UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner
`__________
`
`Case IPR2017-01767
`Patent 9,254,278
`__________
`
`DECLARATION OF DR. GREGORY M. ENNS
`
`Horizon Exhibit 2006
`Par v. Horizon
`IPR2017-01767
`
`Page 1 of 73
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`

`

`TABLE OF CONTENTS
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`INTRODUCTION .............................................................................................................. 1
`
`QUALIFICATIONS ........................................................................................................... 3
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Education ................................................................................................................ 3
`
`Professional Experience .......................................................................................... 4
`
`Publications and Presentations ................................................................................ 6
`
`Honors and Awards................................................................................................. 6
`
`Professional Organizations and Service Activities ................................................. 7
`
`LEGAL PRINCIPLES ........................................................................................................ 7
`
`SUMMARY OF OPINIONS .............................................................................................. 9
`
`PERSON OF ORDINARY SKILL IN THE ART ............................................................ 11
`
`TECHNOLOGY BACKGROUND .................................................................................. 15
`
`VII. OVERVIEW OF THE ’278 PATENT .............................................................................. 22
`
`A.
`
`The Claims of the ’278 Patent .............................................................................. 25
`
`VIII. CLAIM CONSTRUCTION .............................................................................................. 28
`
`A.
`
`“upper limit of normal” ......................................................................................... 28
`
`IX.
`
`THE PRIOR ART DOES NOT DISCLOSE OR SUGGEST THE SUBJECT MATTER
`OF CLAIMS 1-15 ............................................................................................................. 29
`
`A.
`
`B.
`
`The Prior Art Does Not Disclose Increasing a Dosage of Glyceryl Tri-[4-
`phenyl-butyrate] in a Patient with a Fasting Plasma Ammonia Level
`Between Half the ULN and the ULN ................................................................... 29
`
`The Prior Art Provides No Reason to Adjust the Treatment Regimen of a
`Subject with a Fasting Plasma Ammonia Level in the Normal Range ................. 42
`
`1.
`
`2.
`
`The Prior Art as a Whole Provided no Reason to Increase the
`Dosage When Plasma Ammonia Levels were Already in the
`Normal or Near-Normal Range ................................................................ 44
`
`The Reported Variability in Plasma Ammonia Levels Discouraged
`Reliance on Normal Plasma Ammonia Levels in Making Dosage
`Adjustment Decisions ............................................................................... 49
`
`i
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`The Prior Art Did Not Suggest Reliance on Fasting Plasma
`Ammonia Measurements for Dosage Adjustments .................................. 55
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`3.
`
`C.
`
`D.
`
`There Was No Reasonable Expectation that Administering an Increased
`Dosage to a Patient with a Plasma Ammonia Level Already in the Normal
`Range Would Confer a Treatment Benefit ........................................................... 59
`
`The Prior Art Did Not Disclose or Suggest Targeting a Plasma Ammonia
`Level at or Below Half the ULN ........................................................................... 61
`
`X.
`
`CONCLUSION ................................................................................................................. 69
`
`ii
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`Page 3 of 73
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`I, Dr. Gregory M. Enns, hereby declare as follows:
`INTRODUCTION
`I.
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`1.
`
`I, Dr. Gregory M. Enns, have been retained by Green, Griffith & Borg-Breen LLP
`
`on behalf of Horizon Therapeutics, LLC, as an independent expert in the field of clinical
`
`biochemical genetics. My curriculum vitae establishes my qualifications in this area. (Ex.
`
`2007.) I am being compensated for the time I spend on this matter, but no part of my
`
`compensation depends directly or indirectly on the outcome of this proceeding or any related
`
`proceeding.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 9,254,278 (“the ’278
`
`patent”). (Ex. 1001.) I understand that the application for the ’278 patent was filed on August 3,
`
`2015, as a continuation of U.S. Patent Application No. 13/775,000, filed February 22, 2013, now
`
`U.S. Patent No. 9,095,559 (“the ’559 Patent”). The ’278 patent is also the subject of currently
`
`pending IPR No. 2017-01159, filed by Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively,
`
`“Lupin”). I have submitted an expert declaration on behalf of Patent Owner, Horizon
`
`Therapeutics, LLC in IPR2017-01159. I have also submitted expert declarations on behalf of
`
`Patent Owner Horizon Therapeutics, LLC in the currently pending IPR proceedings also filed by
`
`Lupin concerning related U.S. Patent No. 9,326,966 (“the ’966 patent”), Lupin Ltd. et al. v.
`
`Horizon Therapeutics, LLC, IPR2017-01160, and the ’559 patent, Lupin Ltd. et al. v. Horizon
`
`Therapeutics, Inc., IPR2016-00829. Finally, I have also submitted expert declarations on behalf
`
`of Patent Owner Horizon Therapeutics, LLC in the currently pending IPR proceedings filed by
`
`instant Petitioner Par Pharmaceutical, Inc. (“Par”) concerning the ’966 patent, Par
`
`Pharmaceutical, Inc. et al. v. Horizon Therapeutics, LLC, IPR2017-01769, and the ’559 patent,
`
`Par Pharmaceutical, Inc. et al. v. Horizon Therapeutics, LLC, IPR2017-01768.
`
`1
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`Case No. IPR2017-01767
`
`US. Patent No. 9,254,278
`
`3.
`
`I understand that the ’278 patent issued on February 9, 2016, and that the ’278
`
`patent claims priority to Provisional Application No. 61/564,668 (“the ’668 application”), filed
`
`on November 29, 2011, and Provisional Application No. 61/542,100, filed on September 30,
`
`2011. 03x. 1001 .) I have therefore considered the state of the art and the prior art available as of
`
`September 30, 2011.
`
`4.
`
`I understand that Petitioner has asserted that claims 1-15 of the ’278 patent are
`
`unpatentable on the grounds listed in the table below:
`
`§ 102
`
`The ’859 Publication
`
`Challenged ’278 Patent
`Claims
`
`Independent Claim: 1 Dependent Claim: 2-3
`
`
`
`2
`
`3
`
`4
`
`Fernandes in View of the ’859
`Publication and Lee or Lichter—
`
`Independent Claim: 1
`
`Konecki, optionally in further View
`of Blau or Simell
`
`Dependent Claims: 2—3
`
`Fernandes in View of the ’859
`Publication, optionally in further
`View of Blau, Simell and/or Lee
`
`Fernandes in View of the ’859
`Publication and Lee or Lichter—
`
`Konecki, optionally in further View
`of Blau or Simell
`
`Independent Claims: 4, 8,
`12
`
`Dependent Claims: 6, 7,
`10, 11, 14, 15
`
`Dependent Claims: 5, 9,
`l3
`
`
`
`5.
`
`In preparing this declaration, I have considered the ’278 patent and its prosecution
`
`history, the Petition for Inter Partes Review ofNo. US. Patent 9,254,278, the Declaration of Dr.
`
`Sondheimer (Ex. 1002) (“Sondheimer”), the prior art and references identified in the Petition and
`
`the Sondheimer Declaration, my knowledge and expertise in the art, and any additional materials
`
`cited herein.
`
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`II.
`
`QUALIFICATIONS
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`A.
`
`6.
`
`Education
`
`I received a Bachelor of Arts degree in Biology from Pomona College in 1984. In
`
`1987, I obtained a Diploma in Medical Science from the University of St. Andrews, Scotland. In
`
`1990, I received my U.K. Medical Degree from the University of Glasgow, Scotland.
`
`7.
`
`From 1990 to 1991, I was a Junior House Officer at the Royal Hospital for Sick
`
`Children and the Glasgow Royal Infirmary, working in both Pediatric Surgery and General
`
`Medicine. I then completed my U.S. residency training in Pediatrics at the Children’s Hospital
`
`of Los Angeles (“CHLA”), beginning as Intern and Resident from 1991 to 1994, and serving as
`
`Chief Resident from 1994 to 1995. From 1995 to 1998, I completed a fellowship in Medical
`
`Genetics at the University of California, San Francisco, including training in Clinical
`
`Biochemical Genetics from 1997 to 1998. During my training at the University of California,
`
`San Francisco I frequently diagnosed and managed patients with urea cycle disorders, including
`
`treatment with nitrogen scavenging medications, under supervision of a specialist in Biochemical
`
`Genetics.
`
`8.
`
`I am a licensed physician in California, Hawaii, and the United Kingdom. I am
`
`Board Certified in Clinical Genetics and Clinical Biochemical Genetics by the American Board
`
`of Medical Genetics and Genomics (“ABMGG”). Certification by the ABMGG in clinical
`
`genetics implies that I have a broad knowledge in human and medical genetics. Furthermore,
`
`ABMGG certification in clinical biochemical genetics means that I have further subspecialist
`
`knowledge related to biochemical genetics. In particular, this further certification implies that I
`
`have broad knowledge of: (a) basic biochemistry and genetics; (b) the application of biochemical
`
`techniques to the diagnosis and management of genetic diseases; and (c) the etiology,
`
`3
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`pathogenesis, clinical manifestations, and management of human inherited biochemical
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`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
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`disorders, including urea cycle disorders. (See Ex. 2026 (ABMGG).)
`
`B.
`
`9.
`
`Professional Experience
`
` I am a Professor at Stanford University School of Medicine, where I began as an
`
`Assistant Professor of Pediatrics. In 2006 I became an Associate Professor, and in 2015 I was
`
`promoted to Professor. Since completing my fellowship in 1998, I have also worked as a
`
`Clinical Instructor in Pediatrics at the University of California, San Francisco. While Chief
`
`Resident at CHLA, I worked as a Clinical Instructor in Pediatrics at the University of Southern
`
`California.
`
`10.
`
`During my tenure at Stanford University School of Medicine, I have provided
`
`lectures and taught numerous courses focusing on Medical Genetics and Biochemical Genetics.
`
`These lectures and courses frequently included discussion related to the diagnosis and
`
`management of urea cycle disorders. I have also taught trainees at all levels—from medical
`
`students to post-doctoral fellows—about the management of inborn errors of metabolism,
`
`including urea cycle defects. Furthermore, as an internationally recognized expert in the
`
`treatment of urea cycle disorders, I have been invited to present at regional, national, and
`
`international meetings specifically on the topic of treatment of urea cycle disorders. I have been
`
`the Director of the Biochemical Genetics Program at Stanford since my appointment in 1998. As
`
`part of my duties, I oversee the wide-ranging clinical, research, and educational goals of the
`
`Biochemical Genetics Program. In addition, I am the Director of the Medical Biochemical
`
`Genetics Residency Training Program at Stanford University, and am responsible for training
`
`post-doctoral trainees in the practice of clinical biochemical genetics.
`
`4
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`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
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` I maintain an active clinical practice that is focused on the diagnosis and ongoing
`
`11.
`
`management of patients with inborn errors of metabolism of all forms, including urea cycle
`
`disorders (“UCDs”), and currently provide ongoing treatment for approximately forty urea cycle
`
`disorder patients. In addition, I have served as a Medical Consultant at the Newborn Screening
`
`Area Service Center at Stanford since 2003, where I advise medical providers caring for
`
`neonates with positive screens for inborn errors of metabolism, including urea cycle disorders,
`
`on a daily basis. I have also participated in clinical trials using alternative pathway therapy for
`
`the treatment of urea cycle disorders.
`
`12.
`
`Over the course of my career, I have cared for roughly 70 to 100 urea cycle
`
`disorder patients. I estimate that 60% of my time currently is devoted to clinical practice, and I
`
`see approximately 600 to 700 patients with inborn errors of metabolism, or who are suspected of
`
`having a biochemical genetic or neurogenetic disorder, annually. For the urea cycle disorder
`
`patients that I manage, I prescribe nitrogen scavenging medications on nearly all patients who
`
`have not undergone liver transplantation. In these patients, I am the primary provider who
`
`adjusts nitrogen scavenging medication dosages and manages the overall care plan, including
`
`tailoring dietary treatment and emergency management. I have been the lead investigator on a
`
`clinical trial involving emergency treatment of urea cycle disorder patients with intravenous
`
`nitrogen scavenging medications, with the results of this study published in the New England
`
`Journal of Medicine in 2007. (Ex. 2028 (Enns).) In addition, because of the active involvement
`
`of our Biochemical Genetics Program in the diagnosis and management of urea cycle disorder
`
`patients, our site has recently joined the Urea Cycle Disorders Consortium (“UCDC”), the
`
`premier international collaborative consortium consisting of sites with significant experience in
`
`5
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`the diagnosis and treatment, as well as research, of urea cycle disorders that are dedicated to
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`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`improving the lives of individuals affected by this disorder. (Ex. 2027.)
`
`C.
`
`13.
`
`Publications and Presentations
`
` I have published at least 90 articles in peer reviewed journals, and have
`
`published articles related to urea cycle disorder diagnosis and treatment in peer reviewed
`
`journals, including the New England Journal of Medicine, Molecular Genetics and Metabolism,
`
`Obstetrics and Gynecology, and Seminars in Pediatric Neurology. I have written book chapters
`
`and invited reviews on the topics of hyperammonemia and alternative pathway therapy,
`
`including a chapter on “Hyperammonemia” in the recently published book Signs and Symptoms
`
`of Genetic Conditions: A Handbook, a book for which I am also a co-editor. (Ex. 2029.) I have
`
`also presented clinical research data related to urea cycle disorders at regional, national and
`
`international meetings.
`
`14.
`
` As a physician-scientist, I perform peer review on a regular basis for scientific
`
`journals and serve or have served on the editorial boards for the major journals in the field of
`
`Clinical Biochemical Genetics including, Molecular Genetics and Metabolism, Journal of
`
`Inherited and Metabolic Disease, and Molecular Genetics and Metabolism Reports. I have also
`
`been an ad hoc manuscript reviewer for over fifty other journals. In this capacity, I am
`
`frequently asked to review manuscripts related to urea cycle disorder research, or participate in
`
`the editorial process related to the review of such manuscripts.
`
`D.
`
`15.
`
`Honors and Awards
`
` In 2011-2012, I received the Stanford University School of Medicine Excellence
`
`in Teaching Citation. In 2011, I received the Distinguished Service Citation from the American
`
`Academy of Pediatrics. I also received the Neil Arnott Memorial Prize in Clinical Physics at the
`
`6
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`University of Glasgow in 1988. I received the CHLA Board of Directors Award for outstanding
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`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
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`service as Pediatric Chief Resident in 1995.
`
`E.
`
`16.
`
`Professional Organizations and Service Activities
`
`I am a member of several professional societies, including: The Society of
`
`Inherited Metabolic Disorders, Society for the Study of Inborn Errors of Metabolism, Western
`
`Society for Pediatric Research, the General Medical Council, U.K. and the American Society of
`
`Human Genetics.
`
`17.
`
`I have participated in public and professional service activities and have served on
`
`committees throughout my medical career. For example, I have served on the Molecular
`
`Pathology Education Committee since 2005 at Stanford University Hospital, and have served as
`
`Chair of the Newborn Screening Metabolic Disorders Guidelines Committee for the California
`
`Department of Health Services from 2009 to 2012. I was on the Board of Directors of the
`
`Society for Inherited Metabolic Disorders from 2007 to 2014 and served on the American
`
`Academy of Pediatrics Committee on Genetics from 2005 to 2011. I also formed the Stanford
`
`University Mitochondrial Interest Group in 2004, and helped establish the Bay Area
`
`Mitochondria Association in 2004. I have been active in the American College of Medical
`
`Genetics Clinical Genomics Workgroup since 2014, and have been on the National Organization
`
`for Rare Disorders (“NORD”) Scientific and Medical Advisory Committee since 2012.
`
`III. LEGAL PRINCIPLES
`
`18.
`
`I am not an attorney and offer no legal opinions. But in the course of my work, I
`
`have studied and analyzed patents and patent claims from the perspective of a person of ordinary
`
`skill in the art. In formulating my opinions and conclusions, I have been provided with an
`
`7
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`understanding of the principles of U.S. patent law that govern the issues of claim construction,
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`anticipation and obviousness.
`
`19.
`
`I understand that assessing the patentability of a patent claim involves a two-step
`
`analysis. In the first step, the claim language must be properly defined to determine its scope
`
`and meaning from the perspective of a person of ordinary skill in the art (“POSA”). I understand
`
`that the factors to consider in determining the qualifications or experience of the POSA include
`
`the type of problems encountered in the art, prior art solutions to those problems, rapidity with
`
`which innovations are made, sophistication of the technology, and educational level of active
`
`workers in the field. Accordingly, in determining the qualifications of the POSA in this context,
`
`I considered the expertise that would be required to understand the disclosure of the ’278 patent
`
`and to implement the instructions of the patent as it relates to managing and caring for complex
`
`patients who have urea cycle disorders.
`
`20.
`
`In the second step of assessing patentability of a claim, the claim at issue must be
`
`compared to the prior art to determine whether the claim is invalid.
`
`21.
`
`I have been advised that in inter partes review proceedings before the U.S. Patent
`
`and Trademark Office (“USPTO”), a patent claim receives the broadest reasonable construction
`
`in light of the specification of the patent in which it appears. I have also been advised that, at the
`
`same time, claim terms are given their ordinary and accustomed meaning as they would be
`
`understood by one of ordinary skill in the art. I have been informed that the construction of a
`
`patent claim applied during this proceeding may differ from that in a district court proceeding or
`
`a proceeding before the International Trade Commission.
`
`8
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`I discuss certain terms from the claims of the ’278 patent below and what I
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`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`22.
`
`understand to be the broadest reasonable construction of these terms from the perspective of one
`
`of ordinary skill in the art.
`
`23.
`
`I have also been told that the obviousness inquiry is a question of law based on
`
`four factual predicates: (a) the scope and content of the prior art; (b) the differences between the
`
`prior art and the claims at issue; (c) the level of ordinary skill in the pertinent art; and (d)
`
`secondary considerations such as commercial success, long felt but unsolved needs, failure of
`
`others.
`
`24.
`
` I have also been informed that determining whether there are any material
`
`differences between the scope and content of the prior art and each asserted claim of the
`
`challenged patent requires consideration of the claimed invention as a whole to determine
`
`whether or not it would have been obvious in light of the prior art. If the prior art discloses all
`
`the limitations in separate references, consideration should be given to whether it would have
`
`been obvious to combine those references. I understand that a claim is not obvious merely
`
`because all of the features of that claim already existed in the prior art. Further, a person of
`
`ordinary skill in the art who is combining references should have a reasonable expectation of
`
`success.
`
`IV.
`
`SUMMARY OF OPINIONS
`
`25.
`
`The method recited by independent claim 1 includes the steps of administering
`
`glyceryl tri-[4-phenylbutyrate] (also known as “glycerol phenylbutyrate,” “HPN-100” or “GPB”)
`
`to a subject in need thereof in an amount sufficient to produce a fasting plasma ammonia level
`
`that is less than half the upper limit of normal. (Ex. 1001 at 24:20-26) (’278 patent).) Claims 2
`
`and 3 depend from claim 1, and further recite a specific value for the upper limit of normal (35
`
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`µmol/L), and that the glyceryl tri-[4-phenylbutyrate] is administered orally, respectively. (Ex.
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`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`1001 at 24:27-30 (’278 patent).)
`
`26.
`
`The methods recited in independent claims 4, 8 and 12 include the steps of
`
`administering an increased dosage of glyceryl tri-[4-phenylbutyrate] to a subject who has
`
`previously been administered an initial dosage of glyceryl tri-[4-phenylbutyrate] when the
`
`subject’s plasma ammonia level is between half the upper limit of normal (“ULN”) and the upper
`
`limit of normal (Ex. 1001 at 24:31-45; 24:56-25:7; 25:16-26:13 (’278 patent).) Accordingly,
`
`these claims recite increasing the dosage of glyceryl tri-[4-phenylbutyrate] when a subject’s
`
`plasma ammonia is in a normal range. Claim 4 additionally recites that the method further
`
`comprises restricting the subject’s dietary protein intake. (Ex. 1001 at 24:31-47 (’278 patent).)
`
`Claim 8 additionally recites the method further comprises “monitoring the subject’s ammonia
`
`levels if the glyceryl tri-[4-phenylbutyrate] is not being adequately digested by the subject’s
`
`pancreatic lipases.” (Ex. 1001 at 24:56-25:7 (’278 patent).) Claim 12 additionally recites that
`
`the subject has previously been administered an initial dosage of sodium phenylbutyrate and that
`
`the administration of the initial dosage of glyceryl tri-[4-phenylbutyrate] is determined by the
`
`amount of the initial dosage of sodium phenylbutyrate. (Ex. 1001 at 25:16-26:13 (’278 patent).)
`
`27.
`
`Claims 5-7, 9-11, and 13-15 depend from claims 4, 8, or 12. Specifically, claims
`
`6, 7, 10, 11, 14 and 15 further specify that the initial or adjusted dosage of glyceryl tri-[4-
`
`phenylbutyrate] is administered orally, while claims 5, 9 and 13 further recite repeating the steps
`
`of measuring a fasting plasma ammonia level, comparing it to the upper limit of normal, and
`
`administering an increased dosage of glyceryl tri-[4-phenylbutyrate] if the fasting plasma
`
`ammonia level is greater than half the upper limit of normal until the subject exhibits a fasting
`
`plasma ammonia level at or below half the ULN.
`
`10
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`As explained in detail below, the methods recited in independent claims 1, 4, 8
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`Case No. IPR2017-01767
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`28.
`
`and 12 of the ’278 patent would not have been obvious over the prior art relied upon by Dr.
`
`Sondheimer. Specifically, in my opinion there is no teaching or suggestion in the prior art to
`
`practice the methods recited by independent claims 1, 4, 8 and 12 and the claims dependent
`
`therefrom. No prior art reference discloses increasing the dosage of a nitrogen scavenging drug
`
`or initiating dosing when a patient has a normal plasma ammonia value. To the contrary, the
`
`prior art viewed normal plasma ammonia values as acceptable and indicative of an effective
`
`treatment, with acceptable plasma ammonia values often including those two to three times
`
`greater than the upper limit of normal. Moreover, one of ordinary skill would have had no
`
`reason to adjust the treatment regimen when a subject’s plasma ammonia levels were normal,
`
`especially given the unreliability of plasma ammonia levels.
`
`29.
`
`In addition to the failure of the prior art to teach increasing a dosage when plasma
`
`ammonia is in the normal range, discussed above, in my opinion there is also no teaching or
`
`suggestion in the prior art of targeting a plasma ammonia value at or below half the upper limit
`
`of normal. For this independent reason, I do not believe that the prior art disclosed or suggested
`
`the features of dependent claims 5, 9 and 13. In addition, I do not believe that the prior art
`
`disclosed or suggested the features of independent claim 1 and its dependent claims 2 and 3,
`
`which are also directed to a method targeting a fasting plasma ammonia level less than half the
`
`ULN.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`30.
`
` A person of ordinary skill in the art of the ’278 patent would have had the
`
`following qualifications: (a) an M.D. or equivalent degree; (b) at least three years of
`
`residency/fellowship training in Medical Genetics, including Biochemical Genetics, followed by
`
`11
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`certification in Clinical Genetics and Clinical or Medical Biochemical Genetics by the American
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`Case No. IPR2017-01767
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`Board of Medical Genetics and Genomics; and (c) at least five years of experience treating
`
`patients with nitrogen retention disorders, including urea cycle disorders.
`
`31.
`
`I disagree with Petitioner’s and Dr. Sondheimer’s definition that requires “a
`
`physician or scientist with a Ph.D. or M.D. degree and specialized training in the diagnosis or
`
`treatment of inherited metabolic disorders, such as UCD and other nitrogen retention disorders.”
`
`(Pet. at 18; Ex. 1002 at ¶ 40 (Sondheimer).) The ’278 patent claims are directed to, inter alia,
`
`methods of administering and adjusting the dosage of a nitrogen scavenging medication in
`
`subjects being treated for urea cycle disorder. (Ex. 1001 at 24:20-26:21 (’278 patent).) A doctor
`
`or scientist trained only in diagnosing urea cycle disorders would not have an understanding of
`
`the various complicated factors involved in designing a treatment plan for a patient with a urea
`
`cycle disorder. Such a physician or scientist would not understand the state of the art with
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`respect to the use of ammonia levels in treating urea cycle disorder patients. They, for example,
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`would have a fundamental misunderstanding of the goal in treating a patient with a urea cycle
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`disorder and the role of “normal” plasma ammonia levels in making treatment decisions.
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`32.
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`I also disagree with Petitioner’s and Dr. Sondheimer’s definition because it does
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`not specify the amount of specialized training needed in the treatment or diagnosis of patients
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`with nitrogen retention disorders, such as UCDs, to qualify as a POSA, nor require any of the
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`relevant Board certifications. Instead, Petitioner and Dr. Sondheimer provide that “such a person
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`may also have post-graduate training to fulfill the requirements of the American Board of
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`Medical Genetics and Genomics in Clinical Genetics, Clinical Biochemical Genetics, or Medical
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`Biochemical Genetics.” (Pet. at 18-19.) But the complex treatment of UCD or other nitrogen
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`disorders requires experienced personnel with specific expertise in metabolic disorders in order
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`to understand the various complicated factors involved in designing a treatment plan for a patient
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`with a urea cycle disorder. Accordingly, a person of ordinary skill would need at least three
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`years of residency/fellowship training in Medical Genetics, including Biochemical Genetics,
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`followed by dual certification in both Clinical Genetics and Clinical or Medical Biochemical
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`Genetics by the American Board of Medical Genetics and Genomics, and at least five years of
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`experience treating patients with nitrogen retention disorders. Dual certification in the above-
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`referenced specialties is required to ensure that the physician’s training imparts the fundamental
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`knowledge needed to care for the complex needs of UCD patients. Training in Clinical Genetics
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`requires exposure to inborn errors of metabolism as part of the curriculum, but such exposure is
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`typically basic and not designed to provide the trainee with the specialist-level knowledge
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`needed for treating and managing UCD patients. With further certification in Clinical or
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`Medical Biochemical Genetics, a physician obtains training in basic biochemistry and genetics,
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`the application of biochemical techniques to the management of genetic diseases, and the
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`etiology, pathogenesis, clinical manifestations, and management of human inherited biochemical
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`disorders such as UCD.
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`33.
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`Furthermore, a considerable amount of time in practice, such as at least 5 years, is
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`required to gain adequate experience in the longitudinal management of UCD patients due to the
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`rarity of UCD and the small number of patients that even a busy practice will follow. Less
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`qualified physicians would not understand the state of the art with respect to the use of ammonia
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`levels in treating urea cycle disorder patients. Those without this level of skill, for example,
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`would have a fundamental misunderstanding of the goal in treating a patient with a urea cycle
`
`disorder and the role of “normal” plasma ammonia levels in making treatment decisions.
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`I disagree that the definition of one of ordinary skill would include someone with
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`34.
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`residency training only in general pediatrics or internal medicine, and an indefinite amount of
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`“specialized training” in nitrogen retention disorders such as UCD that falls short of the
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`requirements as laid out in my definition above. (See ¶ 30, supra.) Treatment of urea cycle
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`disorders requires specialized expertise and training that a general pediatrician would not
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`possess. For example, a general pediatric residency program may only include a one-hour
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`lecture on inborn errors of metabolism and a resident may never even see a patient with urea
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`cycle disorder. A general pediatrician therefore would not be responsible for prescribing
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`nitrogen scavenging medicine for the treatment of urea cycle disorders. Just as a pediatrician
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`would refer a patient in cardiac failure to a cardiologist, a patient with thyroid issues to an
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`endocrinologist, and a patient with kidney problems to a nephrologist, a pediatrician would refer
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`a patient with urea cycle disorder to a biochemical geneticist. Because of the rarity of these
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`disorders (only approximately 113 new patients per year) and high mortality rate, a general
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`pediatrician would not have any exposure to these types of patients. (Ex. 2035 at 180 (Summar
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`2013); Ex. 2019 at 1-2 (Häberle); Ex. 2036 at 1423 (only 35% survival of patients presenting
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`with hyperammonemia within first 30 days of life) (Summar 2008).) Even experienced Clinical
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`Geneticists without certification in either Clinical or Medical Biochemical Genetics refer UCD
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`patients to physicians with further subspecialist biochemical qualifications for management. One
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`publication notes that even experienced metabolic specialists may only ever manage fewer than
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`50 urea cycle disorder patients. (Ex. 2037 at S86 (Wilcken).) The prior art consistently
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`emphasizes the importance of referring urea cycle disorder patients to specialized care centers so
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`they can receive proper care, thus ensuring their growth and survival. (Ex. 2017 at S66, S67,
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`S69 (discussing the importance of specialized metabolic centers and the increase in survival of
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`UCD patients when treated in specialized metabolic centers) (Enns 2010); Ex. 2034 at S33
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`(Summar 2001); Ex. 2037 at S87 (stressing the need to tr