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—O1993
`
`Patent 8,399,514 B2
`
`DECLARATION OF CARMEN BOZIC, M.D.
`
`

`

`TABLE OF CONTENTS
`
`Personal Background and Introduction ......................................................... ..1
`
`Dr. Gilmore O’Neill’s Idea to Treat MS with 480 mg/day of DMF ............. .. 7
`
`III. MS Investigational New Drug Application (IND) Preparation,
`Submission, and Clinical Hold Response (at least March 2005 — June
`2006) ............................................................................................................ ..13
`
`IV. MS Phase III Clinical Trials——Preparation (at least June 2006 —
`February 2007) ............................................................................................ .. 14
`
`

`

`1, Carmen Bozic, have personal knowledge of the facts stated herein and
`
`provide the following testimony:
`
`Personal Background and Introduction
`
`1.
`
`I am currently Senior Vice President of Global Development at
`
`Biogen and have held this position since April 2015. My department is responsible
`
`for developing and obtaining regulatory approval of therapies in Biogen’s
`
`therapeutic focus areas of Neurology, Immunology and Hematology. I have held
`
`several positions within Biogen, including Senior Director, Medical Research from
`
`2003 to 2005; Senior Director, Clinical Trial Drug Safety and Risk Management in
`
`2005; Senior Director and Global Head, Drug Safety and Risk Management from
`
`2005 to 2006; Vice President and Global Head, Drug Safety and Risk Management
`
`from 2006 to 2009; Senior Vice President and Global Head, Safety and Benefit-
`
`Risk Management from 2009 to 2013; and Senior Vice President, Clinical and
`
`Safety Sciences from 2013 to 2015. In addition to these positions, I was chairman
`
`of Biogen’s Clinical Trial Review Board (CTRB) from at least 2003 to 2009.
`
`2.
`
`I received a Doctor of Medicine at McGill University in Montreal,
`
`Canada, where I also did a residency in internal medicine. I completed a fellowship
`
`in Pulmonary and Critical Care Medicine at Brigham and Women's Hospital in
`
`Boston and was an Associate Physician at Beth Israel Deaconess Medical Center
`
`and Harvard Medical School before joining industry.
`
`

`

`3.
`
`I understand that the U.S. Patent and Trademark Office has instituted
`
`a proceeding involving Biogen’s U.S. Patent No. 8,399,514 (“the ’5 14 patent,” Ex.
`
`1001)
`
`4.
`
`I oversaw the development of Biogen’s multiple sclerosis (MS)
`
`treatment Tecfidera®, specifically as to the approval of clinical trial protocols and
`
`safety and risk management
`
`throughout Biogen’s drug-development program
`
`called BG-12. Tecfidera® is Biogen’s drug product containing DMF as the sole
`
`active agent
`
`(also referred to as “a DMF—only” product) and one or more
`
`pharmaceutically acceptable excipients. See Ex. 2373 at 5. Tecfidera® is approved
`
`as an oral therapy using 480 mg per day of DMF to treat MS patients.
`
`5.
`
`I provide this declaration to document Dr. O’Neill’s idea to use 480
`
`mg/day of DMF to treat MS. I also detail the work that I and others at Biogen‘
`
`were doing between May 2006 and February 2007, when I understand Biogen’s
`
`priority application for the ’5l4 patent was originally filed. 2 The project leading to
`
`' As used herein, activities by “Biogen” refers to activities by me, other Biogen
`
`employees, and/or Biogen’s contracted agents.
`
`I previously provided a declaration in Biogen’s Interference No. 106,023
`
`involving the ’5l4 patent to document the work that I and others at Biogen
`
`

`

`the development and approval of Tecfidera® was a high priority at Biogen.
`
`Developing a pharmaceutical treatment and obtaining regulatory agency approval
`
`to bring it to market are inherently large and intensive undertakings typically
`
`requiring several years of nonclinical and clinical
`
`testing and the efforts of
`
`numerous groups within a company to plan, prepare for, carry out, and evaluate the
`
`tests and to thoroughly prepare required submissions and documentation to one or
`
`more regulatory agencies throughout the clinical development process.
`
`6.
`
`Biogen’s tremendous efforts throughout
`
`this process to develop,
`
`obtain approval
`
`for and bring to market Tecf1dera® were diligently and
`
`simultaneously advanced by numerous groups within Biogen, such as Clinical
`
`development, Clinical Operations, Regulatory Affairs, Drug Safety and Risk
`
`Management, Biostatistics, Medical Writing, Data Management, and other
`
`important groups.
`
`7.
`
`More specifically, Biogen3 planned and conducted several non-
`
`clinical (animal) trials to provide critical, required support for the development and
`
`performed beginning in 2003 and continuing into 2011 and to document Dr.
`
`O’Neill’s idea to use 480 mg/day of Dl\/[F to treat MS.
`
`3 Within the context of preparing for and carrying out nonclinical (animal) and
`
`clinical (human) trials, reference to “Biogen” throughout this declaration also
`
`

`

`approval of Tecfidera®. Throughout the course of these overlapping nonclinical
`
`trials, Biogen performed daily administration of study drug (i.e., DMF) to animals
`
`from at least August 2004 to June 2007.
`
`Six-month rat toxicity study: daily dosing from Aug. 17, 2004, to at least
`
`Feb. 14, 2005. Ex. 2273 at §§ 8, 9 and 10.4.4 (pages 10, 16);
`
`Two-year rat carcinogenicity study: daily dosing from Oct. 26, 2004, to at
`
`least Oct. 23, 2006. Ex. 2375 at 18;
`
`Two-year mouse carcinogenicity study: daily dosing from June 28, 2005,
`
`to at least June 25, 2007. Ex. 2375 at 26;
`
`Eleven-month dog toxicity study: daily dosing from Oct. 18, 2005, to at
`
`least Sept. 13, 2006. Ex. 2275 at §§ 5 and 6.5 (pages 9, 14-15); and
`
`One-year monkey toxicity study: daily dosing from Jan. 17, 2006, to at
`
`least Jan. 15, 2007. Ex. 2276 at §§ V(A),V(D) (pages 9-11).
`
`8.
`
`Biogen also planned, conducted, and evaluated a proof-of-concept
`
`Phase IIb clinical study on MS patients outside the U.S. The study began in
`
`includes the numerous entities and individuals contracted to perform trial—related
`
`services on Biogen’s behalf, such as Contract Research Organizations (CROs) and
`
`other vendors, manufacturers,
`
`laboratories,
`
`investigators, medical
`
`researchers,
`
`technicians, etc.
`
`

`

`November 2004, when the first patient received the first study dose, and finished in
`
`March 2006, when the last patient study visit took place. Ex. 2092 at cover page.
`
`Forty—three investigators enrolled a total of 256 patients into the trial across 43
`
`sites. Ex. 2372 at 27. Biogen then prepared for and conducted MS Phase III
`
`clinical trials in the U.S. and worldwide collectively spanning about 4.5 years,
`
`beginning in March 2007 and finishing in August 2011. Biogen conducted two
`
`main studies in its Phase III clinical trials. The first study involved a total of 1237
`
`MS patients at 198 sites in 28 countries worldwide. Ex. 2376 at 6 and 12. The
`
`second Phase III study overlapped with the first and involved a total of 1430 MS
`
`patients at 200 sites in 28 countries worldwide. Id. The result of these persistent,
`
`diligent efforts was approval, marketing and patenting of Tecf1dera®.
`
`9.
`
`All the exhibits that I refer to in this declaration are 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 employees or Biogen’s contractors
`
`having knowledge of those matters (i.e., business records) or documents that are
`
`publicly available at 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, 2228, 2229, 2230, 2231, 2250, 2273, 2275, 2276, 2309, 2310,
`
`

`

`2311, 2316, 2318, 2321, 2322, 2360, 2367, 2368, 2369, 2370, and 2371 are
`
`Biogen’s business record documents. Ex. 2297 is a letter enclosing a Memorandum
`
`of Meeting Minutes from the U.S. Food and Drug Administration (“FDA”)
`
`published
`
`on
`
`the
`
`FDA’s
`
`official
`
`website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063 Orig 1 s000Admin
`
`corres.pdf. 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/2013/2040630rigls0O0MedR.
`
`pdf. Ex. 2373 is an Initial Quality Assessment relating to Biogen’s Tecf1dera®
`
`product
`
`published
`
`by
`
`the
`
`FDA at
`
`the
`
`FDA’s
`
`official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/2040630rig1s000Chem
`
`R.pdf. Ex. 2375 is a Statistical Review and Evaluation of Carcinogenicity 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/2013/2040630rig1 s000StatR.
`
`pdf. Ex. 2376 is a Statistical Review and Evaluation of Clinical Studies relating to
`
`Biogen’s Tecf1dera® product published by the FDA at the FDA’s official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/2040630rig1s000StatR.
`
`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 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
`
`testimony is based on my personal knowledge through my direct involvement in
`
`the BG~12 program (Biogen’s highly organized research program relating to
`
`Tecf'1dera®), and, additionally, through the exhibits cited herein. For example,
`
`Exhibit Nos. 2092, 2229, 2230, 2231, 2250, 2309, 2310, 2311, 2318, 2360, 2367,
`
`2368, 2369, 2370, and 2371 are true and accurate copies of original documents that
`
`I prepared, reviewed, and/or received at or around the time indicated in the
`
`documents, and Exhibit Nos. 2297, 2372, 2373, 2375, and 2376 are true and
`
`accurate copies of documents published by the FDA on an official government
`
`website.
`
`Dr. Gilmore O’Neill’s Idea to Treat MS with 480 mg/day of DMF
`
`11.
`
`In 2003, there were no FDA-approved orally administered therapies
`
`for treating multiple sclerosis, a chronic and debilitating disease. FDA-approved
`
`MS treatments at
`
`that
`
`time were administered by injection. Biogen is a
`
`pharmaceutical company that develops important therapies for people suffering
`
`from a variety of diseases, including MS. In 2003, an important goal at Biogen was
`
`to develop an orally—administered treatment for MS that
`
`improved upon the
`
`

`

`existing therapies. Dr. Gilmore O’Neill was one of Biogen’s leading MS clinicians
`
`at that time.
`
`12.
`
`In late September 2003, Biogen licensed certain exclusive worldwide
`
`rights from a company called Fumapharm AG to develop and market a treatment
`
`for MS and a treatment for psoriasis using a DMF-only (i.e., DMF as the sole
`
`active agent) drug product. Biogen called this development program “BG-12.” Ex.
`
`2318 at 1 (Oct. 10, 2003, e-mail concerning initiation of the BG-12 program).
`
`Under
`
`the BG—l2 program, Biogen simultaneously began working on two
`
`therapeutic areas: an MS indication and a psoriasis indication. Each indication had
`
`its own clinical development team (i.e. an MS clinical development team and a
`
`psoriasis clinical development team).
`
`13. Dr. Gilmore O’Neil1—who is a named inventor on the ’5l4 patent—
`
`was the Medical Director for BG—l2 MS clinical development and was responsible
`
`for designing a Phase Ilb clinical trial involving MS patients. Ex. 2318 at 1. In
`
`particular, Dr. O’Neill considered 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”).
`
`14.
`
`By at least February 2004, Dr. O’Neill conceived of treating MS
`
`patients by orally administering BG-12 at a therapeutically effective amount of 480
`
`

`

`mg per day DMF. More specifically, Biogen’s clinical development procedure
`
`required Dr. O’Neill to present his protocol design concept for the Phase IIb trial to
`
`Biogen’s Clinical Trial Review Board (CTRB). The CTRB was a committee
`
`responsible for reviewing protocol concepts and providing corporate approval for
`
`clinical studies sponsored by Biogen. In February 2004, I was the CTRB chairman
`
`and participated in a meeting on February 19th where Dr. O’Neill proposed a lead
`
`dosing option for the Phase Ilb MS clinical trial consisting of four dosing arms of
`
`DMF: 120 mg BID (i.e., 120 mg twice per day, totaling 240 mg), 120 mg TID (i.e.,
`
`120 mg three times per day, totaling 360 mg), 240 mg BID (i.e., 240 mg twice per
`
`day, totaling 480 mg) and 240 mg TID (i.e., 240 mg three times per day, totaling
`
`720 mg). Ex. 2309 at 1-2 (Feb. 19, 2004, e-mail circulating Dr. O’Neill’s slides for
`
`the CTRB meeting), id. at 14, 16 (Dr. O’Neill’s attached slide presentation); Ex.
`
`2310 at 2 (Feb. 19, 2004, CTRB meeting minutes). Dr. O’Neill also proposed three
`
`alternative, secondary options: option two included DIVIF dosing arms of 120 mg
`
`per day, 360 mg per day, 480 mg per day and 720 mg per day; option three
`
`included 120 mg per day, 360 mg per day and 720 mg per day; and option four
`
`included 720 mg per day and 1080 mg per day. Ex. 2309 at 14, 21; Ex. 2310 at 2.
`
`As indicated above, the 240 mg BID (480 mg/day) dose was included in Dr.
`
`O’Neill’s top two proposals, and I recall his belief at
`
`that
`
`time that orally
`
`

`

`administering BG-12 at 480 mg per day of DMF could be therapeutically effective
`
`to treat MS patients and should be tested in a clinical trial.
`
`15. Dr. O’Neill’s proposed options for the Phase IIb study confirm that he
`
`had conceived of a method of treating a subject in need of treatment for MS by
`
`orally administering a pharmaceutical composition containing a therapeutically
`
`effective amount of DMF and one or more pharmaceutically acceptable excipients,
`
`in which the therapeutically effective amount was 480 mg per day. His idea
`
`included the administration of 480 mg per day in two equal doses of 240 mg (Ex.
`
`2309 at 14, Options 1 and 2). He also contemplated that such treatment should be
`
`administered over a long period of time given the chronic nature of MS. The
`
`proposed initial trial phase was 24 weeks. Ex. 2309 at 16. At the time in February
`
`2004, Biogen had a capsule formulation for its DMF-only product, and as a result,
`
`that is the pharmaceutical formulation that Dr. O’Neill planned to use for any of
`
`his proposed options in the Phase Ilb study. These ideas were part of the slide
`
`presentation that Dr. O’Neill gave at the CTRB meeting that I chaired. Those slides
`
`were distributed to me and other Biogen personnel a day ahead of time on
`
`February 18, 2004.
`
`16.
`
`At the CTRB meeting, various opinions were shared regarding Dr.
`
`O’Neill’s dosing options. Members of the CTRB offered certain scientific and
`
`pragmatic reasons in support of the three active-dosing arms in option 3, i.e., 120
`
`

`

`mg/day DMF, 360 mg/day DMF and 720 mg/day DMF, for the Phase Ilb trial. For
`
`example, option 3 was considered by some to be a true dose-ranging study. Ex.
`
`2310 at 2. Limiting the trial to three active doses—as is typical in a Phase Ilb
`
`trial—also aligned with Biogen’s goals to promptly commence and complete the
`
`Phase Ilb trial to confirm proof of concept of BG-12 for treating MS patients and
`
`to expeditiously advance clinical development toward approval and bringing a
`
`product to market. A fourth active dosing arm would require a greater number of
`
`total patients, and would lengthen the time to conduct the study. Further, as to the
`
`highest dose of Option 3, 240 mg TID (720 mg/day) made sense to the CTRB
`
`because it had already been safely studied as the highest dose tested in an earlier
`
`study by Fumapharm on psoriasis patients. The CTRB supported 120 mg QD (120
`
`mg/day) as the lowest dose for a potentially minimally effective dose for a dose-
`
`ranging study. Regarding the third dose, the CTRB favored 120 mg TID (360
`
`mg/day) because it would maintain consistency with the three-times-per-day
`
`dosing regimen of the higher 240 mg TID arm. Biogen could not vary both the
`
`dose and the dose frequency while maintaining a reasonably-sized and rapidly-
`
`feasible three-active-dose trial. Furthermore,
`
`the three-active-arm proposal of
`
`Option 3 would result in more patients enrolled per dosing arm, increasing the
`
`statistical certainty of the resulting safety and efficacy data relative to the four-
`
`active—arrn proposals of Options 1 and 2. The CTRB did not give final approval at
`
`

`

`the meeting in order to allow the BG-12 MS team to reach a consensus on a final
`
`proposal. Ex. 2310 at 2. Soon thereafter, I received a final proposal from the team
`
`proposing Option 3, which I approved.
`
`17.
`
`Biogen’s Phase Ilb clinical
`
`trial was a critical step toward the
`
`development and approval of Tecfidera® because it was necessary to establish
`
`proof-of-concept in Phase II for using BG-12 to treat MS patients before Biogen
`
`could commence pivotal Phase IH clinical trials. Further, I and other members
`
`involved in the BG-12 program understood that the 480 mg per day dose could be
`
`included in Biogen’s subsequent pivotal Phase III clinical trials once Biogen had
`
`the benefit of evaluating data at the surrounding doses, i.e., 360 mg per day and
`
`720 mg per day doses from the Phase Ilb trial. More specifically, Biogen was
`
`confident that the safety data obtained at the 720 mg per day dose from the Phase
`
`Ilb trial would be directly relatable to the safety of the 480 mg per day dose.
`
`18.
`
`In addition, Dr. O’Neill’s 240 mg BID (480 mg/day) dose had been
`
`positively received by those who had attended the February 19, 2004, CTRB
`
`meeting (Ex. 2310 at 2), and it remained a continuing interest as clinical
`
`development moved forward. Alter that February 2004 CTRB meeting, Dr.
`
`O’Neill and I discussed on several occasions his idea to treat.MS with DMF in a
`
`daily dose of 480 mg/day.
`
`I recall discussing his idea with him again after the
`
`

`

`Phase Ilb study results came in, and Dr. O’Neill again conveyed to me that the 480
`
`mg/day dose should be included in Phase III studies.
`
`19.
`
`Following the February 2004 decision,
`
`in the second and third
`
`quarters of 2004, the MS BG-12 team planned and prepared for the MS Phase Ilb
`
`clinical trial.
`
`(IND) Preparation,
`III. MS Investigational New Drug Application
`Submission, and Clinical Hold Response (at least March 2005 — June
`2006)
`
`20. While conducting the Phase Ilb MS trial, Biogen diligently worked at
`
`least from March 2005 to February 2006 to prepare for a pre-IND meeting with the
`
`FDA and then to prepare and file the MS IND, which was submitted to the FDA in
`
`February 2006. 1, and/or a person in my department under my supervision, was
`
`involved in the review process of both the pre-IND meeting package and the MS
`
`IND prior to submission to the FDA. See, e.g., Ex. 2311 (Jul. 15, 2005, e-mail
`
`circulating a draft pre-IND meeting package); Ex. 2322 at 1-2 (Dec. 27, 2005, e-
`
`mail regarding MS H\ID preparation).
`
`21.
`
`In March 2006, about one month after Biogen filed its IND for using
`
`BG-12 for the treatment of MS, the FDA placed the IND on clinical hold. Ex. 2250
`
`at 2 (Mar. 27, 2006, e-mail chain concerning the clinical hold). Biogen worked
`
`diligently throughout April and part of May 2006 to prepare and submit a clinical
`
`hold response, and this dedicated effort resulted in the FDA lifting the clinical hold
`
`

`

`in June 2006. Ex. 2321 at 1-2 (June 14, 2006, e-mail noting that the clinical hold
`
`on the BG—l2 MS IND was lifted).
`
`IV. MS Phase HI Clinical Trials——Preparation (at
`February 2007)
`
`least June 2006 —
`
`22. After the MS Phase Ilb trial concluded in March 2006 and as Biogen
`
`worked to prepare a response to the MS IND clinical hold noted above, Biogen
`
`considered in more detail the design for the MS Phase III clinical trials and worked
`
`to prepare a briefing document for European regulatory agencies and an End-of-
`
`Phase-2 (EOP2) meeting package for submission to the FDA. The Phase Ilb trial
`
`showed that BG-12 at 720 mg per day was safe and effective, thus confirming
`
`proof of concept of using BG-12 to treat MS. Ex. 2372 at 29, 30. The 120 mg QD
`
`(120 mg/day) and 120 mg TID (360 mg/day) doses were not statistically
`
`significant versus placebo. Id.
`
`23. As discussed above, the Phase IIb trial established the safety of the
`
`480 mg per day dose. Consistent with Dr. O’Neill’s continued belief that 480 mg
`
`per day could be effective to treat MS and should be tested, there was an enduring
`
`belief in his 240 mg BID (480 mg/day) dose. Thus, by at least June 2006, Biogen
`
`began preparing for the potential inclusion of 240 mg BID (480 mg/day) to the MS
`
`Phase III trial design. Ex. 2316 at 1-2 (July 6, 2006, e-mail regarding June 2006
`
`calculations concerning the 480 mg/day dosing arm), id. at 5-6 (attached July 5,
`
`

`

`2006, MS CDT meeting minutes). In particular, there was a lot of interest within
`
`Biogen to add a 480 mg/day dose to the Phase III studies.
`
`24.
`
`As Biogen evaluated this potential inclusion, it diligently prepared the
`
`EOP2 meeting package and initial Phase III study protocols, which were to be
`
`submitted to the FDA for discussion during Biogen and the FDA’s EOP2 meeting
`
`scheduled for August 30, 2006.
`
`In particular,
`
`I received a draft of the EOP2
`
`meeting package for my review on June 29, 2006, and of the initial MS Phase III
`
`protocols (two main Phase III trials were plarmed: “109MS301” and “109MS3 02”)
`
`on July 21, 2006. Ex. 2367 (Jun. 29, 2006, e—mail circulating the draft EOP2
`
`meeting package; Ex. 2368 (Jul. 21, 2006, e—mail circulating the draft Phase III
`
`protocols). Biogen’s EOP2 package, including the protocols, was submitted to the
`
`FDA on July 28, 2006. Ex. 2360 (Jul. 31, 2006, e—mail circulating the EOP2
`
`meeting package submitted Jul. 28, 2006). With evaluation of the 240 mg BID
`
`(480 mg/day) dosing arm ongoing, the EOP2 package included only the higher 240
`
`mg TID (720 mg/day) dose that had been part of the Phase IIb trial. The goal of
`
`this initial briefing to the FDA was to gain principal agreement on major issues,
`
`such as the clinical end points and the highest dose to be tested in the Phase III
`
`study; it was not intended to be a final decision with respect to Phase III dosing.
`
`Going into the EOP2 meeting, Biogen believed that if the FDA agreed to the
`
`higher 240 mg TID (720 mg/day) dose for testing in Phase III, Biogen would have
`
`

`

`the flexibility to choose to include the lower 240 mg BID (480 mg/day) dose-
`
`which would presumably be at least as safe as the higher dose.
`
`25.
`
`On August 30, 2006, Biogen met with the FDA for the EOP2 meeting,
`
`which I attended along with other members involved with the BG-12 program. Ex.
`
`2297 at 1- 2 (EOP2 meeting minutes received from the FDA). During the meeting,
`
`the FDA was excited about the drug as it showed a good efficacy profile, was
`
`generally well tolerated, and was orally administered instead of injected. The FDA
`
`also encouraged, but did not require, Biogen to test a lower dose in its Phase IH
`
`trials and was not prescriptive on the dose to potentially include. Biogen took the
`
`FDA’s remarks under advisement,
`
`recognizing that
`
`it was already carefully
`
`evaluating and preparing for the possible addition of a lower dose to the Phase III
`
`trial design. As discussed above, leading into the EOP2 meeting, the only lower
`
`dose under consideration from Biogen’s perspective was 240 mg BID (480
`
`mg/day).
`
`26.
`
`Biogen immediately held discussions following the meeting with the
`
`FDA to fiirther discuss the Phase III dosing and decided to include 240 mg BID
`
`(480 mg/day) in the Phase III trial design. Ex. 2228 at 1 (Sept. 11, 2006, clinical
`
`development team meeting minutes). Because of Biogen’s thorough evaluation of
`
`and preparation for the 240 mg BID (480 mg/day) dosing arm prior to the EOP2
`
`meeting with the FDA, we rapidly finalized the first Phase III study (1 O9MS30l). I
`
`

`

`approved and signed that protocol on September 21, 2006. Ex. 2369 and Ex. 2229
`
`at 1 (Sept. 21, 2006, final protocol for study 109MS301). Shortly thereafter, on
`
`October 16, 2006,
`
`I approved and signed the protocol for the second Phase III
`
`study (109MS302). Ex. 2376 at 6; Ex. 2231 at l. I approved and signed Version 2
`
`of the protocol for the first Phase III study on October 25, 2006. Ex. 2230 at 1.
`
`27.
`
`Biogen diligently prepared for and carried out the MS Phase III trials,
`
`which were large and significant undertaking over several years, requiring daily
`
`patient intake of BG-12 or placebo. The first Phase III study (lO9MS301) involved
`
`a total of 1,237 patients at 198 sites in 28 countries worldwide. Ex. 2376 at 12. The
`
`first patient began treatment in March 2007, and the last patient completed the
`
`study in February 2011. Id. at 6. The second Phase III study (109MS302) involved
`
`a total of 1430 patients at 200 sites in 28 countries worldwide. Id. at 12. The first
`
`patient was treated in July 2007, and the last patient completed the study in August
`
`2011. Id. at 6. Throughout the Phase III trials, hundreds of MS patients on a daily
`
`basis took BG-12 (i.e., a pharmaceutical composition containing DMF as the sole
`
`active agent and at least one pharmaceutically acceptable excipient) at an amount
`
`of480 mg per day DMF. Ex. 2376 at 12 and 13.
`
`28.
`
`I received regular updates on the progress of the Phase III trials. See,
`
`e.g., Ex. 2370 at 1, 3 (Mar. 1, 2007, Neurology TA Committee meeting minutes);
`
`Ex. 2371 at 1, 3 (Aug. 15, 2007, Neurology R&D Committee meeting minutes). I
`
`

`

`was particularly involved in events relating to the clinical trial protocols and drug
`
`safety and risk management.
`
`29.
`
`I became aware of the efficacy results of the first Phase III study
`
`(lO9MS30l) at or around the time they were accessed by members of the BG-12
`
`team in April 2011. I was thrilled to observe that Dr. O’Neill’s idea of orally
`
`administering BG-12 at an amount of 480 mg per day DMF to treat MS patients
`
`was proven to be successful. I recognized that the 480 mg per day dose was
`
`therapeutically effective for treating MS patients because the MS patients who
`
`received that dose attained certain desired biological outcomes,
`
`including
`
`decreased patient relapse, decreased number of T2-hyperintense lesions, and
`
`decreased Gd-enhancing lesions. Furthermore, I was quite surprised that the dose
`
`demonstrated similar efficacy to the higher 720 mg per day dose with a high level
`
`of statistical significance.
`
`30.
`
`I hereby declare that all
`
`statements made herein of my own
`
`knowledge are true and that all statements made on information and belief are
`
`believed to be true, and, further, that these statements are made with knowledge
`
`that willful false statements and the like are punishable by fine or imprisonment, or
`
`both, under Section 1001 of Title 18 of the United States Code and may jeopardize
`
`the validity of Biogen’s U.S. Patent No. 8,399,514.
`
`

`

`31.
`
`In signing this declaration, I understand that the declaration will be
`
`filed as evidence in a contested case before the Patent Trial and Appeal Board of
`
`the United States Patent and Trademark Office.
`
`I acknowledge that I may be
`
`subject to cross examination in the case and that cross examination will take place
`
`within the United States. If cross examination is required of me, I will appear for
`
`cross examination within the United States during the time allotted for cross
`
`examination.
`
`Date:
`
`061 jl//\/E3’0[(a
`
`Carmen Bozic, M.D.
`
`

`

`
`
`
`
`
`
`
`
`APPENDIX 1
`
`
`
`APPENDIX 1APPENDIX 1
`
`
`
`
`
`Page 22 of 27
`
`

`

`
`
`
`
`Name: Carmen Rosemarie Bozic MD
`
`Address: 101 Manet Road, Chestnut Hill, MA 02467
`
`Place of Birth: Edmonton, Alberta, Canada
`
`Education:
`
` 1986 M.D., C.M. McGill University Faculty of Medicine, Montreal, Canada
`
`Industry Experience:
`
`
`Curriculum Vitae
`
`Associate Director, Medical Research, Biogen
`Director, Medical Research, Biogen
`Senior Director, Medical Research, Biogen Idec
`Senior Director, Clinical Trial Drug Safety and Risk Management, Biogen
`
`Senior Director and Global Head, Drug Safety and Risk Management,
`
`VP and Global Head, Drug Safety and Risk Management, Biogen Idec
`Senior VP and Global Head, Safety and Benefit-Risk Management,
`
`Senior VP, Clinical and Safety Sciences, Biogen Idec
`Senior VP, Global Development, Biogen
`
`1998-2001
`2001-2003
`2003-2005
`2005-2005
`Idec
`2005-2006
`Biogen Idec
`2006-2009
`2009-2013
`Biogen Idec
`2013-2015
`2015-present
`
`
`
`Industry Career Highlights:
`
` 
`
` Experienced leader in biopharmaceutical drug development with over 15 years
`of progressively increasing responsibilities leading multiple functions within
`Research and Development, overseeing global clinical development programs
`in all phases of development, regulatory filings, and launches in several
`therapeutic areas, and addressing complex issues in patient safety and benefit-
`risk. Dr. Bozic has overseen functions accountable for the regulatory filing
`and approvals of multiple therapies, including TECFIDERA (dimethyl
`fumarate), TYSABRI (natalizumab) and PLEGRIDY (pegylated interferon
`beta-1a) for multiple sclerosis, as well as ELOCTATE (Factor VIII Fc fusion
`protein) and ALPROLIX (Factor IX Fc fusion protein) for the treatment of
`severe Hemophilia A and B in multiple countries.
`
`
`Page 23 of 27
`
`

`

` Current leadership of Global Development organization, a department with
`over 500 people within Research and Development. Her department is
`responsible for developing and obtaining regulatory approval of therapies in
`Biogen’s therapeutic focus areas of Neurology, Immunology and Hematology.
`Functions include global clinical development, regional clinical development
`in Japan and Europe, safety and benefit risk management, global clinical
`operations, medical writing as well as biostatistics, data management and
`statistical programming.
`
`
` Former leadership of Clinical and Safety Sciences, a department of 200
`personnel within Research and Development, responsible for managing global
`clinical development, safety and benefit-risk management, preclinical safety,
`as well as Japan Development for all products in the pre-approval and post-
`approval phases within Biogen Idec’s therapeutic focus areas of Neurology,
`Immunology, Fibrosis and Hematology.
`
` Former leadership of world-class global safety and benefit-risk management
`department of 110 personnel, accountable for patient safety for all pipeline and
`marketed products worldwide. Department included medical safety and
`benefit-risk management, safety operations, compliance, safety database
`strategy and analytics, epidemiology as well as preclinical safety functions.
`
`
`
`
`
` Led multi-functional team in design and implementation of complex risk
`management plan and was major contributor for sBLA in support of re-
`marketing after product suspension for TYSABRI (natalizumab). Presented at
`FDA Advisory Committee on this topic, leading to regulatory approval of
`TYSABRI (natalizumab).
`
`
`
`Postdoctoral training:
`
` Internship and Residency:
`
` 1986-1987 Intern in Medicine, Royal Victoria Hospital, McGill University, Montreal,
`Canada
` 1987-1988 Junior Assistant Resident in Internal Medicine, Royal Victoria Hospital,
`Montreal
` 1988-1989 Senior Assistant Resident in Internal Medicine, Royal Victoria Hospital,
`Montreal
` 1989-1990 Chief Medical Resident, Royal Victoria Hospital, Montreal
`
` Fellowship:
`
` 1990-1991 Pulmonary Fellow, Combined Pulmonary and Critical Care Division, Brigham
`and
`
`Page 24 of 27
`
`

`

` Women's Hospital and Beth Israel Hospital, Harvard Medical School, Boston
` 1991-1992 Critical Care Fellow, Combined Pulmonary and Critical Care Division,
`Brigham and
`