UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`
`Patent Owner
`
`________________
`
`Case IPR 2016-00829
`
`Patent 9,095,559
`
`________________
`
`DECLARATION OF DR. GREGORY M. ENNS
`
`Horizon Exhibit 2001
`Lupin v. Horizon
`IPR2017-01159
`
`Page 1 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`
`TABLE OF CONTENTS
`Introduction ...................................................................................................... 1
`I.
`II. Qualifications ................................................................................................... 2
`A. Education ................................................................................................. 2
`
`B. Professional Experience ........................................................................... 3
`
`C. Publications and Presentations ................................................................. 6
`
`D. Honors and Awards .................................................................................. 7
`
`E. Professional Organizations and Service Activities .................................. 7
`
`III. Legal Principles ............................................................................................... 8
`IV. Summary of Opinions .................................................................................... 10
`V.
`Person of Ordinary Skill in the Art ................................................................ 12
`VI. Technology Background ................................................................................ 15
`VII. Overview of the ’559 Patent .......................................................................... 23
`VIII. Claim Construction ........................................................................................ 28
`A. “upper limit of normal” .......................................................................... 28
`
`B. “the subject” ........................................................................................... 29
`
`IX. Prior Art Does Not Disclose or Suggest Subject Matter of Claims 1-15 ...... 31
`A. Prior Art Did Not Disclose Increasing or Initiating A Dosage of
`Glyceryl Tri-[4-phenylbutyrate] in a Patient With a Plasma
`Ammonia Level Between Half the ULN and the ULN ......................... 31
`
`B. No Motivation To Adjust Treatment Regimen for Subject with
`Plasma Ammonia Levels in Normal Range ........................................... 44
`
`1. One of Ordinary Skill Would Not Have Been Motivated to
`Combine the ’859 Publication with Simell or Blau ...................... 46
`
` 
`
`ii
`
`Page 2 of 70
`
`

`

`2. One of Ordinary Skill Did Not Account for a Fasting vs.
`Fed Ammonia Level When Making Dosing Determinations ....... 53
`
`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`
`3. Prior Art Disclosed Normal Plasma Ammonia Levels Were
`Acceptable and Only Increased Treatment When Levels
`Were Well Above Normal ............................................................ 58
`
`C. No Reasonable Expectation That An Increased Dosage Would
`Lower A Patient’s Baseline Ammonia or Ensure A Normal
`Plasma Ammonia ................................................................................... 63
`
`D. Prior Art Did Not Disclose or Suggest Targeting a Plasma
`Ammonia Level Below Half the Upper Limit of Normal ..................... 65
`
`XI. Conclusion ..................................................................................................... 67
`
` 
`
`iii
`
`Page 3 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`
`I, Dr. Gregory M. Enns, hereby declare as follows:
`I.
`
`Introduction
`1.
`
`I, Dr. Gregory M. Enns, have been retained by Finnegan on behalf of
`
`Horizon Therapeutics, Inc. as an independent expert in the field of clinical
`
`biochemical genetics. My curriculum vitae establish 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 on the outcome of this proceeding.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 9,095,559
`
`(“the ’559 patent”). (Ex. 1001.) I understand that the application for the ’559 patent
`
`was filed on February 22, 2013, as U.S. Patent Application No. 13/775,000 (“the
`
`’000 application”), and that the patent issued on August 4, 2015. (Ex. 1001.) I
`
`understand that the ’559 patent claims priority to Provisional Application No.
`
`61/542,100 (“the ’100 application”), 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.
`
`3.
`
`None of my opinions would change if I were to assume in the
`
`alternative that the date of invention was February 22, 2013, which is the date on
`
`which the application for the ’559 patent was filed.
`
`4.
`
`I understand that Petitioner has asserted that a combination of the ’859
`
`Publication (Ex. 1007), Blau (Ex. 1006), and Simell (Ex. 1005) render obvious
`
` 
`
`1
`
`Page 4 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`claims 1, 2, 4, 5, 7-10, 12, and 13 of the ’559 patent and that this combination with
`
`the addition Brusilow ’84 (Ex. 1004) renders obvious claims 3, 6, 11, 14, and 15.
`
`(Petition at 13.) In preparing this declaration, I have considered the ’559 patent and
`
`its prosecution history, the Petition for Inter Partes Review of U.S. Patent No.
`
`9,095,559, the Declaration of Dr. Vaux (Ex. 1002), the prior art and references
`
`identified in the Petition and Dr. Vaux’s Declaration, my knowledge and expertise
`
`in the art, and any additional references cited herein.
`
`II. Qualifications
`A. Education
`5.
`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 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
`
` 
`
`2
`
`Page 5 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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 became an Associate
`
`Professor, and in 2015 I was promoted to Professor. Since completing my
`
` 
`
`3
`
`Page 6 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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 University of Southern California.
`
`9.
`
`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.
`
`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,
`
` 
`
`4
`
`Page 7 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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 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
`
` 
`
`5
`
`Page 8 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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 also presented clinical research data related to urea cycle disorders at
`
`regional, national and 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
`
` 
`
`6
`
`Page 9 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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. Honors and Awards
`14.
`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
`
` 
`
`7
`
`Page 10 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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
`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 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
`
` 
`
`8
`
`Page 11 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`to determine its scope and meaning. In the second step, the claim must be
`
`compared to the prior art to determine whether the claim is invalid.
`
`19.
`
`I have been advised that in inter partes review proceedings before the
`
`U.S. Patent and Trademark Office, 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.
`
`20.
`
`I discuss certain terms from the claims of the ’559 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.
`
`21.
`
`I have 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.
`
`22.
`
`I have also been informed that determining whether there are any
`
`material differences between the scope and content of the prior art and each
`
` 
`
`9
`
`Page 12 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`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
`23. The methods recited in independent claims 1 and 2 include
`
`administering an increased dosage of glyceryl tri-[4-phenylbutyrate] when the
`
`subject’s plasma ammonia level is between half the upper limit of normal and the
`
`upper limit of normal. (Ex. 1001 at 24:20-48 (’559 patent).) In other words, these
`
`claims recite increasing the dosage of glyceryl tri-[4-phenylbutyrate] when a
`
`subject’s plasma ammonia level is within the normal range. (See Ex. 1001 at
`
`24:20-48 (’559 patent).) Claim 3 recites a method of administering an initial
`
`dosage of glyceryl tri-[4-phenylbutyrate] to a subject if their fasting plasma
`
`ammonia level is greater than half the upper limit of normal and less than the upper
`
`limit of normal for plasma ammonia. (Ex. 1001 at 24:49-60 (’559 patent).) Claims
`
`4, 5, 7-10, 12, and 14 depend from either claim 1 or 2. (Ex. 1001 at 24:20-26:19
`
` 
`
`10
`
`Page 13 of 70
`
`

`

`(’559 patent).) Claims 6, 11, 14, and 15 depend from claim 3. (Ex. 1001 at 25:1-
`
`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`
`26:21 (’559 patent).)
`
`24.
`
`In my opinion there is no teaching or suggestion in the prior art to
`
`practice the methods recited by claims 1-15. 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 values as acceptable and indicative of an effective treatment, with
`
`acceptable plasma ammonia levels 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 plasma ammonia levels were normal,
`
`especially given the unreliability of plasma ammonia levels.
`
`25. Claim 5 of the ’559 patent repeats the measuring, comparing, and
`
`administering steps of claims 1 or 2 until the subject has a fasting plasma ammonia
`
`level at or below half the upper limit of normal. (Ex. 1001 at 24:64-67 (’559
`
`patent).) In addition to the failure of the prior art to teach increasing a dosage when
`
`plasma ammonia is in the normal range, there is certainly no teaching or
`
`suggestion in the prior art of targeting a value 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 claim 5.
`
` 
`
`11
`
`Page 14 of 70
`
`

`

`Person of Ordinary Skill in the Art
`26. A person of ordinary skill in the art of the ’559 patent would have the
`
`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`
`V.
`
`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 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.
`
`27.
`
`I disagree with Petitioner’s and Dr. Vaux’s definition that includes
`
`one of ordinary skill as someone with specialty training only in the diagnosis of
`
`urea cycle disorders but not treatment. (Petition at 8; Ex. 1002 at ¶ 19 (Vaux).) The
`
`’559 patent claims are directed inter alia to 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 (’559 patent).) A doctor 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 would not understand the state of the art with
`
`respect to the use of ammonia levels in treating urea cycle disorder patients. They,
`
`for example, would have a fundamental misunderstanding of the goal in treating a
`
` 
`
`12
`
`Page 15 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`patient with a urea cycle disorder and the role of “normal” plasma ammonia levels
`
`in making treatment decisions.
`
`28.
`
`I disagree that the definition of one of ordinary skill would include
`
`someone with training only in general pediatrics. Treatment of urea cycle disorder
`
`requires specialized expertise and training that a general pediatrician would not
`
`possess. A general pediatric residency program may only include a one hour
`
`lecture on inborn errors of metabolism and a resident may never even see a patient
`
`with urea cycle disorder. A general pediatrician therefore would not be responsible
`
`for prescribing nitrogen scavenging medicine for the treatment of urea cycle
`
`disorder. Just as a pediatrician would refer a patient in cardiac failure to a
`
`cardiologist, a patient with thyroid issues to an endocrinologist, and a patient with
`
`kidney problems to a nephrologist, a pediatrician would refer a patient with urea
`
`cycle disorder to a biochemical geneticist. Because of the rarity of this disorder
`
`(only approximately 113 new patients per year) and high mortality rate, a general
`
`pediatrician would not have extensive exposure to these types of patients. (Ex.
`
`2042 at 180 (Summar 2013); see Ex. 2019 at 1-2 (Haberle Suggested Guidelines);
`
`Ex. 2043 at 1423 (only 35% survival of patients presenting with hyperammonemia
`
`within first 30 days of life)(Summar 2008).) One publication notes that even
`
`experienced metabolic specialists may only ever manage fewer than 50 urea cycle
`
`disorder patients. (Ex. 2044 at S86 (Wilcken).) The prior art consistently
`
` 
`
`13
`
`Page 16 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`emphasizes the importance of referring urea cycle disorder patients to specialized
`
`care centers so they can receive proper care, thus ensuring their growth and
`
`survival. (Ex. 2017 at S66, S67, S69 (discussing the importance of specialized
`
`metabolic centers and the increase in survival of UCD patients when treated in
`
`specialized metabolic centers) (Enns 2010); Ex. 2040 at S33 (Summar 2001); Ex.
`
`2044 at S87 (stressing the need to transport patients to a dedicated UCD facility)
`
`(Wilcken).)
`
`29.
`
`I also disagree that one of ordinary skill in the art would encompass
`
`someone with training in inherited metabolic disorders that did not include urea
`
`cycle disorders. The category “inherited metabolic disorders” is an extensive list of
`
`varying disorders with different symptoms and treatments. (See, e.g., Ex. 2038 at 1
`
`(WebMD).) A person with training in treating only lipid or carbohydrate errors of
`
`metabolism, for example, would not have the skills or expertise necessary to treat
`
`urea cycle disorders. Each disorder involves a different metabolic issue (e.g.
`
`metabolism of carbohydrates, metabolism of fats, metabolism of amino acids) and
`
`have distinct and nuanced approaches to therapy. Therefore, in my opinion this
`
`definition is incorrect as it fails to require training and experience with urea cycle
`
`disorders. It also is not consistent with the subject matter of the claims, which are
`
`specifically directed to urea cycle disorder patients. (Ex. 1001 at 24:20-60 (’559
`
`patent).)
`
` 
`
`14
`
`Page 17 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`30. Petitioner’s definition is therefore overly broad and incorrect as it
`
`does not require any experience treating patients with nitrogen retention disorders
`
`such as urea cycle disorder.
`
`VI. Technology Background
`31. Humans are unable to synthesize certain of the amino acids needed in
`
`the body, either at all or in sufficient levels for growth and maintenance. (Ex. 2014
`
`at 4-6 (Wu).) Accordingly, dietary protein is an essential component of the human
`
`diet because it provides these essential amino acids. (Ex. 2014 at 4-6 (Wu).) The
`
`digestion and breakdown of dietary proteins results in the creation of nitrogen
`
`waste. (Ex. 2008 at 1 (Auron).) In a healthy human, amino acids that are not
`
`necessary for a body’s growth or repair are metabolized through different chemical
`
`pathways and the remaining nitrogen waste is excreted as urea. (Ex. 2008 at 1
`
`(Auron).)
`
`32. Nitrogen retention disorders are conditions wherein the body is unable
`
`to remove this excess nitrogen and they are characterized by elevated blood
`
`ammonia levels. (Ex. 1001 at 1:15-20 (’559 patent).) Nitrogen retention disorders
`
`include urea cycle disorders, which are rare inherited conditions that feature
`
`decreased activity of enzymes or transporters needed for the synthesis of urea from
`
`ammonia, and include the enzymes that constitute the urea cycle and transporters
`
`that affect urea cycle function. (Ex. 1001 at 1:15-47 (’559 patent).) Patients who
`
` 
`
`15
`
`Page 18 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`have urea cycle disorders tend to accumulate waste nitrogen because their intrinsic
`
`capacity to excrete nitrogen is less than the production of waste nitrogen by the
`
`body. (See Ex. 2024 at 148-152 (Brusilow 1996).) A normal diet contains a
`
`significant amount of protein, and, as such, dietary intake will cause nitrogen
`
`accumulation in patients who have urea cycle disorders. (See Ex. 2024 at 148-152
`
`(Brusilow 1996).) In short, patients with nitrogen retention disorders are constantly
`
`faced with the potential to accumulate excess body nitrogen.
`
`33. When present in high concentrations, ammonia is toxic. (Ex. 2008 at 1
`
`(Auron).) Increased blood ammonia levels manifest mainly as central nervous
`
`system dysfunctions such as stupor, convulsions, and coma. (Ex. 2016 at 1605S
`
`(Endo).) Irreversible impairment to the central nervous system may occur at high
`
`levels of blood ammonia. (Ex. 2016 at 1605S-06S (Endo).) Hyperammonemia
`
`refers to the clinical condition associated with increased ammonia levels that
`
`manifests as a variety of primarily neurological symptoms. (Ex. 2008 at 1-2
`
`(Auron); Ex. 2020 at 21 (Haberle Clinical); Ex. 2016 at 1605S-06S (Endo).) Actual
`
`clinical manifestations depend on the metabolic defect involved as well as the age
`
`of the patient, the patient’s nutritional status, and whether the patient has any
`
`infections. (Ex. 2016 at 1605S (Endo); Ex. 2008 at 8 (Auron).) It is estimated that
`
`one out of only 35,000 live births have this disorder, resulting in only 113 new
`
` 
`
`16
`
`Page 19 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`patients in the U.S. per year. (Ex. 2042 at 1 (Summar 2013); see also Ex. 2019 at
`
`1-2 (Haberle).)
`
`34. Regardless of the particular symptoms, hyperammonemia is a life
`
`threatening and often fatal condition. (Ex. 2020 at 21 (Haberle Clinical); Ex. 2017
`
`at S65 (Enns 2010); Ex. 2009 at S46 (Batshaw).) Symptoms of this disorder often
`
`appear within 24 to 48 hours after a normal birth when a newborn begins to exhibit
`
`progressive lethargy, hypothermia, and apnea. (Ex. 2033 at 1 (Brusilow Online);
`
`Ex. 2019 (Haberle).) Onset of symptoms, however, can appear at any age. (Ex.
`
`2019 at 2 (Haberle).) Historically, survival in patients with urea cycle disorders
`
`was low and any survivor had a poor neurological outlook. (Ex. 2017 at S65-S66
`
`(Enns 2010); Ex. 2009 at S46 (Batshaw).) Between 1982 and 2003, patients
`
`presenting with hyperammonemia within the first 30 days of life had only a 35%
`
`survival rate (65% mortality rate). (Ex. 2043 at 1425 (Summar 2008); see also Ex.
`
`2017 at S66 (Enns 2010).) Survival was therefore the original goal of treating of
`
`patients diagnosed with a urea cycle disorder. Over the years, genetic specialists
`
`have developed emergency protocols to treat patients undergoing acute episodes of
`
`hyperammonemia. (See, e.g. Ex. 2023 (Summar).) These protocols include
`
`discontinuing protein intake, intravenous infusions of sodium benzoate and
`
`phenylacetate, and dialysis. (Ex. 2025 at S2 (Consensus); Ex. 2017 at S65 (Enns
`
`2010); Ex. 2023 (Summar).) With the advent of alternative pathway therapy (e.g.,
`
` 
`
`17
`
`Page 20 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`nitrogen scavenging drugs), survival improved drastically, but the mental
`
`development of many patients was still delayed. (Ex. 2016 at 1608S (Endo); Ex.
`
`2021 at 33-34 (Leonard); Ex. 2009 at S46 (Batshaw); Ex. 2022 at e492 (Niemi).)
`
`For example, in 2010 I reviewed IQ data following survival of a neonatal
`
`hyperammonemic coma. (Ex. 2017 at S68 (Enns 2010); Ex. 2030 at 1502 (Msall).)
`
`Following treatment with alternative pathway therapy, 79% of patients had at least
`
`one developmental disability and only 21% of patients ages 12-74 months had an
`
`IQ over 70. (Ex. 2017 at S68 (Enns 2010); Ex. 2030 at 1502 (Msall).)
`
`35. The main goal of treatment is therefore a balance between correcting
`
`the biochemical issue, preventing the development of hyperammonemia, and
`
`ensuring that the patient’s nutritional needs for growth and development are met.
`
`(Ex. 2018 at 104 (Feillet); Ex. 2010 at 924 (Maestri); Ex. 2033 at 46 (Brusilow
`
`Online); Ex. 2008 at 8 (Auron); Ex. 2021 at 32 (Leonard); Ex. 1001 at 4:29-36
`
`(’559 patent); Ex. 2019 at 12 (Haberle).)
`
`36. Chronic treatment of urea cycle disorders primarily involves the use
`
`of a low-protein diet, amino acid supplementation, and alternative pathway therapy
`
`with nitrogen scavenging drugs. (Ex. 2019 at 13 (Haberle).) Treatment of a patient
`
`with a urea cycle disorder is a coordinated therapeutic regimen involving each of
`
`these components. (Ex. 2017 at S67 (Enns 2010).) Because of the rarity and
`
`complexity of UCD, it requires the supervision of specialists in metabolic genetic
`
` 
`
`18
`
`Page 21 of 70
`
`

`

`Case No. IPR2016-00829
`U.S. Patent No. 9,095,559
`
`disorders rather than general practitioners. (Ex. 2017 at S66-67, S69 (Enns 2010);
`
`Ex. 2040 at S33 (Summar 2001); Ex. 2044 at S86-87 (Wilcken).)
`
`37. Dietary treatment is considered the “cornerstone of therapy.” (Ex.
`
`2019 at 13 (Haberle).) Minimizing protein intake, for example, will decrease the
`
`nitrogen load on the urea cycle. (Ex. 2019 at 12 (Haberle).) But protein restriction
`
`will also decrease the amount of essential nutrients needed for growth and normal
`
`development, and therefore supplementation with essential amino acid mixtures or
`
`use of nitrogen scavengin