UNITED STATES PATENT AND TRADEMARK OFFICE
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`APOTEX INC. and APOTEX CORP.,
`Petitioners,
` v.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-00854
`U.S. Patent No. 9,187,405
`______________________
`
`DECLARATION OF FRED D. LUBLIN, M.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2003
`
`
`______________________
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`APOTEX INC. and APOTEX CORP.,
`Petitioners,
` v.
`NOVARTIS AG,
`Patent Owner.
`______________________
`Case IPR2017-00854
`U.S. Patent No. 9,187,405
`______________________
`
`DECLARATION OF FRED D. LUBLIN, M.D.
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2003
`
`
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`I, Fred D. Lublin, M.D., declare as follows:
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`I.
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`Introduction
`I am a Professor of Neurology and the Director of the Corinne
`1.
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`Goldsmith Dickinson Center for Multiple Sclerosis at the Icahn School of Medicine
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`at Mount Sinai, and Attending Neurologist at Mount Sinai Hospital in New York
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`City. My full qualifications are below and in my CV (Ex. 2004).
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`2.
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`Counsel for Novartis AG has asked for my view on issues related to the
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`Apotex Petitioners’ proposed challenges to U.S. Patent No. 9,187,405 in this
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`proceeding. The ’405 Patent claims a method of using fingolimod to treat relapsing-
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`remitting multiple sclerosis (RRMS), a debilitating disease in which the immune
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`system attacks the body’s own central nervous system. The method involves
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`administering 0.5 mg of fingolimod daily without any loading dose to a subject in
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`need of reducing, preventing, or alleviating RRMS relapses; treating RRMS; and/or
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`slowing progression of the disease. Fingolimod is the active ingredient in Novartis’s
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`Gilenya® RRMS medication, and Gilenya’s label instructs doctors to use the method
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`claimed in the ’405 Patent. I understand Apotex argues that the ’405 Patent’s method
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`would have been obvious to a person of skill in the art in June 2006, when Novartis
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`filed the application for the Patent.
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`Counsel has asked me two questions. First, who would be a “person of
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`3.
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`skill in the art” for purposes of the ’405 Patent? Second, what would the differences
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`among the Patent’s claims mean to a person of skill?
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`4.
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`I set out my full conclusions below. In summary, a “person of skill”
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`here would be a team of people skilled in drug-dose development. That would
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`include one or more people with skill in pharmacology, typically with biology
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`degrees and expertise analyzing pharmacokinetic (PK) and pharmacodynamic (PD)
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`data. I understand that Apotex and its expert Dr. Barbara Giesser contend that a
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`person of skill would be solely a medical doctor. I disagree. A physician might be
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`on the team, but, unless he or she had the necessary PK/PD skills, they would not
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`develop initial dose strategies. They would lack the skills needed to interpret and
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`extrapolate from data measuring how the drug behaves in the body.
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`5.
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`As for the differences among the ’405 Patent’s claims, they would be
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`important to a person of skill. Claims 1 and 2 describe a method for a subject in
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`need of “reducing or preventing or alleviating relapses in” RRMS; claims 3 and 4
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`describe a method for a subject in need of “treating” RRMS; and claims 5 and 6
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`describe a method for a subject in need of “slowing progression” of RRMS. These
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`different therapeutic claims describe different aspects of the disease. As a result, a
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`person of skill would understand the inventors had patented methods that treat
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`multiple dimensions of RRMS, unlike other therapies that might treat only one.
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`Having a single medicine that could accomplish all of these goals was a significant
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`advance in June 2006.
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`6.
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`I understand that Apotex and Dr. Giesser argue that these differences
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`among the Patent’s claims do not matter because all RRMS patients need the benefits
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`the claims describe. I disagree. The inventors here developed methods that would
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`provide relief for different aspects of the disease at the same time, unlike other
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`available treatments. I read the claims’ use of these different terms to reflect that
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`discovery.
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`7. My analysis here is based on the knowledge that I have acquired as a
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`practicing neurologist for approximately 40 years; my research in the fields of
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`neurology and MS; articles with which I am familiar; and the Exhibits I have cited
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`within this declaration.
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`II. Qualifications
`I am a licensed physician in both New York and Pennsylvania, and have
`8.
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`been certified by the American Board of Medical Examiners and the American
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`Board of Psychiatry and Neurology.
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`9. My professional
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`interests relate primarily
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`to neurology and
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`neuroimmunology, and specifically the scientific and clinical aspects of MS, as well
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`as the research and development of therapies for treating MS. I have authored or co-
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`authored over 190 peer-reviewed academic publications in the field of neurology,
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`with an emphasis on MS. In addition, I co-wrote the textbook Multiple Sclerosis in
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`Clinical Practice, Martin Dunitz, Ltd. (2003), and have written or co-written over
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`240 textbook chapters, editorials, abstracts, and letters in my areas of interest.
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`10.
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`I received an A.B. from Temple University in 1968 (magna cum laude),
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`and an M.D. from Jefferson Medical College in 1972 (summa cum laude). From
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`1972-1973, I interned at the Bronx Municipal Hospital-Albert Einstein Medical
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`Center in New York City, specializing in internal medicine. Also in 1972, I
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`completed an externship at the National Hospital for Nervous Disease in London.
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`From 1973-1976, I was a resident in Neurology at New York Hospital-Cornell
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`Medical Center in New York City, NY.
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`11.
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`I have maintained an active neurology practice for the last 40 years,
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`first as a resident at New York Hospital (1973-1976), and then as an attending
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`physician at Thomas Jefferson University Hospital (1976-1996), Medical College of
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`Pennsylvania Hospital and Hahnemann University Hospital (1996-2000), and
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`Mount Sinai Hospital (2000-present).
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`12. From 1975-1976, I was an Instructor in Neurology at Cornell Medical
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`College. From 1976-1978, I was an Instructor in Neurology and a Research
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`Associate in Biochemistry (Immunology) at Jefferson Medical College of Thomas
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`Jefferson University. In 1978, I was promoted to Assistant Professor of Neurology
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`and Assistant Professor of Biochemistry. In 1982, I was further promoted to
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`Associate Professor of Neurology, and in 1983, to Associate Professor of
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`Biochemistry & Molecular Biology. In 1986, I was promoted to Professor of
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`Neurology. In 1987, I was appointed Director of the Division of Neuroimmunology,
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`and was named Vice-Chairman of the Department of Neurology. I was promoted to
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`Acting Chairman of the Department of Neurology in 1995.
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`13.
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`In 1996, I joined MCP Hahnemann University as a Professor of
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`Neurology, Vice-Chairman for Clinical Affairs in Neurology, Director of the
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`University's newly-created Multiple Sclerosis Center, and Director of the
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`Neurological Clinical Trials Center.
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`14.
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`In 2000, I joined Mount Sinai School of Medicine as a Professor of
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`Neurology and Director of the Corinne Goldsmith Dickinson Center for Multiple
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`Sclerosis-positions that I hold to this day. In 2004, I was named the Saunders Family
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`Professor of Neurology, an endowed chair that is an honor I hold to this day.
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`15.
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`I am a member of several professional medical organizations, including
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`the American Academy of Neurology and the American Neurological Association,
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`where I was named a Fellow in 2004 and 2013, respectively. I am also a member of
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`the National Multiple Sclerosis Society, where I have chaired several committees. I
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`serve on the editorial boards of several influential journals in my field. For example,
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`I have served as Co-Chief Editor for the quarterly journal Multiple Sclerosis and
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`Related Disorders since its inception in 2011. I have also been the recipient of
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`numerous major grants from respected institutions, including one of the largest
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`grants ever given for MS research by the National Institutes of Health.
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`16.
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`I have served as Principal or Co-Investigator for clinical trials relating
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`to a wide range of MS treatments, including interferons, biologic medical products,
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`and chemical drugs. I have also served as a member for the Data Safety and
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`Monitoring Boards for several MS treatments, including Antegren (Biogen-Idec),
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`and Gilenya (Novartis). In my work in clinical trials, I have witnessed first-hand
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`how drug doses are determined.
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`17. Although I am presently an advisor to Novartis (for which I am
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`compensated at fair market value for my time), I have no stock or other financial
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`interest in the Patent Owners. I similarly have no financial interest in the ’405 Patent,
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`and have had no contact with the named inventors of the ’405 Patent.
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`18.
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`I am being compensated for my time at my normal consulting rate for
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`my work in this case. My compensation is not dependent on and in no way affects
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`the substance of my statements in this Declaration.
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`III. Analysis
`I analyze the two questions counsel has given me separately. I first
`19.
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`address the level of skill in the art relevant to the ’405 Patent, based on my
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`experience in the clinical investigation of pharmaceutical treatments for RRMS. I
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`then address the differences among the ’405 Patent’s claims from the perspective of
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`a person of skill.
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`A. A Person of Skill For Purposes of the ’405 Patent
`Would Be a Drug Development Team That
`Includes a Skilled Pharmacologist
`20. The ’405 Patent claims methods for dosing fingolimod for a subject in
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`need of certain effects. I have been involved in numerous drug-dosing studies for
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`potential MS therapies. Every drug dosing effort employs one or more people with
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`expertise in pharmacology. They develop candidate doses based on PK/PD data
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`derived from animal and/or early human studies.
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`21. Practicing physicians (unless they are also PK/PD experts) do not
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`become involved until later, when testing different doses in humans. We monitor
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`patients in clinical trials and use our expertise in diagnosis and treatment to provide
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`feedback to the dosing developers on apparent efficacy, side-effects, and the like.
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`We do not develop initial doses ourselves.
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`22. While I am not an expert pharmacologist, I am familiar with the role
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`pharmacologists play in drug development from my experience working with them.
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`Pharmacologists are usually biologists with advanced degrees. Some medical
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`doctors have that expertise, but in my experience that is the exception rather than the
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`rule. Pharmacologists study how the body processes and clears a drug
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`(pharmacokinetics [PK]), and how the drug affects the body’s processes
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`(pharmacodynamics [PD]). They collect and analyze PK and PD data from animal
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`and human studies to assess a drug’s potential efficacy and safety at different doses.
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`Often, their models of drug behavior in the body employ sophisticated mathematical
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`analyses.
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`23. Pharmacology studies are central to evaluating drug doses. Fingolimod
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`provides a good example to illustrate how.
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`24. By June 2006, pharmacologists had developed many PD models for
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`how fingolimod sequesters lymphocytes in lymphatic tissue out of the blood stream,
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`inducing a condition called “lymphopenia.” Studies showed further that fingolimod
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`induced these effects by interacting with receptors on the surface of lymphocyte cells
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`called “S1P receptors.” Researchers knew that these receptors are present on other
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`tissues as well. As a result, pharmacologists had studied fingolimod’s effects not
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`only in the lymphatic system, but also in other systems such as the cardiac,
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`pulmonary, and vascular systems. (Ex. 1008 at 1073 (identifying transient
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`bradycardia); Ex. 2009 at 758; Ex. 2012 at 13839.)
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`25.
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`In developing a drug dosing regimen,
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`team members with
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`pharmacology expertise would analyze data like these to identify a drug’s potential
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`therapeutic window, the range of doses in which the drug’s efficacy could justify its
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`known risks. I emphasize that the pharmacologists would examine both efficacy
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`and risk. If a drug showed efficacy only in doses that posed too great a risk of
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`adverse events, then drug development would stop.
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`26. Medical doctors would become involved primarily at the point of
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`introducing candidate doses into humans. A physician’s role then is to protect
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`patient safety by monitoring for and, if need be, treating potential adverse events.
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`The physician would also collect data on the drug’s safety and efficacy for further
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`study. Physicians likewise would typically supervise clinical trials in the aggregate,
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`monitoring for patterns of adverse events reported across all clinical trial subjects.
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`27. The subject matter of the publications cited in Apotex’s Petition and
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`Dr. Giesser’s declaration is directed to both physicians and pharmacologists. For
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`instance, the Budde reference (Ex. 1008) was a Phase I single-dose stable renal
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`transplant study on 20 patients. Conducting such clinical studies is commonly a
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`team effort between physicians and pharmacologists.
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`28. The Budde paper thus predictably reports a mix of medical and
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`pharmacological information. For instance, the medical information includes the
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`study design and the discussions of safety monitoring protocols and adverse events.
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`(Id. at 1074.) In contrast, the pharmacological information includes PK
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`measurements such as AUC, Cmax, half-life, and PD measurements of lymphocyte
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`counts. Each of these data sets are discussed in relation to specific doses
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`administered in the trial. (Id. at 1078–79 (Tables 3–4).) The paper contains a
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`separate section on “pharmacodynamics,” which focuses almost entirely on the
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`extent of lymphopenia the drug induced at various single doses. (Id. at 1078.)
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`29. Similarly, other key references are directed to both physicians and
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`pharmacologists. Three examples are the Kahan 2003 paper (Ex. 1031); the Park
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`paper (Ex. 1019); and the Webb paper (Ex. 2014).
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`30. Kahan 2003 reports a multi-dose Phase I study to assess fingolimod’s
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`safety for more prolonged use. The study “examined the safety, pharmacodynamics,
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`and pharmacokinetics” for doses of 0.125, 0.25, 0.5, 1.0, 2.5, and 5.0 mg or placebo
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`administered over 28 days in stable renal transplant patients.
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`31. Like Budde, Kahan 2003 also contains a mix of medical and
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`pharmacological information. Among the important pharmacological analyses is a
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`chart showing the average level of lymphopenia achieved at various dose levels after
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`28 days of use. (Ex. 1031 at 1081.) That chart shows 0.5 mg daily achieved a
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`maximum average lymphopenia of about 60%. This data would certainly inform
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`further drug dose development, as I discuss below.
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`32. Park, too, was a multi-dose study in transplant patients. Park
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`“investigated the relationship between the dose of FTY720 or blood concentration
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`(pharmacokinetics, PK) and peripheral lymphopenia (pharmacodynamics, PD) in 23
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`kidney transplant recipients[.]” (Ex. 1019 at 683.) “FTY720 dose, blood
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`concentrations and lymphocyte counts were determined weekly before and 4 to 12
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`10
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`weeks after transplantation.” (Id.) In this study, “FTY720 produced a dose-
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`dependent increase in mean percent reduction of peripheral lymphocyte counts[.]”
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`(Id.) Based on PK/PD modeling, the authors concluded that, “[u]sing lymphopenia
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`as an FTY720 PD surrogate marker, high % reduction (80%) in peripheral
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`lymphocytes are required to achieve best efficacy to prevent acute allograft
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`rejection.” (Id.) Further, the study showed seven measurements of 0.5 mg daily
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`doses yielded from 20-60% lymphocyte reduction—far less than what was needed
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`to be effective. (Id. at 690 (Fig. 7).)
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`33. Finally, Webb studied pharmacological data in an animal model often
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`used to test potential MS drugs, the “EAE” model. Webb showed that “[i]n dose
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`response experiments, we found that a threshold of about 70% depletion of
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`peripheral lymphocytes was required to see any efficacy, and thereafter, the dose-
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`response relationship between clinical benefit and lymphopenia was very steep.”
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`(Ex. 2014 at 118.) Webb further found some “disconnection between lymphopenia
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`and clinical scores … particularly seen at the initiation and termination of dosing.”
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`(Id.)
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`34. Taken together, these papers show that sophisticated PK/PD knowledge
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`would be required to interpret the available data to predict likely efficacious and safe
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`doses. Pharmacologists would be essential to evaluating these issues. They collect,
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`analyze, and model data to predict potential therapeutic doses in light of the known
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`and modeled risks. Apotex and Dr. Giesser are thus mistaken to define a “person of
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`skill” for purposes of the ’405 Patent as solely a medical doctor. To the contrary, a
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`medical doctor without expertise in pharmacology could not provide an accurate
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`assessment of what a person of skill would predict about the right dose from the
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`existing PK/PD data.
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`35.
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`It would indeed be scientifically unsound for a medical doctor to
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`conduct a clinical trial using a dose that lacked sufficient PK/PD analysis. Too high
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`a dose could have severe or even fatal side effects that could easily have been
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`avoided with appropriate PK/PD analysis. Too low a dose could end up showing
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`insufficient efficacy to justify the risks, an outcome that likewise could have been
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`avoided with appropriate PK/PD analysis. Unless they are also PK/PD experts
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`themselves, medical doctors would not undertake such predictions.
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`36. The facts here illustrate the risks of proceeding without a robust
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`pharmacological analysis. Dr. Giesser contends that a physician would predict a 0.5
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`mg daily dose upon learning of the Phase II results for fingolimod in RRMS, which
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`showed that doses of 1.25 mg and 5.0 mg daily had similar efficacy, but with fewer
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`adverse effects at the lower dose. According to Dr. Giesser, Budde had shown that
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`a single 0.5 mg dose could be safe and would induce some amount of lymphopenia
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`in patients, then understood to be fingolimod’s primary mechanism of action. (Ex.
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`1002 at ¶ 98.)
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`37. Dr. Giesser, however, does not provide a robust analysis of the public
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`data then available to assess whether 0.5 mg daily would actually be effective in
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`treating RRMS. Without that analysis, a physician would lack the necessary data to
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`undertake a clinical trial using 0.5 mg daily. There would be an unacceptable risk
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`that 0.5 mg daily would have no or an insufficient effect.
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`38.
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`It is also impractical to conduct such a trial without solid PK/PD
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`support. MS clinical trials are especially complex and expensive because the
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`condition is chronic but in remission for long periods. MS clinical trials are thus
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`longer than those required for many other conditions, and a pharmaceutical company
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`would not expend resources in adding a dose-testing arm without a solid empirical
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`foundation.
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`39. The risk that 0.5 mg daily would not work appears to have been
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`significant as of June 2006. Available data from animal studies showed that at least
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`70% lymphopenia was needed for fingolimod to have any effect on RRMS models.
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`(Ex. 2014 at 118.) Other data showed that 0.5 mg daily fell short of inducing that
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`basic minimum response needed for any effect. The Kahan 2003 (Ex. 1031) study
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`showed that at least 1.0 mg per day was needed to achieve the minimum required
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`lymphopenia. Similarly, the Park paper showed that patients receiving 0.5 mg daily
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`achieved widely divergent lymphopenia results, ranging from less than 20% to about
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`60%—but all less than the 70% lymphopenia Webb suggested was needed to treat
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`RRMS. In this context, expert pharmacology advice would be essential before
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`embarking on a clinical trial for 0.5 mg daily, to avoid the risk that the 0.5 mg daily
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`dose would effectively be nothing more than another placebo arm in the clinical trial.
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`40. Dr. Giesser provides no such analysis in her declaration, nor could she.
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`I have met Dr. Giesser and I have no doubt that she is a fine and compassionate
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`physician. But she is not a pharmacologist, as her CV shows. None of Dr. Giesser’s
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`past work has focused on pharmacological analyses. I see no evidence that Dr.
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`Giesser has any expertise as a pharmacologist. Nor do I see any evidence that she
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`has designed or led clinical drug trials focused on dosing issues. She performs no
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`PK/PD analysis of the available data in her declaration in this case.
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`41. Dr. Giesser’s report says merely that she is “familiar” with “dosing
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`regimens” and the MS literature. I agree that physicians with MS expertise become
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`familiar with how MS drugs are dosed after they are studied in later phase clinical
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`trials. We of course prescribe drugs to patients informed by the dosing schemes in
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`the drug labels. But I see no evidence that Dr. Giesser has any expertise in the
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`PK/PD skills needed to derive those doses in the first place, nor does she claim to
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`have such expertise.
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`42.
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`In short, Dr. Giesser is not the right person to provide an opinion on
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`whether a person of skill as of June 2006 would have thought a 0.5 mg daily
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`fingolimod dose obvious for RRMS. An opinion from a pharmacologist would be
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`essential in analyzing that question.
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`B. Differences Among the Patent’s Claims Would
`Be Important to a Person of Skill
`43. The ’405 Patent contains three claim pairs, each of which has a different
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`statement of the therapy provided by a 0.5 mg daily dose of fingolimod or fingolimod
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`hydrochloride. Claims 1 and 2 say that 0.5 mg daily is for a subject in need of
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`“reducing or preventing or alleviating relapses” in RRMS; claims 3 and 4 say that
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`the dose is for a subject in need of “treating” RRMS; and claims 5 and 6 say the dose
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`is for a subject in need of “slowing progression” of the disease. Each of these phrases
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`means something different to a physician.
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`44. MS is a disease in which the body’s immune system attacks the central
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`nervous system.
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` MS’s symptoms include weakness; numbness; tingling;
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`incoordination; gait difficulty; visual problems, spasticity; bladder, bowel, and/or
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`sexual dysfunction; fatigue; psychiatric disorders; and the like. It is a chronic life-
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`long condition that tends to strike people in their 20s to their 40s, especially women.
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`The cause is unknown and there is no cure.
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`45. As of 2006, MS was categorized in four forms: (1) “relapsing-
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`remitting,” or “RRMS”; (2) “secondary progressive,” or “SPMS”; (3) “primary
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`progressive,” or “PPMS”; and (4) “progressive relapsing,” or “PRMS.” RRMS is
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`the most common. It affects patients in cycles, first with an acute phase; then
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`remission; and then acute relapses. Within the nervous system, this process degrades
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`the myelin sheathing around neurons, disrupting nerve signals and causing the build-
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`up of scar-tissue. Some patients transition into a more progressive form of the
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`disease. At that point, neurodegenerative processes possibly separate from the
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`immune system take over, and the disease worsens in a more consistent manner with
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`no remissions.
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`46. The following graph from Lublin et al., Defining the clinical course of
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`multiple sclerosis: Results of an international survey, 46 Neurology 907 (1996),
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`shows the disease course of RRMS, as understood as of 2006 (Ex. 2010 at 908 (Fig.
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`1).):
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`47. As shown above, the peaks represent relapses. After each relapse, a
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`patient may or may not return to prior baseline neurological function. The following
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`chart below shows how RRMS could progress into SPMS (Id. at 909 (Fig. 3).):
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`48. As shown above, SPMS begins with an initial relapsing-remitting
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`course, followed by progression of variable rate that may also include occasional
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`relapses and minor remissions.
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`
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`49. Against this backdrop, the Patent’s terms come into sharp focus.
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`• “Reducing or preventing or alleviating” relapses—required in
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`claims 1 and 2—means to stop, reduce the frequency, or reduce the
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`effects of an RRMS relapse.
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`• In contrast, “treating” RRMS—required in claims 3 and 4—is a
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`broader term that can include all aspects of MS, including
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`improving symptoms such as spasticity; bladder, bowel, sexual
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`17
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`dysfunction; fatigue; psychiatric disorders; and the like. This would
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`also include treating to improve recovery and repair of any damage
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`and impeding any more gradual underlying pathologies that might
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`not express themselves clinically early in the disease course.
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`• Finally, “slowing progression”—required in claims 5 and 6—is
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`different. After an acute attack, RRMS patients in remission return
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`to a baseline of neurological function. Over time as relapses occur,
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`that baseline progressively worsens. A drug that slows progression
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`of the disease retards this progressive worsening. In addition, one
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`of the goals of therapy would be to prevent patients with RRMS
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`from transitioning into progressive MS, i.e., SPMS.
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`50. The differences among these terms are confirmed by the fact that
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`physicians use different therapies to address these different aspects of the disease.
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`For instance, physicians have used steroids for decades to treat RRMS’s acute
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`inflammatory symptoms. But steroids do not reduce or prevent relapses, nor do they
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`slow progression of the disease.
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`51. Another example
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`is “plasmapheresis,” a
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`treatment
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`to remove
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`circulating factors in a patient’s blood that might be attacking the nervous system.
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`A machine can be used to remove the affected plasma and replace it with good
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`plasma or a plasma substitute. The process is similar to kidney dialysis. It may
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`improve recovery from an RRMS attack, but has no lasting effect on disease course.
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`52. Likewise, most disease modifying therapies have been shown to reduce
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`relapse frequency, but not treat symptoms when relapses occur. Nor do disease-
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`modifying therapies directly treat the symptoms of MS, such as spasticity, bladder
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`dysfunction, or pain.
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`53. Physicians even use different tools to measure these different aspects
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`of the disease. They measure the frequency of relapses; they assess each symptom
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`according to its own criteria; and they measure progressive deterioration in the
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`neurological baseline by assessing function through the “Expanded Disability Status
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`Scale,” or “EDSS,” or similar scales.
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`54. By using these different terms, the ’405 Patent inventors specified
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`different aspects of the disease. It would be a mistake to read these terms out of the
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`claims, as Apotex and Dr. Giesser propose.
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`55. To begin with, Apotex and Dr. Giesser are mistaken to assert that all
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`RRMS patients are “subjects in need” of these effects described. An RRMS patient
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`who has not experienced an attack or other evidence of disease activity in many
`
`years would have an inactive form of the disease, and thus would not be “in need”
`
`of any treatment. Moreover, even a patient with an active form of the disease, to
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`have a single medicine that could supply the effects listed in the different claims
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`would be very meaningful.
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`56. Under penalty of perjury, all statements made herein of my own
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`knowledge are true, and I believe all statements made herein on information and
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`belief to be true. I have been warned and am aware that willful false statements and
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`the like are punishable by fine or imprisonment or both under Section 1001 of Title
`
`18 of the United States Code.
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`57.
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`In signing this Declaration, I understand that it will be filed as evidence
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`in a contested case before the Patent Trial and Appeal Board of the United States
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`Patent and Trademark Office. I acknowledge that I may be subject to cross-
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`examination in the case and that cross-examination will take place in the United
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`States. If cross-examination is required of me, I will appear for cross-examination
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`within the United States during the time allotted.
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`DATED: May 2, 2017
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`By:
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`Fred D. Lublin, M.D.
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`20
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