IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`
`Case No. IPR2016-00204
`Patent No. RE 38,551
`
`DECLARATION OF CARL W. BAZIL, M.D., Ph.D., IN SUPPORT OF
`PATENT OWNER RESPONSE PURSUANT TO 37 C.F.R. § 42.120
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` DC: 6105540-8
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`RESEARCH CORPORATION TECHNOLOGIES, INC.,
`Patent Owner.
`
`Case No. IPR2016-00204
`Patent No. RE 38,551
`
`DECLARATION OF CARL W. BAZIL, M.D., Ph.D., IN SUPPORT OF
`PATENT OWNER RESPONSE PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`
`
`
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`
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` DC: 6105540-8
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`IPR2016-00204
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`TABLE OF CONTENTS
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`I.
`
`II.
`
`Introduction ..................................................................................................... 1
`
`Professional Background and Education ........................................................ 2
`
`III. The ’551 Patent and My Experience with Lacosamide .................................. 6
`
`IV. Background ..................................................................................................... 8
`
`A. Definition and Types of Epilepsy ........................................................ 8
`
`B.
`
`C.
`
`Effects of Epilepsy ............................................................................. 13
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`Categories of Epilepsy Treatment ...................................................... 18
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`1.
`
`2.
`
`Diet, Devices, and Surgery ...................................................... 18
`
`Antiepileptic Drugs .................................................................. 20
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`D.
`
`Challenges with Treatment of Epilepsy ............................................. 26
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`V.
`
`Lacosamide is a Valuable Addition to the Armamentarium of AEDs
`That Had Long Been Needed in 1996 .......................................................... 33
`
`A.
`
`Lacosamide Satisfies a Long-Felt Need for an AED with
`Lacosamide’s Unique Combination of Properties ............................. 35
`
`1.
`
`2.
`
`Need in 1996 for Various Properties of AEDs ........................ 35
`
`Lacosamide Meets the Need Recognized in 1996 ................... 44
`
`B.
`
`Lacosamide’s Success Was Unexpected ............................................ 62
`
`C. Other AEDs Failed ............................................................................. 62
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`D.
`
`Lacosamide Has Been Praised ........................................................... 65
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`VI. Conclusion .................................................................................................... 68
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`I, Carl W. Bazil, M.D., Ph.D., declare as follows:
`
`I.
`
`Introduction
`
`1.
`
`
`I have been retained by Patent Owner Research Corporation
`
`Technologies, Inc., (“Patent Owner”) in the present inter partes review. I
`
`understand that the petition names Argentum Pharmaceuticals LLC as the
`
`petitioner, and that Intelligent Pharma Research LLC, APS GP LLC, and APS GP
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`Investors LLC have been identified as real parties-in-interest. I further understand
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`that KVK-TECH, Inc. has also been identified as a potential real party-in-interest.
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`I have no financial interest in, or affiliation with, the petitioner, the identified
`
`actual or potential real parties-in-interest, or the patent owner. I am being
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`compensated at my usual and customary hourly rate, and my compensation is not
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`dependent upon the outcome of, or the content of my opinions in, this proceeding
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`or in any other proceeding. The opinions I set forth herein are my own and are
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`based on my review of materials in this matter and the education, experience,
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`training, and skills I have accumulated.
`
`2.
`
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`I am a clinical epileptologist with decades-long experience in treating
`
`patients with epilepsy, in publishing and reviewing literature regarding epilepsy,
`
`teaching students, residents, and other doctors regarding epilepsy, and in
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`conducting studies regarding epilepsy. In this Declaration, I offer my opinions on
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`the effects of epilepsy on patients, the treatment of epilepsy, the need for improved
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`antiepileptic drugs (“AEDs”) particularly as of 1996, a failure to meet that need,
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`and also the contributions of lacosamide to the armamentarium of practicing
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`epileptologists such as myself.
`
`3.
`
`
`I have reviewed the articles and documents cited in this Declaration. I
`
`am aware of information generally relied upon by physicians and others treating
`
`people with epilepsy at the relevant times, and my opinions below are based on
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`such awareness.
`
`II.
`
`Professional Background and Education
`
`4.
`
`
`I am the Caitlin Tynan Doyle Professor of Neurology at the College of
`
`Physicians and Surgeons, Columbia University. I am also the Director of the
`
`Comprehensive Epilepsy Center at New York Presbyterian Hospital/Columbia.
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`Additionally, since 1996, I have been an attending neurologist at New York
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`Presbyterian Hospital, specializing in epilepsy. Since 2006, I have also taught at
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`the City University of New York. Before joining the medical faculty at Columbia
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`University in 1996, I served on the faculties at Long Island University (adjunct)
`
`and Mount Sinai School of Medicine.
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`
`
` My primary research interests are in the areas of epilepsy and sleep 5.
`
`disorders.
`
`6.
`
`
`I received an undergraduate degree in 1983 from the Massachusetts
`
`Institute of Technology. I also have a M.S. in pharmacology and Ph.D. in
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`pharmacology from Emory University, and an M.D. from Emory University. After
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`medical school, I was an intern in internal medicine at Emory University from
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`1989 to 1990 and then completed a residency in neurology at New York University
`
`from 1990 to 1993. Thereafter, from 1993 to 1995, I completed a clinical
`
`fellowship in epilepsy/EEG at the Neurological Institute, Columbia Presbyterian
`
`Medical Center.
`
`7.
`
`
`I received Board Certification from the National Board of Medical
`
`Examiners in 1990, from the American Board of Clinical Neurophysiology in
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`1996, and from the American Board of Sleep Medicine in 2005. Additionally, I
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`received Board Certification from the American Board of Neurology and
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`Psychiatry in 1995 (last recertified in 2015), with added qualifications in Clinical
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`Neurophysiology (1999), Sleep Medicine (2009), and Epilepsy (2013).
`
`8.
`
`
`I am the author of more than 160 scientific papers, scholarly reviews,
`
`and book chapters on neurology, including articles on epilepsy, as well as three
`
`books on epilepsy. See, e.g., Carl W. Bazil et al., What Do I Do Now? Epilepsy
`
`(2011) (Ex. 2077) (“What Now?”); Carl W. Bazil et al., Epilepsy, 13 Merritt’s
`
`Neurology 468 (2016) (Ex. 2078); Carl W. Bazil & Timothy A. Pedley, Epilepsy,
`
`12 Merritt’s Neurology 927 (2010); Carl W. Bazil et al., Epilepsy, 11 Merritt’s
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`Neurology 990 (2005); Carl W. Bazil, Living Well with Epilepsy and Other Seizure
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`Disorders (2004) (Ex. 2079) (“Living Well”); Carl W. Bazil, Epilepsy:
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`Management, 6 Encyclopedia of Life Sciences 487, 487-94 (2002); Carl W. Bazil
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`et al., Epilepsy, 10 Merritt’s Neurology 813 (2000); Carl W. Bazil & Timothy A.
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`Pedley, Neurophysiology of antiepileptic drugs. 4 Antiepileptic Drugs 79-89
`
`(1995). I have conducted clinical trials on several antiseizure drugs, including
`
`phase-III trials (pivotal trials used for the approval of drugs for the FDA) for
`
`lacosamide (Vimpat®), pregabalin, and rufinamide, and phase-IV trials (trials
`
`conducted after approval to address additional questions that are of clinical
`
`importance) for zonisamide, oxcarbazepine, gabapentin, and diazepam rectal gel.
`
`9.
`
`
`Over the past 21 years, I have held additional professional positions.
`
`From 1995-2008, I served as the Director of Clinical Anticonvulsant Drug Trials at
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`Columbia University. From 1997-2004, I served as an Examiner for the American
`
`Board of Clinical Neurophysiology. Since 2003, I have served as the Epilepsy
`
`Section Editor for Current Neurology and Neuroscience Reports. I have served as
`
`a Reviewer for Epilepsia; European Journal of Neurology; Physiology and
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`Behavior; Annals of Neurology; Archives of Neurology; Sleep; Brain; Clinical
`
`Therapeutics; Neuroscience Letters; Neuropediatrics; Epileptic Disorders; Journal
`
`of Clinical Sleep Medicine; Neuropharmacology; JAMA; JAMA Neurology; and
`
`Epileptic Disorders. I have been a Contributing Editor for Epilepsy Currents and
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`The Medical Letter. I served as a grant reviewer for Citizens United for Research
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`in Epilepsy (CURE). I am on the Editorial Board for JAMA Neurology and
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`Epilepsy.com and was previously on the Editorial Board for Epilepsy Research. I
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`also previously served on the Board of Directors for the American Clinical
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`Neurophysiology Society, the NIH peer review panel, and the AAN Practice
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`Parameter Guideline Committee on New AEDs.
`
`
`
` Since 2008, I have served as the Director of the Comprehensive 10.
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`Epilepsy Center at New York Presbyterian Hospital/Columbia, which serves
`
`several thousand patients each year. As director, I am responsible for all activities
`
`of the epilepsy center, which includes nine other neurologists specializing in
`
`epilepsy in addition to myself, three nurse practitioners, between four and seven
`
`epilepsy fellows in training in any given year, as well as neurology residents. In
`
`my role as director, I oversee the clinical care of all of the patients in the Center
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`seen not only by me, but also the other attending physicians, fellows, and residents.
`
`I also oversee the clinical research performed on anticonvulsant drugs at the
`
`Center.
`
`
`
` Moreover, my group performs an advisory role to the approximately 11.
`
`one hundred other attending neurologists in the neurology department at Columbia.
`
`Epilepsy is a common condition, and it may affect patients who are seeing a
`
`neurologist for another reason. Sometimes, the patent’s caretaker will feel
`
`comfortable with the patient’s epilepsy treatment. However, if they have a
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`question about a challenging or difficult case of epilepsy, such as epilepsy that is
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`difficult to control or instances where the patient experiences problems associated
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`with other drugs, they come to me and my group for advice on treatment.
`
`12.
`
`
`I have also been invited many times to give lectures and speeches
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`about epilepsy and the drugs that are available to treat it. For example, for the past
`
`four years I have directed the course in epilepsy therapy at the American Academy
`
`of Neurology annual meeting, the largest meeting in the country for neurologists.
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`The course I direct is specifically designed to instruct practicing neurologists in the
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`treatment of epilepsy. The status of available antiseizure drugs (“AEDs”) is an
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`important topic discussed in this course.
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`13.
`
`
`I have been caring for patients with epilepsy since medical school in
`
`the 1980s and regularly and consistently since 1990. I currently see approximately
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`125 patients per month, and approximately 700–1000 patients per year. I have seen
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`many thousands of patients during my career.
`
`14.
`
`
` A copy of my curriculum vitae is submitted as Ex. 2039 with this
`
`Declaration.
`
`III. The ’551 Patent and My Experience with Lacosamide
`I understand that U.S. Patent No. RE38,551 (“the ’551 Patent”) is
`15.
`
`
`involved in this proceeding. I understand that the claims the ’551 Patent are
`
`directed to the compound of an AED known as lacosamide, and methods of
`
`treatment involving lacosamide. Specifically, I understand (a) that Dr. William
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`Roush has opined that the compounds of claims 1–9 encompass lacosamide; (b)
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`that claim 10 is directed to a “therapeutic composition” containing an
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`“anticonvulsant effective amount” of any of the compounds of claims 1–9; and (c)
`
`that claims 11–13 are directed to methods of using the compounds of claims 1–9 in
`
`treating central nervous system disorders. I further understand that the Patent Trial
`
`and Appeal Board (“PTAB”) has construed “therapeutic composition” to mean
`
`“suitable for use as a treatment regimen over an extended period of time (chronic
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`administration)” in this proceeding. I also understand that the year 1996 is the
`
`relevant time in determining the alleged obviousness of the claims of the ’551
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`patent, although later publications may be relevant to the issues of long-felt need,
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`failure of others, unexpected results, skepticism, and praise, which I have
`
`addressed in this Declaration.
`
`16.
`
`
`I have had experience prescribing lacosamide since the early 2000s. I
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`was involved in the clinical trials for lacosamide, and I treated patients using
`
`lacosamide in furtherance of those clinical trials. I have prescribed lacosamide
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`continuously since then to patients for whom it is appropriate. Lacosamide is the
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`active ingredient in a composition sold under the trade name, Vimpat®. See FDA
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`Approved Label for Vimpat® (Ex. 2013).
`
`
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` As of today, I prescribe Vimpat for patients with partial-onset 17.
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`epilepsy and I teach others this practice. I have prescribed Vimpat both as a
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`primary and as an add-on drug, and have used it in both monotherapy and
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`polytherapy and over extended periods of time. Based on this practice, I
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`understand that Vimpat is a “therapeutic composition” as that term has been
`
`construed by the PTAB, suitable for chronic treatment of patients with epilepsy. I
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`also understand that the administration of an anticonvulsant effective amount of
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`Vimpat is a method of treating patients with epilepsy (which is a central nervous
`
`system disorder), and I regularly prescribe Vimpat to my patients for this use.
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`Accordingly, claims 10–13 of the ’551 Patent encompass Vimpat.
`
`IV. Background
`A. Definition and Types of Epilepsy
` Epilepsy is a neurological condition defined as two or more 18.
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`unprovoked seizures occurring more than 24 hours apart. A seizure is defined as a
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`behavioral change caused by abnormal electrical activity in the brain. Seizures can
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`be caused by many conditions other than epilepsy including very high fever,
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`infection in the brain, severe hypoglycemia, or certain drugs. A person who has
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`two, or five, or sixteen seizures due to hypoglycemia does not have epilepsy, as
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`these would all be considered provoked. The definition of epilepsy mainly arises
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`from research showing that someone with an isolated, unprovoked seizure has a
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`good chance of never having another, but that if two or more seizures occur, they
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`are likely to continue if the person is not treated. Many clinicians will also
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`diagnose a person with epilepsy if there is a single seizure plus an EEG
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`(electroencephalogram) showing risk of epilepsy.
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` Epilepsy is one of the most common nervous system disorders, 19.
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`affecting about 1% of the population. What Now? (Ex. 2077), at 54. It is
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`estimated to affect 2.5-3 million Americans and 65 million persons worldwide.
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`See, e.g., “About Epilepsy: The Basics,” Epilepsy Foundation, at
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`http://www.epilepsy.com/learn/about-epilepsy-basics (last visited July 11, 2016)
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`(Ex. 2080). Approximately 200,000 new cases of epilepsy are diagnosed each
`
`year.
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` Epilepsy is a very heterogeneous condition: it is not a single disease; 20.
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`rather, it varies considerably between individuals. Epilepsy is sometimes
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`associated with a condition affecting the structure of the brain: stroke, tumor, or
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`abnormal blood vessels (arteriovenous malformations), for example. The
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`spontaneous seizures of epilepsy are more likely to occur following an infection to
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`the brain, brain trauma (even without a clear structural injury), or repeated febrile
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`seizures. In the vast majority of individuals, however, no specific cause can be
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`identified. These are termed “idiopathic,” meaning no definite cause; there is,
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`however, increasing evidence that many of these people may have a genetic
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`difference resulting in a predisposition to epilepsy.
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` Not only do the causes of epilepsy differ, but the seizures themselves 21.
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`also vary in manifestations, duration, and severity. The two broadest categories of
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`epilepsy are “generalized” and “partial” epilepsy. Those categories are
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`characterized by the electrical pattern in the brain during a given seizure, rather
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`than by the severity of the seizure. That is, partial seizures can be as severe as, or
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`even more severe than, generalized seizures, and vice versa.
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`22.
`
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`In generalized epilepsy, the brain as a whole seems to be overly
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`sensitive to seizures. These individuals most commonly experience a “grand mal”
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`or generalized tonic-clonic seizure (“GTC”). A GTC is what most people think of
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`as a seizure: the person suddenly loses consciousness; if standing, the person will
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`fall, typically with a loud outcry followed by diffuse convulsive movements of the
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`arms and legs. The convulsion will last a minute or two, after which the
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`movements stop but the person may be unresponsive for minutes or even hours
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`afterward as the brain recovers. There are still other types of generalized epilepsy,
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`including absence or “petit mal” seizures, where the person (usually a child)
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`simply pauses for a few seconds. Sudden increase in muscle tone is called a
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`“tonic” seizure; sudden loss of muscle tone is called an “atonic” seizure, and
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`isolated or repetitive muscle jerks with retained awareness is called a “myoclonic”
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`seizure. These are all generalized seizure types.
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` Partial or focal seizures are more common, and result from abnormal 23.
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`electrical activity beginning in a specific area or areas of the brain. The
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`manifestations of these seizures depend on the area involved. A seizure beginning
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`in the visual areas, for instance, may manifest as swirling lights or a specific
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`hallucination. One of my patients reported usually seeing an image of a cartoon
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`character as the seizure began. A partial seizure beginning in the area of the brain
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`that controls movement may start with repetitive, uncontrolled jerking of an arm or
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`a leg. The most common area for partial seizures to begin is the temporal lobe, an
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`area closely associated with memory and with emotion. Seizures beginning in that
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`area therefore can start with an intense feeling of déjà vu, jamais vu (a feeling that
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`the familiar is somehow unknown), fear, or ecstasy. The Russian author Fyodor
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`Dostoyevsky famously described his own ecstatic aura through some of the
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`characters in his novels. Partial seizures, then, can manifest as changes in virtually
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`any of the functions of the brain. In a given individual, however, seizures tend to
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`be extremely stereotyped—an electrical fingerprint of sorts for that particular
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`person.
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` Partial seizures also vary in severity. Small partial seizures have been 24.
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`called “simple partial” when there is no alteration in awareness. A person who
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`experiences intense déjà vu or sudden jerking movements but remains fully aware,
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`after which the feeling or movement simply resolves, is experiencing a “simple
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`partial” seizure. Simple partial seizures with no outward manifestations—déjà vu
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`or isolated fear—have also been termed “auras.” If the seizure then spreads to
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`involve a larger area of the brain, however, the person may become confused and
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`not remember what had occurred. That is called a “complex partial” seizure.
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`Partial seizures can spread further to involve the entire brain, resulting in a
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`convulsion similar to that seen in some people with generalized epilepsy. This is
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`termed a “secondarily generalized” seizure. For this type of partial seizure, the
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`seizure could begin with a feeling of déjà vu, for example, followed by staring and
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`loss of awareness as it spreads, and then result ultimately in the person falling and
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`experiencing generalized convulsive movements.
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` The effects during and after a seizure also vary considerably. A 25.
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`person who has only a simple partial seizure consisting of an isolated visual change
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`with no impairment of activity may be able to continue meeting with a client,
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`taking care of her children, or even driving, with no adverse consequences. During
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`complex partial seizures, because of impairment, the person is at risk for injury.
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`For example, a person experiencing confusion during a temporal lobe seizure may
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`not be aware of oncoming traffic and step in front of a bus, or if cooking, may
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`place his hand on a hot burner, resulting in a serious burn. During convulsions,
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`injuries—particularly lacerations, head trauma, or bone fractures—are even more
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`common due to falling and violent movements. After the seizure stops, the person
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`may still be impaired for a period of minutes to hours. For some patients,
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`particularly those who experience a GTC seizure, once consciousness returns they
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`may be able to get up and walk, but still be very confused and not remember what
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`had happened. They may fail to recognize even family members, and may feel
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`threatened. One of my patients repeatedly was arrested after seizures because he
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`would act confused and impaired, police would be called, and as he did not
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`understand questions that the police asked, he would become violent towards them.
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`Behavioral changes do not just happen immediately after a seizure. Some patients
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`enter a psychotic state a day or two after a seizure; in those instances, the patient
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`exhibits schizophrenia-like behavior, including paranoia and delusional thinking,
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`which can last one to two weeks before resolving. A Christian patient of mine
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`believed in her postictal state that she had died and was waiting for Jesus to take
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`her. She refused to eat or take her medications, saying repeatedly “I am dead.
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`Why should I do that?” Of course, the best treatment of this postictal psychosis is
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`prevention of all seizures, though it can also be treated with a brief course of
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`antipsychotic medication.
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`Effects of Epilepsy
`
`B.
` Epilepsy presents a wide-range of life-altering and potentially long-26.
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`
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`standing physical, emotional, psychological, and social effects on those affected.
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`Epilepsy can take a high toll on both patients and their families. Epilepsy is not a
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`benign condition. It can be fatal. Each year, at least 1 in 1000 patients with
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`epilepsy will die suddenly. See, e.g., Carl W. Bazil, Epilepsy: Management, 6
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`Encyclopedia of Life Sciences 487, 490 (2002) (Ex. 2081). The causes of such
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`sudden death cases are poorly understood. See, e.g. id. (Ex. 2081) In patients
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`with uncontrolled epilepsy (e.g., refractory patients), the death rate is even higher,
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`at 1 in 100 each year. Stated another way, if a refractory patient is prescribed an
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`antiepileptic drug that effectively controls his seizures with no serious adverse
`
`effects, he is ten times more likely to live another year. Additionally, patients can
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`suffer neurological disability or death due to a single prolonged severe seizure
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`(status epilepticus). The long-term effects of smaller seizures are controversial.
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`While some patients with partial seizures over many years demonstrate cognitive
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`impairment, it is unclear whether that is caused by the seizures themselves, or
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`whether the underlying condition causing epilepsy causes cognitive decline.
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`
` Epilepsy can dramatically curtail the lifestyle and quality of life of 27.
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`those afflicted. Personal safety is a major concern with patients suffering from
`
`epilepsy also because of the risk of sudden loss of consciousness and other injuries
`
`during seizures—seizures which occur at random and unpredictable times. For any
`
`activity, it is important for a patient with epilepsy to consider the following
`
`question: “What would happen if I had a seizure while doing this?” See, e.g., What
`
`Now? (Ex. 2077), at 185–86.
`
`- 14 -
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2038 - 16/72
`
`
`
`IPR2016-00204
`
`
`
`
` Common, everyday activities that a person might otherwise take for 28.
`
`granted, such as driving, climbing stairs, bathing, and cooking, therefore pose a
`
`substantial risk to the epilepsy patient’s health, and avoiding these activities often
`
`decreases their quality of life. Patients with uncontrolled epilepsy are told to
`
`shower instead of bathe to minimize the risk of drowning. Those prone to falls
`
`during seizures may be required to install a shower seat in the shower and replace
`
`glass shower doors with shatterproof doors. Epilepsy patients are advised to cook
`
`when someone else is nearby, if possible; to use the back burners of the stove to
`
`prevent accidental burns; to use shatterproof containers as much as possible (which
`
`may require the transfer of store-bought sauces from glass bottles or jars to plastic
`
`containers); and to try to buy foods that are already cut or otherwise limit time
`
`required using knives or other sharp objects. Under most state driving laws, those
`
`with epilepsy cannot drive unless they demonstrate they have been seizure-free for
`
`a required minimum period of time (3-12 months) and/or submit necessary
`
`physician reports. Furthermore, many patients with epilepsy who are licensed to
`
`drive may still choose not to, so as to minimize the risk of injuring themselves or
`
`others should they suffer a seizure while driving. Restrictions are even more
`
`severe for commercial driving licenses and pilots licenses. This may lead to
`
`unemployment and social isolation, making it difficult for an epilepsy patient to
`
`make friends, buy groceries, get and maintain a job, or find a place to live.
`
`- 15 -
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2038 - 17/72
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`
`
`IPR2016-00204
`
`Epileptic parents are advised to feed, nurse, dress, and change infants while sitting
`
`on the floor, in a well-protected area, and to use a safe play area or playpen if alone
`
`with a child at home, to prevent the child from falling down the stairs or wandering
`
`into an unsafe situation if the parent experiences a seizure. See, e.g., Living Well
`
`(Ex. 2079), at 181–88; 211. Stress and lack of sleep are known to trigger epileptic
`
`seizures, which may further limit the career and lifestyle choices and experiences
`
`available to people with epilepsy.
`
`
`
` Epilepsy not only poses a threat to the personal safety of both those 29.
`
`afflicted and those around them, but it also may cause emotional, psychological,
`
`and social effects. The unpredictable and bizarre nature of seizures may lead to
`
`prejudice and fear in onlookers, as well as to embarrassment in patients. Although
`
`the social stigma of epileptic seizures has declined over the years, it is not gone.
`
`Patients may experience discrimination at work. Employers often have unrealistic
`
`fears about the effects of seizures on employees with epilepsy, the potential for
`
`liability for any work-related incidents, and higher insurance costs.
`
`
`
` Because of the unpredictable nature of epilepsy, those with epilepsy 30.
`
`may choose to avoid certain professions or alter their life goals. They may also
`
`fear and/or avoid being in public places or social settings, which may lead to social
`
`isolation. I have had patients with epilepsy who became completely isolated in
`
`their homes, and even years after their seizures were completely controlled
`
`- 16 -
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2038 - 18/72
`
`
`
`IPR2016-00204
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`continued to have a persistent fear of leaving their house or interacting with
`
`strangers. Epilepsy impacts both the patients themselves and also the family or
`
`friends who care for them. People with epilepsy often must depend on others for
`
`assistance with routine aspects of daily life, and may feel a loss of independence.
`
`
`
` Epilepsy affects people of all ages, races, ethnic, and socioeconomic 31.
`
`backgrounds. It begins most often, however, among the very young and the very
`
`old. One out of every one hundred children in the United States is diagnosed with
`
`epilepsy. The most common cause of epilepsy in children is congenital
`
`malformations. See, e.g., Carl W. Bazil, Epilepsy: Management, 6 Encyclopedia
`
`of Life Sciences 487, 488 (2002) (Ex. 2081). Epilepsy may significantly impact a
`
`child’s education. Absence seizures in children may be mistaken for
`
`inattentiveness, and can contribute to academic underachievement.
`
`
`
` Common causes of epilepsy in the elderly are cerebrovascular and 32.
`
`degenerative diseases. Id. (Ex. 2081) Elderly epilepsy patients may face
`
`additional challenges with respect to treatment and management of their disorder.
`
`Many elderly epilepsy patients have other medical conditions and, therefore, must
`
`be mindful of potential interactions with or effects of their epilepsy medication on
`
`other medications. Additionally, elderly epilepsy patients may be particularly
`
`vulnerable to falls or physical injuries during a seizure and to the cognitive adverse
`
`- 17 -
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`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2038 - 19/72
`
`
`
`IPR2016-00204
`
`effects of some epilepsy medications. Approximately 300,000 senior citizens in
`
`the United States have epilepsy.
`
`33.
`
`
`In addition to children and the elderly, another patient population who
`
`faces special considerations and risks relating to treatment and management of
`
`epilepsy are women of childbearing age. Women of childbearing age must
`
`consider the potential and, in many cases, presently unknown, risks of epilepsy
`
`drug treatments on the developing infant or on fertility and on effectiveness of oral
`
`contraceptive agents.
`
`C. Categories of Epilepsy Treatment
` There is no known medical cure for epilepsy. There are two major 34.
`
`
`approaches to the management of epilepsy: medical and surgical. Medical
`
`approaches include drug therapy and the ketogenic diet. For the overwhelming
`
`majority of epilepsy patients, treatment consists of the long-term—and often life-
`
`long—administration of drugs (commonly referred to as anticonvulsant drugs,
`
`antiseizure drugs, or AEDs) for the prevention of epileptic seizures.
`
`1.
`
`Diet, Devices, and Surgery
`
`35.
`
`
`In rare cases, particularly with children in whom drug treatment has
`
`failed, the ketogenic diet is used. The ketogenic diet is typically used for only 1–2
`
`years in a given patient, but sometimes is used longer. This diet is designed to
`
`mimic a state of starvation in patients, which in some individuals can improve
`
`- 18 -
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2038 - 20/72
`
`
`
`IPR2016-00204
`
`seizure control. The ketogenic diet severely restricts carbohydrates, such that the
`
`majority of calories are from protein and fat. Under these circumstances, the brain
`
`is forced to use ketone bodies (derived from fat and protein) rather than glucose as
`
`fuel. As this is difficult to administer and maintain, and can severely interfere with
`
`a patient’s lifestyle, it is usually not a good option, particularly in adults. See, e.g.,
`
`What Now? (Ex. 2077), at 147.
`
`
`
` Additionally, there are two surgically implanted devices approved in 36.
`
`the United States for the treatment of refractory epilepsy. The vagus nerve
`
`stimulator is a FDA-approved device that consists of a cuff surgically placed over
`
`one of the major cranial nerves, the vagus. Wires lead into a battery placed in t
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