UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`
`Patent Owner
`
`Case IPR 2017-01159
`
`Patent 9,254,278
`
`DECLARATION OF DR. GREGORY M. ENNS
`
`Horizon Exhibit 2006
`Lupin v. Horizon
`IPR2017-01159
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`Page 1 of 67
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`

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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`Introduction ......................................................................................................................... 1
`
`Qualifications ...................................................................................................................... 2
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`Education ................................................................................................................ 2
`
`Professional Experience .......................................................................................... 3
`
`Publications and Presentations ................................................................................ 5
`
`Honors and Awards................................................................................................. 6
`
`Professional Organizations and Service Activities ................................................. 6
`
`Legal Principles .................................................................................................................. 7
`
`Summary of Opinions ......................................................................................................... 9
`
`Person of Ordinary Skill in the Art ................................................................................... 11
`
`Technology Background ................................................................................................... 14
`
`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`VII. Overview of the ’278 Patent ............................................................................................. 21
`
`A.
`
`B.
`
`The Claims of the ’278 Patent .............................................................................. 24
`
`Prosecution History of the ’278 Patent ................................................................. 26
`
`VIII. Claim Construction ........................................................................................................... 28
`
`A.
`
`B.
`
`“upper limit of normal” ......................................................................................... 28
`
`“the subject” .......................................................................................................... 29
`
`IX.
`
`The Prior Art Does Not Disclose or Suggest Subject Matter of Claims 1-15 .................. 30
`
`A.
`
`B.
`
`The Prior Art Does Not Disclose Increasing a Dosage of Glyceryl Tri-[4-
`phenyl-butyrate] in a Patient with a Plasma Ammonia Level Between Half
`the ULN and the ULN ........................................................................................... 30
`
`No Motivation to Adjust the Dosage of Nitrogen Scavenging Drug for a
`Subject with Plasma Ammonia Levels in the Normal Range ............................... 39
`
`1.
`
`A POSA Did Not Account for a Fasting v. Fed Ammonia Level
`When Making Dosing Determinations .................................................... 40
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`The Prior Art Disclosed Normal Plasma Ammonia Levels Were
`Acceptable and Only Increased Dosage When Levels Were Well
`Above Normal ........................................................................................... 44
`
`A POSA Would Not Have Been Motivated to Combine the ’859
`Publication with Simell or Blau ................................................................ 50
`
`2.
`
`3.
`
`C.
`
`D.
`
`No Reasonable Expectation that an Increased Dosage Would Lower a
`Patient’s Baseline Ammonia and Ensure a Normal Plasma Ammonia over
`the Course of a Day............................................................................................... 56
`
`The Prior Art Did Not Disclose or Suggest Targeting a Plasma Ammonia
`Level Below Half the ULN ................................................................................... 58
`
`X.
`
`Conclusion ........................................................................................................................ 63
`
`
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`iii
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`I, Dr. Gregory M. Enns, hereby declare as follows:
`Introduction
`I.
`
`Case No. IPR2017-01159
`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 ’559 patent is the subject of IPR No. 2016-
`
`00829. As discussed further below, I have submitted an expert declaration on behalf of Patent
`
`Owner, Horizon Therapeutics, LLC in the IPR proceeding concerning the ’559 patent claims.
`
`(See Ex. 2001, Declaration of Dr. Gregory M. Enns, M.D., Lupin Ltd. et al. v. Horizon
`
`Therapeutics, Inc., IPR2016-00829 (“Enns ’559 Declaration.”).) I have also submitted an
`
`expert declaration on behalf of Patent Owner Horizon Therapeutics, LLC in the IPR proceeding
`
`concerning related U.S. Patent U.S. 9,326,966 (“the ’966 patent”), Lupin Ltd. et al. v. Horizon
`
`Therapeutics, Inc., IPR2017-01160. I note that Lupin’s expert in this proceeding, Dr. Keith
`
`Vaux, has also submitted declarations in support of Lupin’s Petitions in the IPR proceedings
`
`concerning the ’559 and ’966 patents, which rely on the same primary prior art references and
`
`largely the same arguments as those included in the instant matter.
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`
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`1
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`I understand that the ’278 patent issued on February 9, 2016, and that the ’278
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`3.
`
`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. (Ex. 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 the ’859 Publication (Ex. 1007)
`
`renders obvious claims 1-3 of the ’278 patent; that a combination of Blau (Ex. 1006), Simell (Ex.
`
`1005), and the ’859 Publication renders obvious claims 4-7, and 12-15; and that a combination of
`
`Blau, Simell, the ’859 Publication, and the Brusilow ’979 Patent (Ex. 1024) renders obvious
`
`claims 8-11. (Petition at 13.) In preparing this declaration, I have considered the ’278 patent and
`
`its prosecution history, the Petition for Inter Partes Review of No. U.S. Patent 9,254,278, the
`
`Declaration of Dr. Vaux (Ex. 1002) (“Vaux”), the prior art and references identified in the
`
`Petition and the Vaux Declaration, my knowledge and expertise in the art, and any additional
`
`materials cited herein.
`
`II.
`
`Qualifications
`
`A.
`
`5.
`
`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.
`
`6.
`
`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
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`
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`Chief Resident from 1994 to 1995. From 1995 to 1998, I completed a fellowship in Medical
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`
`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.
`
`7.
`
`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,
`
`pathogenesis, clinical manifestations, and management of human inherited biochemical
`
`disorders, including urea cycle disorders. (See Ex. 2026 (ABMGG).)
`
`B.
`
`8.
`
`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.
`
`
`
`3
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`During my tenure at Stanford University School of Medicine, I have provided
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`Case No. IPR2017-01159
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`9.
`
`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.
`
`10.
`
` I maintain an active clinical practice that is focused on the diagnosis and ongoing
`
`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.
`
`11.
`
`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
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`
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`see approximately 600 to 700 patients with inborn errors of metabolism, or who are suspected of
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`Case No. IPR2017-01159
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`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
`
`the diagnosis and treatment, as well as research, of urea cycle disorders that are dedicated to
`
`improving the lives of individuals affected by this disorder. (Ex. 2027.)
`
`C.
`
`12.
`
`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
`
`
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`also presented clinical research data related to urea cycle disorders at regional, national and
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`Case No. IPR2017-01159
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`international meetings.
`
`13.
`
` 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.
`
`14.
`
`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
`
`University of Glasgow in 1988. I received the CHLA Board of Directors Award for outstanding
`
`service as Pediatric Chief Resident in 1995.
`
`E.
`
`15.
`
`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 American Academy of Pediatrics, the General Medical
`
`Council, U.K. and the American Society of Human Genetics.
`
`16.
`
`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
`
`
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`Chair of the Newborn Screening Metabolic Disorders Guidelines Committee for the California
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`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
`
`17.
`
` 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
`
`understanding of the principles of U.S. patent law that govern the issues of claim construction,
`
`anticipation and obviousness.
`
`18.
`
`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
`
`
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`and to implement the instructions of the patent as it relates to managing and caring for complex
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`U.S. Patent No. 9,254,278
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`patients who have urea cycle disorders.
`
`19.
`
`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.
`
`20.
`
`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.
`
`21.
`
`I discuss certain terms from the claims of the ’278 patent below and what I
`
`understand to be the broadest reasonable construction of these terms from the perspective of one
`
`of ordinary skill in the art.
`
`22.
`
`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.
`
`23.
`
` 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
`
`
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`the limitations in separate references, consideration should be given to whether it would have
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`U.S. Patent No. 9,254,278
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`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
`
`24.
`
`The method recited by independent claim 1 includes the steps of administering
`
`glyceryl tri-[4-phenylbutyrate] 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 µmol/L), and that the glyceryl tri-[4-phenylbutyrate] is
`
`administered orally, respectively. (Ex. 1001 at 24:27-30 (’278 patent).)
`
`25.
`
`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 24:34-45; 24:59-25:3; 25:20-26:13 (’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
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`the subject has previously been administered an initial dosage of sodium phenylbutyrate and that
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`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).)
`
`26.
`
`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.
`
`27.
`
`As explained in detail below, the methods recited in independent claims 1, 4, 8
`
`and 12 of the ’278 patent would not have been obvious over the prior art relied upon by Dr.
`
`Vaux. 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.
`
`28.
`
`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
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`suggestion in the prior art of targeting a plasma ammonia value at or below half the upper limit
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`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, for this same reason, 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
`
`29.
`
` 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
`
`certification in Clinical Genetics and Clinical or Medical Biochemical Genetics by the American
`
`Board of Medical Genetics and Genomics; and (c) at least five years of experience treating
`
`patients with nitrogen retention disorders, including urea cycle disorders.
`
`30.
`
`I disagree with Petitioner’s and Dr. Vaux’s definition that requires “specialized
`
`training in the treatment of UCDs and other nitrogen retention disorders,” but does not specify
`
`the amount or type of such “specialized training” necessary to qualify as a POSA. (Petition at
`
`10; Ex. 1002 at ¶ 19 (Vaux).) The ’278 patent claims are directed to, inter alia, methods of
`
`treating UCD and 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).) The
`
`complex treatment of UCD or other nitrogen disorders requires experienced personnel with
`
`specific expertise in metabolic disorders in order to understand the various complicated factors
`
`involved in designing a treatment plan for a patient with a urea cycle disorder. Accordingly, a
`
`person of ordinary skill would need at least three years of residency/fellowship training in
`
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`Medical Genetics, including Biochemical Genetics, followed by dual certification in both
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`Clinical Genetics and Clinical or Medical Biochemical Genetics by the American Board of
`
`Medical Genetics and Genomics, and at least five years of experience treating patients with
`
`nitrogen retention disorders. Dual certification in the above-referenced specialties is required to
`
`ensure that the physician’s training imparts the fundamental knowledge needed to care for the
`
`complex needs of UCD patients. Training in Clinical Genetics requires exposure to inborn errors
`
`of metabolism as part of the curriculum, but such exposure is typically basic and not designed to
`
`provide the trainee with the specialist-level knowledge needed for treating and managing UCD
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`patients. With further certification in Clinical or Medical Biochemical Genetics, a physician
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`obtains training in basic biochemistry and genetics, the application of biochemical techniques to
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`the management of genetic diseases, and the etiology, pathogenesis, clinical manifestations, and
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`management of human inherited biochemical disorders such as UCD. Furthermore, a
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`considerable amount of time in practice, such as at least 5 years, is required to gain adequate
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`experience in the longitudinal management of UCD patients due to the rarity of UCD and the
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`small number of patients that even a busy practice will follow. Less qualified physicians would
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`not understand the state of the art with respect to the use of ammonia levels in treating urea cycle
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`disorder patients. Those without this level of skill, for example, would have a fundamental
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`misunderstanding of the goal in treating a patient with a urea cycle disorder and the role of
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`“normal” plasma ammonia levels in making treatment decisions.
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`31.
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`I disagree that the definition of one of ordinary skill would include someone with
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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 ¶ 29, 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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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`possess. A general pediatric residency program may only include a one hour lecture on inborn
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`errors of metabolism and a resident may never even see a patient with urea cycle disorder. A
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`general pediatrician therefore would not be responsible for prescribing nitrogen scavenging
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`medicine for the treatment of urea cycle disorders. Just as a pediatrician would refer a patient in
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`cardiac failure to a cardiologist, a patient with thyroid issues to an endocrinologist, and a patient
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`with kidney problems to a nephrologist, a pediatrician would refer a patient with urea cycle
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`disorder to a biochemical geneticist. Because of the rarity of these disorders (only approximately
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`113 new patients per year) and high mortality rate, a general pediatrician would not have any
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`exposure to these types of patients. (Ex. 2042 at 180 (Summar 2013); Ex. 2019 at 1-2 (Häberle
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`Suggested Guidelines); Ex. 2043 at 1423 (only 35% survival of patients presenting with
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`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. 2044 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. 2040 at S33
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`(Summar 2001); Ex. 2044 at S87 (stressing the need to transport patients to a dedicated UCD
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`facility) (Wilcken).)
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`Petitioner’s definition is therefore overly broad and incorrect as it does not require
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`32.
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`any specific type or amount of “specialized training” or experience treating patients with
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`nitrogen retention disorders such as urea cycle disorders, and thus does not ensure that a person
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`who meets its definition possesses the expertise necessary to navigate the complex treatment of
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`patients with UCDs or other nitrogen retention disorders.
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`VI.
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`Technology Background
`
`33.
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` Humans are unable to synthesize certain of the amino acids needed in the body,
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`either at all or in sufficient levels for growth and maintenance. (Ex. 2014 at 4-6 (Wu).)
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`Accordingly, dietary protein is an essential component of the human diet because it provides
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`these essential amino acids. (Ex. 2014 at 4-6 (Wu).) The digestion and breakdown of dietary
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`proteins results in the creation of nitrogen waste. (Ex. 2008 at 1 (Auron).) In a healthy human,
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`amino acids that are not necessary for a body’s growth or repair are metabolized through
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`different chemical pathways and the remaining nitrogen waste is excreted as urea. (Ex. 2008 at 1
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`(Auron).)
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`34.
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`Nitrogen retention disorders are conditions wherein the body is unable to remove
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`this excess nitrogen and they are characterized by elevated blood ammonia levels. (Ex. 1001 at
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`1:19-21 (’278 patent).) Nitrogen retention diso