 End of Phase 2 (“EOP2”) meeting with the FDA to discuss Phase 3
`
`clinical trials to investigate BG-12 as a treatment for MS. See Ex. 2281, pp. 34, 37–
`
`39, & 50–53. Submission of the results of nonclinical Study No. P00012-05-05
`
`partially fulfilled the agreement that Biogen had reached with the FDA at the
`
`August 30, 2006 End of Phase 2 (“EOP2”) meeting for IND 73,061, during which
`
`“the Agency requested that Biogen Idec submit the final study report for an ongoing
`
`11-month chronic toxicology study in []e dogs prior to the initiation of Phase 3
`
`clinical trials.” See Ex. 2285 (emphasis added); see also Ex. 2326 (requesting an
`
`amendment to the EOP2 meeting minutes to reflect that a “9 month repeat dose
`
`17
`
`Page 20 of 49
`
`
`
`toxicity study in dogs will be submitted prior to the initiation of Phase 3 clinical
`
`trials in the US”).
`
`31.
`
`On April 20, 2007, Biogen submitted to the FDA the final report for
`
`nonclinical Study P00012-05-05, entitled “BG00012: An 11 Month Toxicity Study
`
`of BG000012 Administered by the Oral (Capsule) Route to Dogs with a 1-Month
`
`Recovery Period.” See Ex. 2285. I was Biogen’s designated contact for the
`
`submission, as indicated in the submission letter. See id. As such, I can confirm that
`
`a true and accurate copy of an excerpt from the final report for Study No. P00012-
`
`05-05 that was submitted to the FDA on April 20, 2007 (to which certain redactions
`
`have been made), is attached hereto as Exhibit 2275.
`
`32.
`
`In Study No. P00012-05-05, BG-12 was administered in two divided
`
`daily doses to the animals for a minimum of 11 months. See, e.g., Ex. 2275 at § 5
`
`(page 9). Dosing began on October 18, 2005 (the “in-life Phase”). See id. Daily
`
`dosing continued until at least September 13, 2006. See id. at § 6.5 (pages 14–15)
`
`(BG-12 was administered as two divided daily doses for a minimum of 331 days).
`
`Animals were checked twice daily throughout the study. See id. at §§ 7.1, 7.2.
`
`P00012-05-08 (1-Year Monkey Toxicity Study)
`
`5.
`On January 10, 2006, Biogen initiated nonclinical Study No. P00012-
`
`33.
`
`05-08, entitled “BG00012: A 1 Year Chronic Toxicity Study of Dimethyl Fumarate
`
`Suspension Administered by Nasogastric Intubation to Cynomolgus Monkeys.” See
`
`18
`
`Page 21 of 49
`
`
`
`Ex. 2276. This study was initiated in response to discussions with the FDA during
`
`the September 1, 2005 Pre-IND meeting. See Ex. 2330, pp. 6–8 & 35 (observing
`
`that “in response to input by the Agency at our Pre-IND meeting,” Biogen had
`
`initiated “[a] one year chronic NHP study with DMF in cynomolgus monkeys.”
`
`Biogen also cited and discussed this study in the “Preclinical Overview” section of
`
`materials submitted in advance of its August 30, 2006 End of Phase 2 (“EOP2”)
`
`meeting with the FDA to discuss Phase 3 clinical trials to investigate BG-12 as a
`
`treatment for MS. See Ex. 2281, pp. 34, 37–39, & 50–54.
`
`34.
`
`Furthermore, Biogen understood that the FDA’s permission to initiate
`
`and conduct Phase 3 clinical trials to determine the effectiveness of BG-12 as a
`
`treatment for MS was contingent upon Biogen’s completion of this long-term, repeat
`
`dose toxicology study in monkeys. This is clear from an October 6, 2006 letter to
`
`the FDA from Biogen’s Senior Vice President of Regulatory Affairs. The letter
`
`discussed the agreement that Biogen had reached with the FDA at the August 30,
`
`2006 End of Phase 2 (“EOP2”) meeting for IND 73,061, whereby the FDA
`
`approved Biogen’s request to “begin their Phase 3 trial prior to submitting the 12
`
`month repeat dose toxicity study in monkeys,” so long as “[t]he monkey study will
`
`be submitted within three months of initiation of the clinical trial.” See Ex. 2326 at
`
`p. 6. On July 3, 2007, Biogen submitted to the FDA the final report for nonclinical
`
`Study P00012-05-08. See Ex. 2286. I was Biogen’s designated contact for the
`
`19
`
`Page 22 of 49
`
`
`
`submission, as indicated in the submission letter. See id. As such, I can confirm that
`
`a true and accurate copy of an excerpt from the final report for Study No. P00012-
`
`05-05 that was submitted to the FDA on April 20, 2007 (to which certain redactions
`
`have been made), is attached hereto as Exhibit 2276.
`
`35.
`
`In Study No. P00012-05-08, BG-12 was administered once-daily to
`
`three of four groups of cynomolgus monkeys for at least 52 consecutive weeks. See,
`
`e.g., Ex. 2276, p. 1; Ex. 2085 at 68–74. Daily dosing began on January 17, 2006 and
`
`continued until at least January 15, 2007. Ex. 2276 at §§ V(A) and V(D)(1) (pages 9
`
`and 10) (First day of dosing: January 17-20 & 27, 2006; animals were dosed daily
`
`for at least 52 consecutive weeks). Animals were evaluated for clinical signs twice
`
`daily throughout the study. See id. at § V(D)(1).
`
`B. C-1900 (Phase 2 BG-12 Dose-Ranging Study in MS Patient-
`Volunteers)
`
`36.
`
`Biogen conducted a Phase 2 clinical study C-1900 called “Double-
`
`Blind, Placebo-Controlled, Dose-Ranging Study to Determine the Efficacy and
`
`Safety of BG00012 in Subjects with Relapsing-Remitting Multiple Sclerosis,” that
`
`began on November 2, 2004. See
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