Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2018-01403
`Patent 8,399,514 B2
`____________________________________________
`
`DECLARATION OF GILMORE O’NEILL, M.D.
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`Biogen Exhibit 2097
`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 13
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`U.S. Patent No. 8,399,514
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________
`
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`BIOGEN MA INC.,
`Patent Owner.
`____________________________________________
`
`Case IPR2018-01403
`Patent 8,399,514 B2
`____________________________________________
`
`DECLARATION OF GILMORE O’NEILL, M.D.
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`Biogen Exhibit 2097
`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 13
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`I.
`II.
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`Personal Background and Introduction ........................................................... 1
`Biogen’s Phase II Clinical Trial of BG-12 ...................................................... 2
`A. My Role as Medical Director of the MS BG-12 Team ......................... 3
`B.
`The Subject Matter of Exhibits 1007, 1046, and 1016 ......................... 6
`Inventorship of the ’514 Patent Claims ........................................................... 8
`III.
`IV. Conclusion ....................................................................................................... 9
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`Table of Contents
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`i
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`Page 2 of 13
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`I, Gilmore O’Neill, have personal knowledge of the facts stated herein and
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`provide the following testimony:
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`I.
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`Personal Background and Introduction
`I am currently Executive Vice President, R&D and Chief Medical
`1.
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`Officer at Sarepta Therapeutics, a position I have held since June of 2018. Prior to
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`this position, I was employed at Biogen for nearly fifteen years, where I held several
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`positions, including Associate Director, Medical Research from 2003 to 2005;
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`Director, Medical Research from 2005 to 2007; Senior Director, Experimental
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`Neurology from 2007 to 2010; Vice President, Experimental Neurology (Early
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`Stage) from 2010 to 2012; Vice President, Global Late Stage Clinical Development
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`from 2012 to 2013; Vice President, Global Neurology Clinical Development from
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`2013 to 2014; Vice President, Research and Development MS Franchise from 2014
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`to 2015; Senior Vice President, Drug Innovation Units from 2015 to 2016; and
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`Senior Vice President, Late Stage Clinical Development from 2016 to 2018.
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`2.
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`I received my medical degree from University College Dublin in 1988
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`and completed residencies and fellowship
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`training
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`in
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`internal medicine,
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`pulmonology and neuropathology in 1993 at Beaumont Hospital, Dublin. I
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`completed my residency in Neurology at Massachusetts General Hospital in 1997
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`and was Chief Resident from 1996 to 1997. I also received a Master of Medical
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`Science degree from Harvard Medical School in 1999. I am a Neurologist at
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`Massachusetts General Hospital and have held that position since 1997.
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`3.
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`I understand that the U.S. Patent and Trademark Office has instituted
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`an Inter Partes Review, IPR2018-01403, involving Biogen’s U.S. Patent No.
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`8,399,514 (“the ’514 patent”), of which I am a named co-inventor.
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`4.
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`I also understand that Mylan has submitted the following exhibits in
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`that proceeding:
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`• Ex. 1007: L. Kappos et al., Efficacy of a Novel Oral Single-
`Agent Fumarate, BG0012, in Patients with Relapsing-Remitting
`Multiple Sclerosis: Results of a Phase 2 Study, 253 (Supp. 2) J.
`Neurol. II27, O108 (2006)
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`• Ex. 1046: L. Kappos et al., Efficacy of a Novel Oral Single-
`Agent Fumarate, BG0012, in Patients with Relapsing-Remitting
`Multiple Sclerosis: Results of a Phase II Study, 253 (16th
`Meeting of the European Neurological Society, May 20, 2006)
`
`• Ex. 1016: NewsRoom document, Oral Compound BG-12
`Achieves Primary Endpoint in Phase II Study of Relapsing-
`Remitting Multiple Sclerosis; Treatment with BG-12 Led to
`Statistically Significant Reductions in MRI Measures (May 30,
`2006)
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`5.
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`I provide this declaration based on my personal knowledge and my role
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`in the Phase II trial of BG-12 for the treatment of multiple sclerosis (MS).
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`II. Biogen’s Phase II Clinical Trial of BG-12
`6. Mylan’s Exhibits 1007, 1046 and 1016 relate to Biogen’s Phase II trial
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`of BG-12 (dimethyl fumarate, now marketed as Tecfidera®) in patients with multiple
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`sclerosis (MS). As the Medical Director of Biogen’s MS BG-12 program, the Phase
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`II subject matter described in those exhibits represents solely my work and the work
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`of those working under my direction and supervision. This is described more fully
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`in the paragraphs below.
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`A. My Role as Medical Director of the MS BG-12 Team
`I was Biogen’s Medical Director for its MS BG-12 program: the person
`7.
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`in charge of Biogen’s Phase II trial. In that role, I was responsible for all aspects of
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`the Phase II trial, including design, execution, and assessment and reporting of
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`results.
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`8.
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`For example, I presented the initial clinical trial concept, including four
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`proposed dosing options, to Biogen’s Clinical Trial Review Board (CTRB) in
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`February of 2004. See Ex. 2088. One of my proposed dosing options—120 mg/day,
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`360 mg/day, 720 mg/day—was the option we ultimately selected to move forward
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`with.
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`9.
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`I also supervised and directed the numerous people, both within and
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`outside Biogen, that were involved in carrying out the clinical trial. For example, I
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`supervised Rebecca Conaghan, the Clinical Trial Manager of the Phase II study. Her
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`role was to coordinate, under my direction and supervision, the administrative
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`aspects of the trial, such as study initiation, monitoring, and data management. On
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`August 16, 2004, Ms. Conaghan and I sent correspondence to members of the
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`Scientific Advisory Committee scheduling an initial Investigator Meeting in
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`Versailles, France, as shown in Ex. 2089. This correspondence also reflects other of
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`our initial steps in setting up the Phase II trial, including setting up 43 sites across
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`10 countries; setting up an MRI Reading Centre in London; making various ethics
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`and regulatory submissions; packaging and releasing drug supplies; and the
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`numerous other activities that must be undertaken in a clinical trial. See Ex. 2089.
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`I also supervised Minhua Yang, who served as Biogen’s Project Statistician for the
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`Phase II program and worked on compiling the results of the Phase II trial. I
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`reviewed and analyzed the data compiled and processed by Ms. Yang and others
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`working under my direction and supervision from a clinical perspective and these
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`results and analysis are reflected in Exhibits 1007, 1046, and 1016. Both Ms.
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`Conaghan and Ms. Yang worked on the Phase II trial under my direction and
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`supervision.
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`10.
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`In addition to the individuals within Biogen, we also assembled a
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`Scientific Advisory Committee to provide scientific and medical advice for the study
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`and to oversee the administrative process of the study. The Scientific Advisory
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`Committee included subsets of the trial’s Clinical Investigators (Ludwig Kappos,
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`designated “Coordinating Investigator,” Eva Havrdova, Ralf Gold, Chris Polman)
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`and the MRI Reading Centre team (David Miller), as well as consultants (Volker
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`Limmroth). The Clinical Investigators for the trial were responsible for enrolling
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`patients, overseeing administration of the drug, monitoring adverse events, reporting
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`U.S. Patent No. 8,399,514
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`data to Biogen, and ensuring compliance with all aspects of the protocol and
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`applicable policies and procedures. The MRI Reading Centre team was responsible
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`for collecting and compiling the MRI data that we obtained during the study.
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`11. All of these individuals—Biogen’s employees, the members of the
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`Scientific Advisory Committee, the Clinical Investigators, the MRI Reading Centre
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`team, and the various consultants and experts—worked on the Phase II trial under
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`my direction and supervision. For example, I held regular meetings of the Clinical
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`Development Team (CDT) and the Scientific Advisory Committee to obtain input
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`on various aspects of the study and address any issues as they arose. Exhibit 2092
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`is an example of such a meeting that I attended on September 8, 2004. I was also
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`the person responsible for reviewing and analyzing the data from the trial and
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`drawing conclusions about the data from a clinical perspective. Indeed, the Clinical
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`Investigators and Scientific Advisory Committee were blinded to the individual and
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`overall trial data during the course of the trial, and did not see the data or results until
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`after I (with the assistance of Minhua Yang), had analyzed the data and developed
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`conclusions about the data. This is reflected in the flowchart plan that I received on
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`October 25, 2005, Ex. 2090 at 2, which shows that I (“GON”) was one of the first,
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`along with the statisticians, to see, review, and analyze the data from the Phase II
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`trial, which data and analyses were subsequently presented to the investigators in the
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`U.S. Patent No. 8,399,514
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`trial, including the Clinical Investigators.
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`12.
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`In sum, as with all large-scale clinical trials, there were a number of
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`individuals involved in carrying out the study. However, as Medical Director of
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`Biogen’s MS BG-12 program, I was responsible for all aspects of the Phase II trial,
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`including the doses that were tested (120 mg/day, 360 mg/day, 720 mg/day) and the
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`results and conclusions drawn therefrom. As is standard in clinical trials,
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`information related to Biogen’s Phase II trial that was shared and exchanged among
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`those involved in the trial was confidential and non-public.
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`The Subject Matter of Exhibits 1007, 1046, and 1016
`B.
`13. Exhibits 1007 and 1046 are the abstract and slide presentation of the
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`Phase II results at the May 2006 ENS Meeting in Lausanne, Switzerland. As
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`described above, as Medical Director of the MS BG-12 program, I was responsible
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`for the doses that were tested and the results and conclusions drawn therefrom,
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`including the results reported in these two exhibits. Indeed, the subject matter
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`reported in Exhibits 1007 and 1046 is directly traceable to my own slides from
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`months earlier, in which I presented the same data and conclusions at a confidential
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`meeting in Luzern, Switzerland. See, e.g., Ex. 2091, slides 8, 9, 14.
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`14. The additional authors on the Exhibits 1007 and 1046 are individuals
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`both within and outside Biogen who worked on the Phase II trial under my direction
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`and supervision. Collectively, the Scientific Advisory Committee decided before
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`the trial was conducted who would be named as authors on publications of the Phase
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`II results. Ex. 2092. At that time, we agreed that the authors would include the
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`following:
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`• Coordinating Investigator: Ludwig Kappos
`• Scientific Advisory Committee Members: Ludwig Kappos, Eva Havrdova,
`Ralf Gold, Chris Polman, Volker Limmroth, and David Miller
`• Three Members of the MRI Reading Centre Team: Klaus Schmierer,
`David MacManus, Tarek Yousry
`• Study Medical Director: Gilmore O’Neill
`• Lead Statistician: Minhua Yang
`• Top Three Recruiting Investigators: Mefkure Eraksoy, Eva Meluzinova,
`Ivan Rektor
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`15. The authorship on Exhibits 1007 and 1046 was thus made to account
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`
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`for various individuals’ roles in carrying out the Phase II clinical trial. The work
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`described in Exhibits 1007 and 1046—including the dosing regimen and results
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`drawn therefrom—represents my work with help from others working under my
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`direction and supervision.
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`16.
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`I was also the person responsible for determining the material that
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`would be included in Exhibits 1007 and 1046. Drafts were prepared under my
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`direction and revised by me. Following my review and revision, when I was satisfied
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`with the content of the abstract and slide presentation, I circulated the drafts to
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`members of the Scientific Advisory Committee. For example, Exhibit 2093 is an
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`email I sent to Dr. Kappos on January 31, 2006 attaching draft abstracts. Any edits
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`provided by the members of the Scientific Advisory Committee were minimal in
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`nature and were done under my supervision and approval. Id.
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`17. Finally, Exhibit 1016 likewise describes the work of myself and those
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`working under my direction and supervision. Exhibit 1016 is a NewsRoom
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`document reflecting the Phase II work that I led as Medical Director of the MS BG-
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`12 program.
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`18.
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`In summary, Exhibits 1007, 1046, and 1016 concern Biogen’s Phase II
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`trial of BG-12 for the treatment of MS. As Medical Director, I was responsible for
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`the design and execution of that trial, and the reporting of its results. The contents
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`of these exhibits, including the selected doses of 120 mg/day, 360 mg/day, and 720
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`mg/day, the results, and the analysis, is solely the work of me and those working
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`under my direction and supervision.
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`III.
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`Inventorship of the ’514 Patent Claims
`19. The ’514 patent lists two co-inventors: me and Dr. Matvey E.
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`Lukashev, a former co-worker of mine at Biogen. Dr. Lukashev and I made
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`different contributions to the claimed subject matter: my work related to the
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`treatment of patients with MS with a therapeutically effective amount of DMF
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`and/or MMF (about 480 mg), while Dr. Lukashev’s work related to the mechanism
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`of action of dimethyl fumarate, including its interaction with the Nrf2 pathway and
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`effect on NQO1 expression levels. Thus, I am the sole inventor of claims 1-16 and
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`U.S. Patent No. 8,399,514
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`20, while both Dr. Lukashev and I are together co-inventors of claims 17-19.
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`20. These different contributions are reflected in the file history of the
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`patent ’514 patent. Specifically, I was added as an inventor to account for the
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`submission of claims directed to methods of treating MS by administering about
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`480 mg per day of dimethyl fumarate, monomethyl fumarate, or a combination
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`thereof. This is reflected in Exhibits 2094, 2095, and 2096, which I understand
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`were submitted to the U.S. Patent and Trademark Office.
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`IV. Conclusion
`I declare that all statements made herein of my knowledge are true, and
`21.
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`that all statements made on information and belief are believed to be true, and that
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`these statements were made with the knowledge that willful false statements and the
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`like so made are punishable by fine or imprisonment, or both, under Section 1001 of
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`Title 18 of the United States Code.
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`22.
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`In signing this declaration, I understand that the declaration will be filed
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`as evidence in a contested case before the Patent Trial and Appeal Board of the
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`United States Patent and Trademark Office. I acknowledge that I may be subject
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`to cross examination in the case and that cross examination will take place within
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`the United States. If cross examination is required of me, I will appear for
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`Case No. IPR2018—01403
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`US Patent No. 8,399,514
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`cross examination Within the United States during the time allotted for cross
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`examination.
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`DATE:
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`Juk— M yon
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`By:
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`
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`Gilmore O’Nei11,M.D.
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`Page 12 of 13
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`APPENDIX A
`
`
`Description
`U.S. Patent No. 8,399,514, Treatment for Multiple Sclerosis
`(filed Feb. 13, 2012) (issued Mar. 19, 2013)
`L. Kappos et al., Efficacy of a Novel Oral Single-Agent
`Fumarate, BG0012, in Patients with Relapsing-Remitting
`Multiple Sclerosis: Results of a Phase 2 Study, 253 (Supp.
`2) J. Neurol. II27, O108 (2006)
`NewsRoom document, Oral Compound BG-12 Achieves
`Primary Endpoint in Phase II Study of Relapsing-
`Remitting Multiple Sclerosis; Treatment with BG-12 Led
`to Statistically Significant Reductions in MRI Measures
`(May 30, 2006)
`L. Kappos et al., Efficacy of a Novel Oral Single-Agent
`Fumarate, BG0012, in Patients with Relapsing-Remitting
`Multiple Sclerosis: Results of a Phase II Study, 253 (16th
`Meeting of the European Neurological Society, May 20, 2006)
`Clinical Trial Review Board Agenda Item Meeting Minutes
`(February 19, 2004)
`Email from Rebecca Conaghan and Gilmore O’Neill, M.D.
`(August 16, 2004)
`Email from Cara Lansden with Attachment (October 25, 2005)
`Presentation by Dr. Gilmore O’Neill titled “BG00012 in
`RRMS: Update From Phase 2 Study” at confidential meeting of
`Fumapharm-Biogen MC in Luzern, Switzerland on February
`16, 2006
`Email from Gilmore O’Neill, M.D. with Attachment (February
`1, 2006)
`Emails between Gilmore O’Neill, M.D., and Ludwig Kappos,
`M.D., with Attachments (January 31, 2006)
`Prosecution History, U.S. Patent Application No. 12/526,296,
`Preliminary Amendment (June 20, 2011)
`Prosecution History, U.S. Patent Application No. 12/526,296,
`Supplemental Amendment and Reply (October 28, 2011)
`Prosecution History, U.S. Patent Application No. 12/526,296,
`Request to Add Inventor in a Nonprovisional Patent
`Application (October 28, 2011)
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`
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`Exhibit
`1001
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`1007
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`1016
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`1046
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`2088
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`2089
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`2090
`2091
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`2092
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`2093
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`2094
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`2095
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`2096
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`Page 13 of 13
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