`
`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: IPR2016-01993
`U.S. Patent No. 8,399,514
`____________________________________________
`
`DECLARATION OF KATHERINE T. DAWSON, M.D.
`
`
`
`Page 1 of 63
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`Biogen Exhibit 2077
`Coalition v. Biogen
`IPR2015-01993
`
`

`

`TABLE OF CONTENTS
`
`I.
`
`Personal Background and Introduction ........................................................... 1
`
`II. Dr. Gilmore O’Neill’s Idea to Treat MS Using 480 mg/day of DMF ............ 6
`
`III. Overview of Biogen’s Work Towards Treating MS Using 480 mg/day
`of DMF ............................................................................................................ 7
`
`A.
`
`B.
`
`Biogen’s BG-12 MS Team .................................................................... 7
`
`Biogen’s BG-12 MS Phase III Planning and Trials ............................11
`
`1.
`
`2.
`
`3.
`
`Biogen’s Daily Non-Clinical (Animal) Activities ....................12
`
`Biogen’s Daily Clinical (Human) Activities Before the
`FDA EOP2 Meeting ..................................................................15
`
`Biogen’s Daily Clinical (Human) Activities After the
`EOP2 Meeting Until the Start of the Phase III trials ................18
`
`IV. Detailed Description of Phase III Planning: June 2006 - February
`2007 ...............................................................................................................22
`
`A.
`
`B.
`
`June 2006 .............................................................................................23
`
`July 2006 .............................................................................................24
`
`C. August 2006 ........................................................................................26
`
`D.
`
`E.
`
`F.
`
`September 2006 ...................................................................................28
`
`October 2006 .......................................................................................31
`
`November 2006 ...................................................................................32
`
`G. December 2006 ....................................................................................34
`
`H.
`
`I.
`
`January 2007 ........................................................................................35
`
`February 2007 ......................................................................................37
`
`i
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`

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`V. Declaration Submitted During the Prosecution of U.S. Application
`No. 12/526,296 ..............................................................................................39
`
`Case No. IPR2015-01993
`Patent 8,399,514
`
`
`VI. Appendices ....................................................................................................40
`
`VII. Conclusion .....................................................................................................40
`
`ii
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`Page 3 of 63
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`

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`I, Katherine T. Dawson, have personal knowledge of the facts stated herein
`
`and provide the following testimony:
`
`I.
`
`Personal Background and Introduction
`
`1.
`
`I am currently the Vice President of U.S. Medical at Biogen. Since
`
`joining Biogen in 2004, I have held several positions, including Associate Director,
`
`Medical Research/Clinical Development (March 2004 - November 2006),
`
`Director, Clinical Development Neurology, November 2006 - November 2009),
`
`Senior Director of Neurology Clinical Development (November 2009 - January
`
`2013), Vice President of Global Medical Neurology (January 2013 - March 2015)
`
`and Vice President, U.S. Medical from March 2015 until the present.
`
`2.
`
`I received a B.A. in biology/psychology from Columbia College in
`
`1987, and an M.D. from Albert Einstein College of Medicine of Yeshiva
`
`University in 1993. Thereafter, I was a Neurology Resident at Massachusetts
`
`General Hospital until 1997, then a fellow of Clinical Neurophysiology at
`
`Massachusetts General Hospital until 1998. I then became a Clinical Instructor of
`
`Neurology at Massachusetts General Hospital. I continued to hold this position
`
`even after joining Biogen and stayed in this position until March 2014.
`
`3.
`
`I understand that the U.S. Patent and Trademark Office has instituted
`
`review of Biogen’s U.S. Patent No. 8,399,514 (“the ’514 patent”). Ex. 1001.
`
`1
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`Case No. IPR2015-01993
`Patent 8,399,514
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`Biogen’s Tecfidera® is a multiple sclerosis (“MS”) product, which is
`
`4.
`
`administered as an oral therapy of 480 mg per day of dimethyl fumarate (“DMF”)
`
`and one or more pharmaceutically acceptable excipients to treat MS. In June 2006,
`
`I joined the Tecfidera® team and, in July 2006, officially took over as medical
`
`director of the project and oversaw the preparation and operation of Biogen’s
`
`pivotal Phase III trials. A Phase III clinical trial is a study to demonstrate whether
`
`or not a product offers a treatment benefit to a specific population, in this case,
`
`humans suffering from MS. Phase III trials are usually tested on anywhere from
`
`300 to 3,000 patients and last from one to four years. See
`
`www.fda.gov/forpatients/approvals/drugs/ucm405622.htm#Clinical
`
`Research Phase Studies. Phase III studies, like all clinical trials, are conducted
`
`under the guidance and guidelines set out by regulatory agencies such as the U.S.
`
`Food and Drug Administration (“FDA”).
`
`5.
`
`I provide this declaration to document the work that I and others at
`
`Biogen were doing prior to and after Biogen filed the patent applications leading to
`
`the ’514 patent, from 2006 and continuing through 2011. Throughout this time
`
`period, the project leading to the development and approval of Tecfidera® was a
`
`high priority of Biogen. Biogen’s Phase III trials were large and intensive
`
`undertakings requiring years of testing and the efforts of numerous groups across
`
`2
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`Case No. IPR2015-01993
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`the company, including the clinical development, clinical operations, regulatory,
`
`safety, biostatistics, medical writing, manufacturing, and other groups. As
`
`discussed below, Biogen diligently planned, carried out, and evaluated its Phase III
`
`clinical trials. The result of this persistent, diligent effort was approval, marketing
`
`and patenting of Tecfidera®.
`
`6.
`
`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 employees or Biogen contractors
`
`having knowledge of those matters (i.e., business record) or documents that are
`
`publicly available from an official U.S. government website or a peer-reviewed
`
`journal. 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. 2082, 2083, 2086, 2087, 2090,
`
`2106, 2128, 2132, 2134, 2196, 2198, 2203, 2206, 2210-2223, 2225-2242, 2274-
`
`2276, 2308, 2316, 2327, 2328, 2339, 2344, 2352, 2361, and 2377 are Biogen’s
`
`business record documents. Ex. 2085 is a Pharmacological Review report
`
`published by the FDA’s Center for Drug Evaluation and Research (“CDER”)
`
`available at the FDA’s official website:
`
`3
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`http://www.accessdata.fda.gov/drugsatfda
`
`Case No. IPR2015-01993
`Patent 8,399,514
`
`
`docs/nda/2013/204063Orig1s000PharmR.pdf Pages 1-11 of Ex. 2244 are an article
`
`published by the New England Journal of Medicine on Sept. 20, 2012, in vol. 367,
`
`no.
`
`12,
`
`pages
`
`1087-1097
`
`and
`
`further
`
`available
`
`at
`
`http://www.nejm.org/doi/pdf/10.1056/NEJMoa1206328; pages 12-39 are
`
`the
`
`supplementary appendix to that article, available at
`
`http://www.nejm.org/doi/suppl/10.1056/NEJMoa1206328/suppl file/nejmoa
`
`1206328 appendix.pdf; and pages 40-165 are the protocol referred to in the article,
`
`available at
`
`http://www.nejm.org/doi/suppl/10.1056/NEJMoa1206328/suppl file/nejmoa
`
`1206328 protocol.pdf. Pages 1-10 of Ex. 2245 are an article published by the New
`
`England Journal of Medicine on Sept. 20, 2012, in vol. 367, no. 12, pages 1098-
`
`1107
`
`and
`
`further
`
`available
`
`at
`
`http://www.nejm.org/doi/pdf/10.1056/NEJMoa1114287; pages 12-32 are
`
`the
`
`supplementary appendix to that article, available at
`
`http://www.nejm.org/doi/suppl/10.1056/NEJMoa1114287/suppl file/nejmoa
`
`1114287 appendix.pdf; pages 33-278 are the protocol referred to in the article,
`
`available at
`
`4
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`http://www.nejm.org/doi/suppl/10.1056/NEJMoa1114287/suppl file/nejmoa
`
`Case No. IPR2015-01993
`Patent 8,399,514
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`
`1114287 protocol.pdf. Ex. 2297 is a letter enclosing a Memorandum of Meeting
`
`Minutes from the FDA to Biogen dated Sept. 29, 2006, published on the FDA’s
`
`official website:
`
`http://www.accessdata.fda.gov/drugsatfda docs/nda/2013/204063Orig1s000
`
`Admincorres.pdf.
`
`Ex. 2375 is a Statistical Review and Evaluation, Carcinogenicity Studies,
`
`relating to Biogen’s Tecfidera product published on the FDA’s official website:
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204063Orig1s000
`
`StatR.pdf Ex. 2376 is a Statistical Review and Evaluation, Clinical Studies,
`
`relating to Biogen’s Tecfidera product published on the FDA’s official website:
`
`http://www.accessdata.fda.gov/drugsatfda docs/nda/2013/204063Orig1s000
`
`StatR.pdf.
`
`7.
`
`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 or peer-
`
`reviewed journal. 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
`
`5
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`Case No. IPR2015-01993
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`research program relating to Tecfidera®) and, additionally, through the exhibits
`
`cited herein. For example, Exhibit Nos. 2082, 2083, 2086, 2087, 2090, 2106,
`
`2128, 2132, 2134, 2196, 2198, 2203, 2206, 2210-2223, 2226, 2228-2242, 2274-
`
`2276, 2308, 2339, 2344, 2352, 2361, and 2377 are documents 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 an FDA filing
`
`for BG-12, I was aware of the contents of these filings because all FDA filings
`
`related to BG-12 were reported to and discussed by the BG-12 team. Exhibit Nos.
`
`2085, 2297, 2375 and 2376 are true and accurate copies of reports published by the
`
`FDA or the NIH on an official U.S. government website. Exhibit Nos. 2244 and
`
`2245 are true and accurate copies of articles with supplemental materials published
`
`by the New England Journal of Medicine on Sept. 20, 2012, in vol. 367, no. 12,
`
`pages 1087-1107 and further available at http://www.nejm.org/.
`
`II. Dr. Gilmore O’Neill’s Idea to Treat MS Using 480 mg/day of
`DMF
`
`8.
`
`I have known Dr. Gilmore O’Neill—who is a named inventor on the
`
`’514 patent—since 1992 when we were both interviewing for neurology residency
`
`positions. In 2004, we were both at Biogen and our offices were directly next to
`
`each other. At the time, Dr. O’Neill was assigned to work on an orally-
`
`administered pharmaceutical composition containing DMF as the sole active agent
`
`6
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`and various excipients (also referred to as BG-12). Even though I was assigned to a
`
`different project at the time, Dr. O’Neill and I had many conversations about our
`
`respective projects, including Dr. O’Neill’s BG-12 MS project. In planning for
`
`Biogen’s Phase IIb trial with BG-12, Dr. O’Neill thought that 480 mg/day DMF
`
`made medical sense, would be effective, and, because it would be administered
`
`twice daily (“BID”) rather than three times daily (“TID”) as for the other proposed
`
`doses, would be a big advantage for patients. Dr. O’Neill felt very strongly about
`
`this and we had many conversations relating to his idea to use 480 mg/day DMF to
`
`treat MS. He continued to remain a strong proponent of evaluating 480 mg/day
`
`DMF throughout the MS Phase IIb trials and in preparing for the pivotal Phase III
`
`trials. Indeed, Dr. O’Neill was extremely pleased to learn that his idea to use 480
`
`mg/day DMF to treat MS was included in Biogen’s Phase III studies.
`
`III. Overview of Biogen’s Work Towards Treating MS Using 480
`mg/day of DMF
`
`A. Biogen’s BG-12 MS Team
`
`9.
`
`I joined Biogen’s MS BG-12 team in June 2006 and officially
`
`assumed the role as medical director in July 2006. See Ex. 2316 at 5. The BG-12
`
`project was an important, high-priority project at Biogen because it was an oral
`
`drug and at that time there were no oral drugs approved for treating MS. As such,
`
`BG-12 would satisfy an unmet need if approved for the treatment of MS. Thus, in
`
`7
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`order to manage this intense effort, Biogen established a number of teams to work
`
`on the BG-12 project. For example, I was part of the BG-12 Program Team whose
`
`job was to manage the drug (DMF) as a whole, regardless of indication. The team
`
`dealt with anything related to the drug — e.g., development, drug supply and
`
`manufacture, safety, and commercialization. The team met weekly, although
`
`occasionally bi-weekly, to discuss anything and everything relating to BG-12 from
`
`clinical to preclinical work (regulatory, commercial, clinical, etc.). I regularly
`
`attended the BG-12 Program Team meetings. In addition, as medical director for
`
`the Phase III studies, I always received a copy of any prepared meeting minutes,
`
`whether or not I was able to attend a particular meeting.
`
`10.
`
`I was also part of the Study Management Team (“SMT”) whose task
`
`was to administer the actual Phase III trials. The SMT was a cross-functional group
`
`that involved a large number of people from a variety of departments in Biogen:
`
`clinical, regulatory, planning and operations, medical writing, biostatistics,
`
`labelling, drug supply, safety, and so on. The SMT team met weekly or bi-weekly
`
`to discuss activities involved in the planning and execution of the Phase III studies.
`
`I regularly attended the SMT meetings. In addition, as medical director for the
`
`Phase III studies, I always received a copy of any prepared meeting minutes,
`
`whether or not I was able to attend a particular meeting.
`
`8
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`In addition, I was part of the Clinical Development Team (“CDT”)
`
`11.
`
`that made strategic decisions regarding the studies. As Medical Director for the MS
`
`indication, I led the MS CDT, which also included other core positions such as
`
`Manager, Clinical Development and Program Statistician and included lead
`
`representatives from Regulatory Affairs, Drug Safety and Risk Management,
`
`Planning and Operations, Data Management, Clinical Communications, Drug
`
`Logistics, and other important groups at Biogen as needed. The CDT team met
`
`weekly, although sometimes bi-weekly, to discuss study protocols and planning,
`
`medical writing tasks, regulatory issues, etc. I regularly attended the CDT
`
`meetings. In addition, as medical director for the Phase III studies, I always
`
`received a copy of any prepared meeting minutes, whether or not I was able to
`
`attend a particular meeting.
`
`12. From the time I formally took over as medical director of the BG-12
`
`MS program, I worked every day on planning and implementation of the Phase III
`
`trials. In addition, Biogen assigned about 20 full-time employees to the BG-12
`
`Phase III planning and more than 30 full-time employees to carry out the trials.
`
`These individuals, including myself, worked every day on the planning and
`
`implementation of its Phase III clinical trials. Other full-time people on the BG-12
`
`MS project included Ratna Lingamaneni (regulatory), Minhua Yang (biostatistics),
`
`9
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`and Phill Gallacher (clinical trial management). In addition, at least 20 part-time
`
`employees were assigned to the project including Tammy Sarnelli (regulatory),
`
`John O’Gorman (biostatistics), and Carmen Bozic (medical and safety). In total,
`
`hundreds of people at Biogen worked on the BG-12 MS Phase III project,
`
`conducting daily activities to ensure the Phase III trials proceeded as efficiently as
`
`possible.
`
`13.
`
`In addition, Biogen contracted with Contract Research Organizations
`
`(“CROs”) and multiple vendors,
`
`laboratories, manufacturers,
`
`laboratories,
`
`investigators, medical researchers, and medical technicians. The work by these
`
`groups can all be attributed to Biogen as Biogen chose to contract out these
`
`activities rather than conduct those activities itself. This is typical practice in the
`
`pharmaceutical industry as a single company rarely has the internal resources
`
`necessarily to conduct all the intense daily efforts that go into a clinical trial. As
`
`used herein, activities by “Biogen” refers to activities by me, the other Biogen
`
`employees, and/or its contracted agents.
`
`
`
`
`
`
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`
`
`10
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`Biogen’s BG-12 MS Phase III Planning and Trials
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`Case No. IPR2015-01993
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`
`B.
`
`14. When I joined the BG-12 team in June 2006, Biogen had already
`
`submitted its Investigational New Drug application (“IND”)1 to the FDA and had
`
`completed its Phase IIb MS trial (Study No. C-1900). At that time, Biogen was
`
`continuing to work daily on its Phase III protocols, conducting various non-clinical
`
`animal studies, and preparing for an End of Phase II (“EOP2”) meeting with the
`
`FDA in order to receive approval to conduct two Phase III MS trials (Study Nos.
`
`109MS301 and 109MS302). An EOP2 meeting is a meeting with the FDA in
`
`which the drug sponsor and the FDA try to reach an agreement on major issues,
`
`such as the clinical end points2, safety profile, and the highest dose to be tested in a
`
`Phase III study.
`
`
`1 An IND is a request for authorization from the FDA to administer an
`
`investigational drug or biological product to humans.
`
`2 In clinical trials, an end point is an event or outcome that can be measured
`
`objectively to determine whether the intervention being studied is beneficial. For
`
`example, the primary end point in Biogen’s first Phase III trial was the proportion
`
`of subjects who relapsed at 2 years compared with placebo. See, e.g., Ex. 2245 at
`
`abstract.
`
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`Biogen’s Daily Non-Clinical (Animal) Activities
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`Case No. IPR2015-01993
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`1.
`
`15. As part of the regulatory requirements to file a new drug application,
`
`both prior to and during the beginning of its Phase III trials, Biogen was diligently
`
`conducting four FDA-required non-clinical studies, during which animals were
`
`dosed with DMF daily. These FDA-required animal studies were essential steps
`
`toward the development and approval of Tecfidera® because they were a necessary
`
`part of Biogen’s efforts to establish the safety and efficacy of BG-12 as a treatment
`
`for MS in humans. See, e.g., Ex. 2087 at 1 (April 20, 2007, letter from FDA
`
`requiring the submission of the final report on the study prior to the initiation of the
`
`Phase III trials).
`
`16. More specifically, Biogen was conducting an 11-month toxicity study
`
`in dogs (Study No. P00012-05-05). See, e.g., Ex. 2085 at 77-95. In that study, 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 (pages 15-16).
`
`12
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`17. Biogen was also in the middle of conducting a two-year mouse study,
`
`a two-year rat study, and a one-year monkey study. In the mouse study (Study No.
`
`P00012-05-03), BG-12 was administered once-daily to mice for a varying number
`
`of weeks.3 See, e.g., 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 (page 10). But for one day during which dosing was impossible
`
`due to inclement weather, daily dosing continued until at least June 25, 2007. Id. at
`
`§ 6.5 (pages 18-19) (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 (page 19).
`
`18.
`
`In the rat study (Study No. P00012-04-11), BG-12 was administered
`
`once-daily to rats for a varying number of weeks.4 See, e.g., Ex. 2375 at 18 (Study
`
`
`3 Animals in Group 1 were the control group and therefore did not receive any BG-
`
`12. See Ex. 2375 at 26.
`
`4 Animals in Group 1 were the control group and therefore did not receive any BG-
`
`12. See Ex. 2375 at 18.
`
`13
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`duration: 104 weeks (two male dose groups terminated early)); Ex. 2085 at 128-
`
`152. Daily dosing began on October 26, 2004 (the in-life phase). See Ex. 2274 at
`
`§ 5 (page 10). But for two days when dosing was impossible due to inclement
`
`weather, daily dosing continued until October 23, 2006. Id. § 6.6 (page 20) (drug
`
`administered daily to animals for 80, 82, or 104 weeks; dosing was not possible on
`
`Dec. 23, 2004 and Jan. 6, 2005). 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 (page 20-21).
`
`19.
`
`In the monkey study (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 at cover (page 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) (page 10).
`
`20. Thus, with the exception of February 14, 2007 when treatment was
`
`not possible, Biogen was dosing animals in the non-clinical studies on a daily basis
`
`14
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`from the time I joined Biogen in June 2006 and extending at least until June 25,
`
`2007.
`
`2.
`
`Biogen’s Daily Clinical (Human) Activities Before the
`FDA EOP2 Meeting
`
`
`21. The EOP2 meeting with the FDA was held on August 30, 2006. As
`
`detailed below, prior to meeting with the FDA for its EOP2 meeting, Biogen was
`
`working on a number of activities each day in order to advance clinical
`
`development of its Phase III trials. For example, Biogen was drafting its Phase III
`
`protocols, its Investigator’s Brochure (“IB”)5, its Case Report Forms (“CRFs”)6,
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`and its responses to various regulatory inquiries.
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`22.
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`In addition, as discussed in detail below, prior to the FDA meeting,
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`Biogen was preparing to evaluate the QTc interval prolongation potential of BG-12
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`when administered to healthy volunteers (Study No. 109HV101), a study required
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`5 An Investigator’s Brochure is a comprehensive document that summarizes
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`information about a drug product and is provided to clinicians during a clinical
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`trial.
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`6 A Case Report Form is a tool used by a drug sponsor of a clinical trial (in this
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`case, Biogen) to collect data from each participating site. All data on each patient
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`participating in the trial are held and/or documented in the CRF.
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`by the FDA before Biogen could begin its Phase III studies.7 Biogen also worked
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`to secure a contract research organization (“CRO”) to manage the studies and
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`vendors to perform various tasks during the study.
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`23.
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`In addition, in view of the safety and efficacy data from the Phase IIb
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`studies, the advantage of BID dosing versus TID dosing on patient compliance,
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`and the dosing gap in the Phase IIb studies (i.e., no dose between 720 mg/day and
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`360 mg/day), Biogen began running an analysis on the potential addition of a 480
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`mg/day dosing arm to the MS Phase III trial designs.
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`24.
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`In its EOP2 package, Biogen initially proposed testing 720 mg/day in
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`its Phase III trials as that dose had been shown to be effective in the earlier Phase
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`IIb trial and was a logical endpoint for Phase III clinical trials. Biogen also
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`believed that if the FDA would allow Biogen to test a 720 mg/day dose, the FDA
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`would also allow Biogen to test the lower 480 mg/day dose and therefore there was
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`no need to propose this specific dose in the EOP2 package.
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`7 In cardiology, the QT interval is a measure of the time between the start of the Q
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`wave and the end of the T wave in the heart's electrical cycle. A lengthened QT
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`interval is a marker for the potential of ventricular tachyarrhythmias like torsades
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`de pointes and a risk factor for sudden death.
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`25. At the EOP2 meeting, a number of BG-12 team members including
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`myself met with various FDA personnel to discuss Biogen’s proposed Phase III
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`studies. See, e.g., Ex. 2297 at 3-6 (FDA meeting minutes from EOP2 meeting).
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`During the meeting, the FDA was positive about the drug as Biogen’s Phase IIb
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`study showed the drug a good efficacy in MS patients, was generally well
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`tolerated, and was orally administered instead of injected.8 The FDA also raised a
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`number of the points that Biogen had already considered, including adding a lower
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`dose to the trials. Biogen took the FDA’s remarks under advisement, recognizing
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`that Biogen was already carefully evaluating and preparing for the possible
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`addition of a lower dose to the Phase III trial design. As noted above, the only
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`lower dose Biogen was evaluating for the purpose of adding to the Phase III trial
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`was the 480 mg/day dose, as Biogen believed that the dose would be effective for
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`treating MS, albeit less effective than the 720 mg/day dose. The FDA encouraged,
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`but did not require, Biogen to add a lower dose to the Phase III design and was not
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`prescriptive on the dose to potentially include.
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`
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`8 At the time, the only commercial available MS treatments were injectables.
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`Biogen’s Daily Clinical (Human) Activities After the
`EOP2 Meeting Until the Start of the Phase III trials
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`3.
`
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`26. After the EOP2 meeting, I informed Dr. O’Neill regarding the
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`substance of the meeting. In addition, Biogen immediately held internal
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`discussions on Phase III dosing and decided to include 480 mg/day DMF in its
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`Phase III studies. Because of Biogen’s thorough evaluation of and preparation for
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`480 mg/day dosing arm prior to the EOP2 meeting, it took a mere three weeks,
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`which is exceptionally quick, to finalize the protocol for the first Phase III study
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`(Study No. 109MS301). The protocol for the second Phase III study (Study No.
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`109MS302) was finalized less than a month later.
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`27.
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`In addition to finalizing its Phase III protocols, Biogen worked daily
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`on a number of other tasks in order to advance clinical development of its Phase III
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`trials. For example, Biogen began its QTc evaluation study (109HV101), which
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`involved daily administration of BG-12 to healthy volunteers, corresponding with
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`the FDA and other regulatory agencies, and making further amendments to its
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`protocols, CRFs, and Informed Consent Forms (“ICFs”)9.
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`9 An Informed Consent Form is a document that describes the potential risks and
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`benefits of participating in a clinical trial.
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`In addition, in order to ensure the trials were properly run, Biogen
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`28.
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`formed an Advisory Committee (“AC”) to provide scientific and medical direction
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`for the study and to oversee the administrative progress of the Phase III studies.
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`See, e.g., Ex. 2245 at 2; Ex. 2244 at 2. The AC for the 109MS301 study consisted
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`of Dr. Ralf Gold (coordinating investigator and chairperson), Dr. Ludwig Kappos,
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`Dr. Douglas Arnold, Dr. Amit Bar-Or, Dr. Gavin Giovannoni, Dr. Krzystof
`
`Selmaj, myself, Mr. Phill Gallacher, Ms. Carole Milla, and Ms. Minhua Yang. Ex.
`
`2245 at 13. The AC for the 109MS302 study consisted of Dr. Robert J. Fox
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`(coordinating investigator and chairperson), Dr. J. Theodore Phillips, Dr. Michael
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`Hutchinson, Dr. Eva Havrdova, Dr. Mariko Kita, myself, Ms. Kate Wilson, and
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`Ms. Minhua Yang. Ex. 2244 at 15.
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`29. Biogen also established a Data Safety Monitoring Committee
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`(“DSMC”) to review safety data and alert Biogen about possible safety concerns
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`related to the conduct of the study. See, e.g., Ex. 2245 at 2; Ex. 2244 at 2. The
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`DSMC for the both studies consisted of Dr. Jack Antel (Chairperson, Neurology;
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`Montreal Neurological Hospital, Montreal, Quebec, Canada), Dr. George Bakris
`
`(Nephrology; University of Chicago, Pritzker School of Medicine, Chicago, IL,
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`USA), Dr. Raymond Chung (Hepatology; Massachusetts General Hospital, Boston,
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`MA, USA), Dr. Peter R Kowey (Cardiology; Jefferson Medical College,
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`Wynnewood, PA, USA), Dr. Chris Polman (Neurology; VU Medical Center,
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`Amsterdam, The Netherlands), Dr. John Richert (thru February 2010: Neurology;
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`National Multiple Sclerosis Society, New York, NY, USA), Burt Seibert
`
`(Independent Biostatistician; Statistical Services Network, Plaistow, NH, USA),
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`James Ware PhD (Statistics; Harvard School of Public Health, Boston, MA, USA).
`
`Ex. 2245 at 13; Ex. 2244 at 15.
`
`30.
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`In addition, Biogen established an Independent Neurology Evaluation
`
`Committee (“INEC”) in order to obtain a consistent and independent-blinded
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`determination of whether a subject had experienced an MS relapse as defined by
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`the protocols. See, e.g., Ex. 2245 at 13; Ex. 2244 at 15. The INEC for both the
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`109MS301 and 109MS302 studies consisted of Dr. David Brandes (Northridge
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`Multiple Sclerosis Center, Northridge, CA, USA), Dr. David Brassat (INSERM
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`U.563, Hopital Purpan, Toulouse, France), Dr. Bruce Cohen (Fineberg School of
`
`Medicine, Chicago, IL, USA), Dr. Ricarda Diem (University of the Saarland,
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`Homburg/Saar, Germany), Dr. Myla Goldman
`
`(University of Virginia,
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`Charlottesville, VA, USA), Dr. Robert Herndon (University of Mississippi Medical
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`Center, Jackson, MS, USA), Dr. Aaron Miller (Mount Sinai Medical Center, New
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`York, NY, USA), Dr. Hayrettin Tumani (University of Ulm, Ulm, Germany). Ex.
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`2245 at 13; Ex. 2244 at 15.
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`31. Biogen also contracted with various laboratories to acquire and
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`evaluate magnetic resonance imaging (“MRI”) scans, analyze clinical laboratory
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`samples, and evaluate electrocardiograms (“ECG”) collected during the studies.
`
`See, e.g., Ex. 2082 at § 6.3 (page 5); Ex. 2083 at § 6.3 (page 5). In addition,
`
`Biogen contracted with a number of CROs and vendors to perform a number of
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`other services including, for example, communication and data coordinating,
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`patient recruitment, central blinded randomization,