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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`Case No. IPR2018—01403
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`US. Patent No. 8,3 99,5 14
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`MYLAN PHARMACEUTICALS INC.,
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`Petitioner,
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`V.
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`BIOGEN MA INC.,
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`Patent Owner.
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`Case IPR2018-01403
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`Patent 8,399,514 B2
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`DECLARATION OF EVA KUBALA HAVRDOVA, M.D., PH.D.
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`Page 1 0f 8
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`Biogen Exhibit 2099
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`Mylan v. Biogen
`IPR 2018-01403
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`Biogen Exhibit 2099
`Mylan v. Biogen
`IPR 2018-01403
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`Case No. IPR2018—01403
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`US. Patent No. 8,399,514
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`Table of Contents
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`1.
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`Personal Background and Introduction ........................................................... 1
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`II. My Role in the Phase II Trial ..........................................................................2
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`III.
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`Conclusion ....................................................................................................... 5
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`Case No. IPR2018—01403
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`U.S. Patent No. 8,399,514
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`1, Eva Kubala Havrdova, have personal knowledge of the facts stated herein
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`and provide the following testimony:
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`1.
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`Personal Background and Introduction
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`I am a Professor of Neurology at the First Faculty of Medicine,
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`General University Hospital, Charles University in Prague, Czech Republic.
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`I
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`obtained my medical degree from the same university. My clinical specialization
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`is in the area of neurology,
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`including the treatment of diseases like multiple
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`sclerosis (MS).
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`I am a member of the MSIF International Medical and Scientific
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`Board and the Czech Neurological Society Committee. Over the course of my
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`career as a practicing neurologist, I have been involved in several clinical trials
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`involving pharmaceuticals for the treatment of neurological conditions.
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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,
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`involving Biogen’s U.S. Patent No.
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`8,399,514 (“the ’5 14 patent”).
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`3.
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`I also understand that Mylan has submitted the following exhibits in
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`the that proceeding:
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`0 Ex. 1007: L. Kappos et al., Efi'icacy of a Novel Oral Single-
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`Agent Fumarate, 800012, in Patients with Relapsing-Remitting
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`Multiple Sclerosis: Results of a Phase 2 Study, 253 (Supp. 2) J.
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`Neurol. 1127, 0108 (2006)
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`0 Ex. 1046: L. Kappos et al., Efficacy of a Novel Oral Single—
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`Agem‘ Fumarate, BG0012, in Patients with Relapsing-Remitting
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`Case No. IPR2018—01403
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`US. Patent No. 8,399,514
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`Multiple Sclerosis: Results of a Phase II Study, 253 (16th
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`Meeting of the European Neurological Society, May 20, 2006)
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`0 Ex. 1016: NewsRoorn document, Oral Compound BG—12
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`Achieves Primary Endpoint in Phase 11 Study of Relapsing-
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`Remitting Multiple Sclerosis; Treatment with BG-IZ Led to
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`Statistically Significant Reductions in MRI Measures (May 30,
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`2006)
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`4.
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`I provide this declaration based on my personal knowledge and my
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`role in the Phase II trial of BG—12 for the treatment of MS.
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`11. My Role in the Phase II Trial
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`5.
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`I was a member of the Scientific Advisory Committee, and the Czech
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`Republic’s Principal Clinical Investigator, for Biogen’s Phase II trial of BG-l2 for
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`the treatment of MS. The information I received as a member of the Scientific
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`Advisory Committee and investigator in Biogen’s Phase II trial was confidential
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`and non-public. This is standard practice for clinical trials.
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`6.
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`Dr. Gilmore O’Neill was my primary contact for Biogen’s BG-12
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`program. He was Biogen’s Medical Director for the BG—12 MS program and the
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`leader of the Phase II trial. Throughout the study, Dr. O’Neill and Biogen held
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`several meetings of the Scientific Advisory Committee, either in-person or via
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`phone, to discuss issues with the study as they came up. All of us on the Scientific
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`Advisory Committee, as well as the numerous other people whose work went into
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`carrying out the clinical trial, worked under the direction and supervision of Dr.
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`O’Neill and Biogen.
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`7.
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`By the time I became involved in the Phase II study, around 2004,
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`Biogen had already finalized the clinical trial protocol, including the selection of
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`the three doses that would be tested: 120mg, 360mg, and 720mg.
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`I was not
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`involved in selecting those doses.
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`Dr. O’Neill and Biogen provided information and training for the
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`Clinical Investigators, MRI technicians, and others involved in carrying out the
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`clinical trial protocol.
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`In September 2004, prior to the beginning of the study, Dr.
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`O’Neill convened a meeting of the Clinical Investigators in Versailles, France that
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`I attended. At that meeting, Dr. O’Neill and Biogen formally introduced us to the
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`study plan and procedures and provided training to support the execution of the
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`trial.
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`The neurologists (including myself) were trained and certified on the
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`Expanded Disability Status Scale (EDSS) by Dr. Kappos, whom Biogen had
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`designated as “Coordinating Investigator.” See Ex. 2089. MRI technicians were
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`trained by Dr. David Miller’s group. Dr. Miller was another member of the
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`Scientific Advisory Committee. See id.
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`Throughout the Phase II trial, my job, like that of the other Clinical
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`Investigators, was to oversee administration of the drug, monitor adverse events,
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`and ensure compliance with all aspects of the protocol and applicable policies and
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`Case No. IPR2018-01403
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`U.S. Patent No. 8,399,514
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`procedures. None of us (Clinical Investigators, MRI technicians, or Scientific
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`Advisory Committee members) were privy to the overall trial data as the study was
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`being conducted. To the contrary, Biogen collected the data from each study site
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`by sending a monitor to each site at regular intervals to gather hard-copy files and
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`electronic MRI data.
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`I and other investigators did not become aware of the results
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`of the study until Dr. O’Neill presented them to us in late 2005.
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`10.
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`I recognize Exhibits 1007, 1046, and 1016 as relating to the Phase II
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`I was not substantively involved in preparing any of those documents. The
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`abstract (Ex. 1007) and the slides (Ex. 1046) were prepared by Biogen and sent to
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`me and the other Scientific Advisory Committee members for
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`comment.
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`I do not recall having made any edits on either one.
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`I did not have any
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`involvement in the creation of the NewsRoom document (Ex. 1016).
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`11.
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`I understand that one issue in this proceeding is whether the work in
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`Exhibits 1007, 1046, and 1016 is the work of Dr. O’Neill.
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`I can attest that the
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`content of Exhibits 1007, 1046, and 1016, which describes certain results of
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`Biogen’s Phase II BG—12 MS clinical trial, is solely the work of Dr. O’Neill, and
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`those working under his direction and supervision.
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`I and others listed as co-
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`authors on Exs. 1007 and 1046 (L. Kappos, D.H. Miller, D.G. MacManus, R.
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`Gold, V. Limmroth, C. Polman, K. Schmierer, T. Yousry, M. Yang, M. Eraksoy,
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`E. Meluzinova, and I. Rektor) were named because we were members of the
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`Case No. IPR2018-01403
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`US. Patent No. 8,399,514
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`Scientific Advisory Committee or provided other roles in carrying out the Phase II
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`trial. See Ex. 2092. The decision regarding who should be named author on any
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`publications of the Phase II trial results was a decision that we made jointly at an
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`early meeting of the Scientific Advisory Committee in September of 2004. Id.
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`III. Conclusion
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`12.
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`I declare that all statements made herein of my knowledge are true,
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`and that all statements made on information and belief are believed to be true, and
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`that these statements were made with the knowledge that willful false statements
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`and the like so made are punishable by fine or imprisonment, or both, under
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`Section 1001 of Title 18 of the United States Code.
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`13.
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`In signing this declaration, I understand that the declaration will be
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`filed as evidence in a contested case before the Patent Trial and Appeal Board of
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`the United States Patent and Trademark Office. I acknowledge that I may be
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`subject to cross examination in the case and that cross examination will take place
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`within the United States. If cross examination is required of me, I will appear for
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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 :11 £4“qu \F‘LQ \ A]
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`By CLW Maw Li“) W
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`Eva Kubala Havrdova
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`Case No. IPR2018-01403
`U.S. Patent No. 8,399,514
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`Exhibit
`1001
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`1046
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`2089
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`2092
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`APPENDIX A
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`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)
`Email from Rebecca Conaghan and Gilmore O’Neill, M.D.
`(August 16, 2004)
`Email from Gilmore O’Neill, M.D. with Attachment (February
`1, 2006)
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