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 IPR2018-00459
`Patent 9,561,197
`
`__________
`
`DECLARATION OF VERNON REID SUTTON, M.D.
`
`Horizon Exhibit 2001
`Lupin v. Horizon
`IPR2018-00459
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`Table of Contents
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`
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`INTRODUCTION ........................................................................................... 4 
`I. 
`EXPERT QUALIFICATIONS ........................................................................ 5 
`II. 
`III.  LEGAL PRINCIPLES ..................................................................................... 8 
`IV.  SUMMARY OF OPINIONS ......................................................................... 10 
`V. 
`PERSON OF ORDINARY SKILL IN THE ART ........................................ 12 
`VI.  TECHNOLOGY BACKGROUND ............................................................... 14 
`  UCDs and UCD Treatments ................................................................. 14 
`1. 
`Ammonia (or Nitrogen) Scavenging Drugs .............................. 20 
`2. 
`PAA Prodrugs ........................................................................... 21 
`3. 
`PAA Toxicity ............................................................................ 23 
`4. 
`Dosing ....................................................................................... 25 
`  Response to Dr. Vaux’s Technology Overview ................................... 27 
`1. 
`Dr. Vaux Oversimplifies the Metabolism of PAA Prodrugs .... 27 
`2. 
`Dr. Vaux Ignores the Differences in PAA Prodrug Metabolism
`Amongst Various Patient Populations ...................................... 29 
`Dr. Vaux Improperly Assumes a Ratio Can Be Derived from
`Intravenous Studies on PAA or PBA ........................................ 32 
`  The Cited Prior Art ............................................................................... 35 
`1.  MacArthur ................................................................................. 35 
`2. 
`Enns 2010 .................................................................................. 45 
`3. 
`Thibault ..................................................................................... 51 
`4. 
`Piscitelli ..................................................................................... 55 
`5. 
`Zeitlin ........................................................................................ 60 
`6. 
`Simell ........................................................................................ 65 
`VII.  OVERVIEW OF THE ’197 PATENT .......................................................... 70 
`  The ’197 Patent Specification .............................................................. 71 
`  The ’197 Patent Claims ........................................................................ 76 
`1. 
`“A method of treating a UCD in a subject” .............................. 77 
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`3. 
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`2. 
`
`3. 
`
`2. 
`
` 
`
`X. 
`
`“a subject having a plasma PAA to PAGN ratio outside of the
`target range of 1 to 2 [2.5]” ....................................................... 78 
`“administering to [the] subject … a dosage of glyceryl tri-[4-
`phenylbutyrate] (HPN-100) effective to achieve a plasma PAA
`to PAGN ratio within the target range” .................................... 79 
`VIII.  CLAIM CONSTRUCTION .......................................................................... 80 
`“PAA” and “PAGN” ............................................................................ 81 
` 
`“A method of treating a urea cycle disorder in a subject” ................... 82 
` 
`“…a subject having a plasma PAA to PAGN ratio outside the target
` 
`range of [claim 1:1 to 2] [claim 2: 1 to 2.5]” ...................................... 86 
`“administering … a dosage of glyceryl tri-[4-phenylbutyrate] (HPN-
`100) effective to achieve a plasma PAA to PAGN ratio within the
`target range of [claim 1: 1 to 2] [claim 2: 1 to 2.5]” ........................... 89 
`IX.  LUPIN’S PETITION FAILS TO IDENTIFY PRIOR ART THAT
`DISCLOSES A CALCULATED PAA TO PAGN RATIO OR CLAIMED
`TARGET RANGES....................................................................................... 91 
`THE PRIOR ART, ALONE OR IN COMBINATION, FAILS TO TEACH
`OR SUGGEST THE SUBJECT MATTER OF CLAIMS 1-2 ...................... 97 
`  The Prior Art Does Not Teach or Suggest the Use of a PAA to PAGN
`Ratio or a Specific Target Range of a PAA to PAGN Ratio in Treating
`UCDs ................................................................................................... 97 
`The Prior Art Does Not Disclose a PAA to PAGN Ratio or its
`1. 
`Utility in a Method of Treating UCD Patients .......................... 98 
`The Prior Art Does Not Teach or Suggest the Claimed Target
`Range of Ratio Values ............................................................111 
`  A POSA Would Have Had No Reason to Combine the Prior Art .....122 
`  Teaching Away in the Prior Art .........................................................124 
`XI.  CONCLUSION ............................................................................................130 
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`I, Vernon Reid. Sutton, M.D., hereby declare as follows:
`
`I.
`
`INTRODUCTION
`1.
`I have been retained by Green, Griffith & Borg-Breen LLP on behalf
`
`of Horizon Therapeutics, LLC as an independent expert in the field of Molecular &
`
`Human Genetics, including the clinical care and treatment of patients with inborn
`
`errors of metabolism including patients with urea cycle disorders (“UCDs”). My
`
`curriculum vitae establishes my qualifications in this area.1 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. 9,561,197
`
`(“the ’197 patent”). I understand that the application for the ’197 patent was filed
`
`on September 11, 2012, as U.S. Patent Application No. 13/610,580 (“the ’580
`
`application”), and that the patent issued on February 7, 2017. I understand that the
`
`’197 patent claims priority to Provisional Application No. 61/636,256 (“the ’256
`
`application”), filed on April 20, 2012. I have therefore considered the state of the
`
`art and the prior art available as of April 20, 2012. None of my opinions would
`
`
`1 Ex. 2002 (Sutton CV).
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`change if I were to assume in the alternative that the date of invention was
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`September 11, 2012, which is the date on which the application for the ’197 patent
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`was filed.
`
`3.
`
`I understand that Petitioner has asserted that a combination of Enns
`
`2010, MacArthur, and Piscitelli, in view of the knowledge of a person of ordinary
`
`skill in the art, renders obvious all claims (claims 1 and 2) of the ’197 patent.
`
`4.
`
`In preparing this declaration, I have considered the ’197 patent and its
`
`prosecution history, the Petition for Inter Partes Review of U.S. Patent No.
`
`9,561,197 (Paper No. 3, “Petition”), the Declaration of Keith Vaux, M.D.,2 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. EXPERT QUALIFICATIONS
`5.
`I am currently a Professor in the Department of Molecular & Human
`
`Genetics at Baylor College of Medicine, the Medical Director of the Baylor
`
`Biochemical Genetics Laboratory, and the Director of the Inborn Errors of
`
`Metabolism service at Texas Children’s Hospital.
`
`
`2 Ex. 1002 (“Vaux”).
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`I received my undergraduate degree from Transylvania University in
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`6.
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`Lexington, Kentucky, and my M.D. from the University of Kentucky College of
`
`Medicine in Lexington, Kentucky. I completed my residency in Pediatrics at
`
`Washington University School of Medicine in St. Louis, Missouri. I then
`
`completed a Clinical Fellowship in Medical Genetics and Clinical Biochemical
`
`Genetics at Baylor College of Medicine in Houston, Texas.
`
`7.
`
`I have authored over one hundred peer reviewed articles and chapters
`
`on Inborn Errors of Metabolism. These range from basic science publications to
`
`patient care and laboratory management guidelines, including for urea cycle
`
`disorders among others.
`
`8.
`
`I direct the Inborn Errors of Metabolism Service at Texas Children’s
`
`Hospital with around 700 outpatient encounters as well as inpatient admissions for
`
`a wide spectrum of inherited metabolic diseases, including urea cycle disorders.
`
`Additionally, I am the Medical Director of the Baylor Genetics Biochemical
`
`Genetics Laboratory, which offers clinical testing for metabolites in plasma,
`
`including testing for phenylbutyrate (“PBA”) and the ratio of phenylacetic acid
`
`(“PAA”) to phenylacetylglutamine (“PAGN”). In these two complementary roles,
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`I am committed to advancing care through quality improvement processes as well
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`as clinical and laboratory research to investigate new therapies for and
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`pathophysiologic mechanisms at play in inborn errors of metabolism.
`
`9.
`
`I have been a Principal Investigator and co-Principal Investigator on
`
`numerous clinical trials in inborn errors of metabolism, including both
`
`investigator-initiated trials and trials sponsored by the pharmaceutical industry. I
`
`have served as an advisor to BioPharma companies developing therapies for inborn
`
`errors of metabolism.
`
`10.
`
`I am a member of the American Society of Human Genetics, the
`
`International Skeletal Dysplasia Society, the Society of Inherited Metabolic
`
`Diseases, and a fellow of American College of Medical Genetics. I am a past
`
`Member of the Professional Practice and Guidelines Committee of the American
`
`College of Medical Genetics.
`
`11.
`
`I have served on the CDC Clinical Laboratory Advisory Committee
`
`for Biochemical Genetics and the Texas Newborn Screening Advisory Committee.
`
`I am immediate past-Chair of the American Board of Medical Genetics and
`
`Genomics and am a past Book Chief for the Biochemical Genetics certification
`
`examination and have served as a faculty member at the Society of Inherited
`
`Metabolic Diseases, North American Metabolic Academy.
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`12. A complete list of my professional and academic experiences, awards
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`publications and presentations can be found in my curriculum vitae.3
`
`III. LEGAL PRINCIPLES
`13.
`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.
`
`14.
`
`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. In the second step, the claim must be
`
`compared to the prior art to determine whether the claim is invalid.
`
`15.
`
`I have been advised that in IPR proceedings before the U.S. Patent
`
`and Trademark Office, a patent claim receives the broadest reasonable
`
`interpretation 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
`
`
`3 Ex. 2002 (Sutton CV).
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`accustomed meaning as they would be understood by one of ordinary skill in the
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`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.
`
`16.
`
`I discuss certain terms from the claims of the ’197 patent below and
`
`what I understand to be the broadest reasonable interpretation of these terms from
`
`the perspective of one of ordinary skill in the art in light of the specification. I
`
`understand that “in light of the specification” is not whether the specification
`
`proscribes or precludes some broad reading of the claim term adopted by the
`
`Examiner. And it is not simply an interpretation that is not inconsistent with the
`
`specification. It is an interpretation that corresponds with what and how the
`
`inventors of the ’197 patent describe their invention in the specification, i.e., an
`
`interpretation that is “consistent with the specification.”
`
`17.
`
`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.
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`I have also been informed that determining whether there are any
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`18.
`
`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
`19. The treatment methods recited in claims of the ’197 comprise
`
`administering to a subject having a plasma phenylacetic acid (“PAA”) to
`
`phenylacetylglutamine (“PAGN”) ratio outside a target range a dosage of glyceryl
`
`tri-[4-phenylbutyrate] (i.e., the active ingredient in RAVICTI®) effective to
`
`achieve a plasma PAA to PAGN ratio within the claimed target range. In my
`
`opinion, Lupin’s Petition fails to demonstrate how the prior art teaches or suggests
`
`the key PAA:PAGN ratio claim limitations of the ’197 patent claims. Specifically,
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`Lupin’s Petition does not identify where the cited prior art discloses (1) a plasma
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`PAA to PAGN ratio; (2) the claimed target range of plasma PAA to PAGN ratio;
`
`or (3) use of the claimed target range of plasma PAA to PAGN ratio for the
`
`treatment of UCD patients.
`
`20.
`
`In my opinion, none of Lupin’s cited prior art references contains any
`
`teaching or suggestion to practice the methods recited by claims 1-2. The prior art
`
`references are missing any teaching or suggestion for (1) use of a plasma PAA to
`
`PAGN ratio or (2) disclosure of the claimed target range of plasma PAA to PAGN
`
`ratio.
`
`21. Furthermore, the prior art references are devoid of any teaching or
`
`suggestion of (a) measuring plasma PAA to PAGN levels simultaneously in a
`
`single UCD patient and calculating a PAA to PAGN ratio based on such
`
`measurements; (b) the existence of a target range of a PAA to PAGN ratio for
`
`UCD patients, (c) defining the claimed target range PAA to PAGN ratio as 1 to 2
`
`(or 2.5), and (d) the use of the claimed target range of a PAA to PAGN ratio for
`
`dosage adjustments in UCD patients.
`
`22. Nothing in the prior art references teaches or suggests combining
`
`these elements in a method of UCD treatment, let alone provide a reasonable
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`expectation of success. Moreover, as the Petitioner recognizes, the prior art
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`teaches away from the claimed methods.
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART
`23.
`In my opinion a person of ordinary skill in the art (“POSA”) reading
`
`and interpreting these claims would have at least the following qualifications: (a)
`
`an M.D. or equivalent degree, (b) successful completion 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 (or equivalent), and (c) at
`
`least five years of experience treating patients with nitrogen retention disorders,
`
`including UCDs (urea cycle disorders), which experience may be obtained
`
`concurrently with the residency/fellowship training and certification(s) described
`
`in (b).
`
`24.
`
`I disagree with Petitioner’s and Dr. Vaux’s definition that includes in
`
`the definition of a POSA someone who has not successfully completed a residency
`
`or fellowship training in Clinical Genetics.4 I further disagree with Petitioner’s and
`
`
`4 Petition at 27; Ex. 1002 (Vaux) ¶ 21.
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`Dr. Vaux’s definition that includes in the definition of a POSA someone without a
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`certification in Clinical Genetics and Clinical or Medical Biochemical Genetics by
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`the American Board of Medical Genetics and Genomics (or equivalent).5 I also
`
`disagree with Petitioner’s and Dr. Vaux’s definition that includes in the definition
`
`of a POSA someone without at least five years of experience treating patients with
`
`nitrogen retention disorders including UCDs.6
`
`25.
`
`In my opinion, because the claims of the ’197 patent are directed to a
`
`method of treating UCD patients, the POSA would have credentials consistent with
`
`those of the medical specialists charged with treating UCD patients. Dr. Vaux’s
`
`definition of a POSA would include medical professionals that in my judgment
`
`would not be sufficiently qualified to independently treat UCD patients.
`
`26. None of my opinions herein would change if I were to apply in the
`
`alternative Petitioner’s and Dr. Vaux’s definition.
`
`
`5 Id.
`
`6 Id.
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`
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`VI. TECHNOLOGY BACKGROUND
` UCDs and UCD Treatments
`27. UCDs are a group of rare7 inherited diseases in which the patient’s
`
`body lacks the necessary enzymes or transporters necessary to remove waste
`
`nitrogen (i.e., ammonia) produced upon digestion of dietary protein from the
`
`body.8 Removal of ammonia in healthy patients is achieved by the urea cycle. The
`
`urea cycle is a series of biochemical reactions that take place in the liver that
`
`
`7 It is estimated that only one out of 35,000 live births have this disorder, resulting
`
`in only 113 new patients in the U.S. per year. See Marshall Summar et al., “The
`
`Incidence of Urea Cycle Disorders,” Mol. Gen. Metab. 110, 179-180, 180 (2013)
`
`(“Summar 2013”) (Ex. 2003); see also Johannes Haberle et al., “Suggested
`
`Guidelines for the Diagnosis and Management of Urea Cycle Disorders,” Orphanet
`
`J. Rare Dis.,7:32,1-30 at 1-2 (2012) (“Haberle 2012”) (Ex. 2004).
`
`8 See, e.g., Ex. 2004 (Haberle 2012) at 1; Marshall Summar et al., “Current
`
`Strategies for the Management of Neonatal Urea Cycle Disorders,” J. Pediatrics,
`
`138(1), S30-S39, S30 (2001) (“Summar 2001”) (Ex. 2005); see also Ex. 1001
`
`(’197 patent) at col. 1 ll. 19-21.
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`
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`convert ammonia into urea, a chemical that is nontoxic and can be excreted from
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`the body through urine. Because patients with UCDs lack the necessary enzymes
`
`to convert ammonia to urea via the urea cycle, ammonia accumulates in the
`
`patient’s blood. Ammonia is toxic and the presence of excess ammonia in the
`
`blood is medically referred to as “hyperammonemia.”9
`
`28. Hyperammonemia is an extremely dangerous medical condition that
`
`can be fatal if not treated immediately.10 In one longitudinal study, two-thirds of
`
`the severely affected babies diagnosed with a UCD during the first month of life
`
`died by the age of 6, even with the administration of intravenous sodium
`
`phenylacetate/sodium benzoate 10%/10% rescue treatment (AMMONUL®) during
`
`
`9 Ari Auron et al., “Hyperammonemia in Review: Pathophysiology, Diagnosis,
`
`and Treatment,” Pediatr. Neophrol., Feb. 27(2), 207-222, 207 (2012) (“Auron”)
`
`(Ex. 2006); Johannes Haberle, “Clinical Practice: The Management of
`
`Hyperammonemia,” Eur. J. Pediatr. 170:21-34, 21 (2011) (“Haberle 2011”) (Ex.
`
`2007).
`
`10 Id.
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`hyperammonemic crises.11 With the development of newer chronic treatments,
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`survival rates increased, but one in five of severely affected newborns diagnosed
`
`with a urea cycle disorder within the first month of life still died from the condition
`
`within the first year of life.12 Even with treatment, hyperammonemia can lead to
`
`neurological complications, such as brain damage, coma and death.13 In fact, only
`
`
`11 Marshall Summar et al., “Diagnosis, Symptoms, Frequency and Mortality of 260
`
`Patients with Urea Cycle Disorders from a 21-year, Multicenter Study of Acute
`
`Hyperammonaemic Episodes,” Acta Paediatr., 97:1420-1425, 1423, Fig. 3 (2008)
`
`(“Summar 2008”) (Ex. 2008).
`
`12 See FDA Director’s Summary Review of New Drug Application No. 203284 at
`
`p. 3 (“RAVICTI® NDA”) (Ex. 1013); see also Mark Batshaw et al., “Alternative
`
`Pathway Therapy for Urea Cycle Disorders: Twenty Years Later,” J. Pediatr.
`
`138(1):S46-S55, S46 (2001) (“Batshaw”) (Ex. 1008).
`
`13 Ex. 2006 (Auron) at 207; Gregory Enns, “Nitrogen Sparing Therapy Revisited
`
`2009,” Mol. Gen. Metab. 100:S65-S71, S65 (2010) (“Enns 2009”) (Ex. 2009).
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`21% of UCD patients age 12-74 months had an IQ over 70.14 Thus, despite the
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`existence of new drug therapies, outcomes for UCD patients remain poor.15
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`29. UCDs can be extremely difficult to diagnose and to treat because the
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`severity and clinical presentation of UCDs is highly variable.16 UCDs can present
`
`
`14 Ex. 2009 (Enns 2009) at S68.
`
`15 Ex. 2009 (Enns 2009) at S65; Ex. 2004 (Haberle 2012) at 2, 5; Fumio Endo et
`
`al., “Clinical Manifestations of Inborn Errors of the Urea Cycle and Related
`
`Metabolic Disorders During Childhood,” J. Nutrition, 134(6):1605S-1609S,
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`1605S-1606S, 1608S (2004) (“Endo”) (Ex. 2010); Michael Msall et al.,
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`“Neurologic Outcome in Children with Inborn Errors of Urea Synthesis: Outcome
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`of Urea Cycle Enzymopathies,” New Engl. J. Med., 310(23):1500-1505, 1502
`
`(1984) (“Msall”) (Ex. 2011); J.V. Leonard et al., “Urea Cycle Disorders,” Semin.
`
`Neonatol. 7:27-35, 33-34 (2002) (“Leonard”) (Ex. 2012).
`
`16 F. Feillet et al., “Alternative Pathway Therapy for Urea Cycle Disorders,” J.
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`Inher. Metab. Dis. 21:101-111, 101, 109 (1998) (“Feillet”) (Ex. 2013); Gerard
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`Berry et al., “Long-Term Management of Patients with Urea Cycle Disorders,” J.
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`Pediatr. 138(1):S56-S61, S56 (2001) (“Berry”) (Ex. 2014); Nicholas Mew et al.,
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`at any age including infants, children, teenagers and adults, and disease severity
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`varies across the lifespan of an individual patient.17 Most UCDs are transmitted
`
`genetically as autosomal recessive traits, i.e., each parent contributes a defective
`
`gene to the child.18 Newborns with severe disease become catastrophically ill
`
`within hours of birth.19 The spectrum of severity in late-onset UCD is widely
`
`variable ranging from very mild to severe.20
`
`30. Given the great spectrum of severity of UCDs, general dosing
`
`guidelines for a PAA prodrug are of limited value without taking into
`
`consideration the individual patient. Optimal treatment of UCDs requires frequent
`
`
`“Urea Cycle Disorders Overview,” GeneReviews, 1-23 at 3/23-4/23 (2015)
`
`(“Mew”) (Ex. 2015).
`
`17 See, e.g., Ex. 2004 (Haberle 2012) at 1; Ex. 2007 (Haberle 2011) at 21; Ex. 2013
`
`(Feillet) at 101-102; see also Ex. 1001 (’197 patent) at col. 1 ll. 40-47.
`
`18 Ex. 2006 (Auron) at 219; Ex. 2010 (Endo) at 1607S; Ex. 2015 (Mew) at 1.
`
`19 See, e.g., Ex. 2011 (Msall) at 1500.
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`20 See, e.g., Ex. 1008 (Batshaw) at S50; Ex. 2013 (Feillet) at 101-102; Ex. 2014
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`(Berry) at S56; Ex. 2015 (Mew) at 3-4.
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`monitoring from a medical team, typically at a university hospital, consisting
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`minimally of a geneticist/metabolic specialist, metabolic dietician, nurse, and
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`developmental specialist or neuropsychologist specifically experienced in
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`successful management of UCD disorders.21
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`31. The main goals of treatment are therefore reducing dietary protein and
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`waste ammonia so as to prevent the development of hyperammonemia, while
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`ensuring that the patient’s nutritional needs for growth and development are met.22
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`Control of plasma ammonia levels is a primary concern of UCD patient treatment.
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`32. Some patients can achieve control over their blood ammonia levels
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`through a very strict diet that restricts a patient’s protein intake and therefore the
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`nitrogen (ammonia) load on the urea cycle. However, because protein restriction
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`will also decrease the amount of essential nutrients available for normal growth
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`21 Ex. 2009 (Enns 2009) at S66-67, S69; Ex. 2005 (Summar 2001) at S30-S33; Ex.
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`2006 (Auron) at 13; Ex. 2004 (Haberle 2012) at 12-13; Ex. 2014 (Berry) at S56;
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`Ex. 2015 (Mew) at 18/23.
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`22 See, e.g., Ex. 2004 (Haberle 2012) at 12-13; Ex. 2006 (Auron) at 8; Ex. 2013
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`(Feillet) at 104.
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`and development, the majority of UCD patients are also prescribed drugs, known
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`as ammonia (or nitrogen) scavenging agents, that can chemically react with waste
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`ammonia in the body enabling it to be removed by a pathway other than the urea
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`cycle.23
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`1.
`Ammonia (or Nitrogen) Scavenging Drugs
`33. One of the earliest nitrogen scavenging drugs was PAA.24 In 2005,
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`the FDA approved an intravenous injection of sodium phenylacetate in
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`combination with sodium benzoate as AMMONUL®.25 AMMONUL® is
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`indicated as “adjunctive therapy for the treatment of acute hyperammonemia and
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`associated encephalopathy in patients with deficiencies in enzymes of the urea
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`23 See, e.g., Ex. 2004 (Haberle 2012) at 12-13; Ex. 2005 (Summar 2001) at S35;
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`Ex. 2006 (Auron) at 9; Ex. 2007 (Haberle 2011) at 30; Ex. 1008 (Batshaw) at S47;
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`Ex. 2012 (Leonard) at 32; Ex. 2013 (Feillet) at 104; see also Ex. 1001 (’197
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`patent) at col. 2 ll. 10-21.
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`24 Ex. 1008 (Batshaw) at S48.
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`25 Ex. 1019 (AMMONUL Label) at 3323.
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`cycle.”26 AMMONUL® is not commercially available as an oral dosage form and
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`is not indicated for the chronic treatment of UCDs. PAA alone is not
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`commercially available in an oral dosage form.
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`2.
`PAA Prodrugs
`34. A prodrug is a medication that is metabolized in the body into a
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`pharmacologically active drug. Two PAA prodrugs FDA-approved for the chronic
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`treatment of UCDs are sodium phenylbutyrate (BUPHENYL®) and glyceryl tri-[4-
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`phenylbutyrate] (also known as HPN-100 or glycerol phenylbutyrate)
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`(RAVICTI®).27 These drugs are referred to as PAA prodrugs because the body
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`rapidly converts them to PAA.28 Both of these medications are administered
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`orally.
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`35. Sodium phenylbutyrate converts by oxidative mechanisms to PAA in
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`the body.29 Glyceryl-tri-[4-phenylbutyrate] first converts to phenylbutyrate before
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`26 Id. at 3325.
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`27 Ex. 2009 (Enns 2009) at S68-S69; Ex. 1007 (’859 Publication) at [0022].
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`28 Id.; Ex. 1001 (’197 patent) at col. 2 ll. 17-56.
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`29 Ex. 1007 (’859 Publication) at [0022].
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`converting into PAA.30 Once converted in the body, PAA reacts with the ammonia
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`precursor glutamine to form PAGN. 31 PAGN is ultimately excreted in the urine.32
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`Removal of glutamine by reaction with PAA is thus an alternate way of
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`eliminating waste ammonia from the body that does not rely on the enzymes of the
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`urea cycle.
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`36. While the mechanism by which PAA reacts with glutamine in the
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`body to form PAGN is generally known33, the precise relationship between the
`
`
`30 Id.
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`31 Id.
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`32 Ex. 1001 (’197 patent) at col. 2 ll. 33-37.
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`33 See, e.g., Ex. 2009 (Enns 2009) at S68-S69; Brendan McGuire et al.,
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`“Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy adults and
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`Adults with Cirrhosis,” Hepatol., 51(6):2077-2085, 2078 (2010) (Ex. 1015);
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`Marwan Ghabril et al., “Glycerol Phenylbutyrate in Patients with Cirrhosis and
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`Episodic Hepatic Encephalopathy: A Pilot Study of Safety and Effect on Venous
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`Ammonia Concentration,” Clin. Pharm. Drug Dev. 2(3):278-284 (2013)
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`(“Ghabril”) (Ex. 2016).
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`amount of a PAA prodrug, such as phenylbutyrate, that will convert to PAA and
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`then to PAGN is unknown. Stated another way, clinicians understood that
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`administering 1 g of phenylbutyrate to a UCD patient by mouth would not be a
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`one-to-one conversion to 1 g of PAA or 1 g of PAGN in the body because there are
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`alternative reaction pathways for phenylbutyrate and PAA that do not produce
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`PAGN.
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`3.
`PAA Toxicity
`In some individuals, the body’s ability to convert PAA to PAGN is
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`37.
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`impaired such that excess levels of PAA are present in the body if the dose of PAA
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`prodrug administered is too high.34 Elevated PAA levels cannot be ignored
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`because, in prior studies involving cancer patients, high levels of PAA were shown
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`to cause reversible side effects (“PAA toxicity”) such as nausea, headache,
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`34 Ex. 2016 (Ghabril) at 278.
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`vomiting, fatigue, weakness, lethargy, somnolence, dizziness, slurred speech,
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`memory loss, confusion, and disorientation.35
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`38. Mokhtarani 2013 reports on two prior art studies regarding PAA
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`toxicity in non-UCD patients: it notes Simell36 calculated the safe upper PAA
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`concentration limit to be 3.5 mmol/L, equivalent to 476 μg/mL, and that Thibault
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`199537 reported that AEs were associated with PAA levels ranging from 499–1285
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`μg/mL.38
`
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`35 Ex. 1001 (’197 patent) at col. 3 ll. 22-34; Alain Thibault et al., “Phase I Study of
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`Phenylacetate Administered Twice Daily to Patients with Cancer,” Cancer Vol. 75,
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`No. 12, 2932, 2937 (1995) (“Thibault 1995”) (Ex. 2017).
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`36 Ex. 1005.
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`37 Ex. 1009.
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`38 M. Mokhtarani et al., “Elevated Phenylacetic Acid Levels Do Not Correlate with
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`Adverse Events in Patients with Urea Cycle Disorders or Hepatic Encephalopathy
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`and Can Be Predicted Based on the Plasma PAA to PAGN Ratio,” Mol. Gen.
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`Metab. 110:446-453, 447 (2013) (“Mokhtarani 2013”) (Ex. 2018).
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`39. The challenge for a physician treating UCD patients is that the signs
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`and symptoms of hyperammonemia and PAA toxicity are very similar, making it
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`difficult for a