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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`
`
`_____________________
`
`Case IPR: Unassigned
`Patent 9,326,966
`_____________________
`
`DECLARATION OF NEAL SONDHEIMER, M.D., Ph.D.
`
`
`
`
`
`
`
`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`TABLE OF CONTENTS
`
` I.
`
` II.
`
`
`
`INTRODUCTION ........................................................................................... 1
`BACKGROUND ............................................................................................. 6
`
`The ’966 Patent ..................................................................................... 8
`A.
`
`The Urea Cycle .................................................................................... 16
`B.
`
`Prior Art Treatment Protocols Using Nitrogen Scavenging Drugs .... 21
`C.
` LEVEL OF SKILL IN THE ART ................................................................. 23 III.
`
`
`IV.
`INTERPRETATIONS OF THE ’966 PATENT ........................................... 24
`LEGAL PRINCIPLES ................................................................................... 25
`
`V.
`VI.
` THE PRIOR ART AND ITS HOLDINGS ................................................... 27
`
`Fernandes ............................................................................................. 27
`A.
`
`The ’859 Publication ........................................................................... 32
`B.
`
`Blau ...................................................................................................... 38
`C.
`
`D.
`Simell ................................................................................................... 39
`
`Lee ....................................................................................................... 39
`E.
`
`Lichter-Konecki ................................................................................... 43
` F.
`
`OPTIONALLY IN VIEW OF BLAU, SIMELL AND/OR LEE (CLAIMS 1-
`3, 5, 6, 8, 9, AND 11) .................................................................................... 44
`A.
`
`Claims 1-3, 5, 6, 8, 9, and 11 are Obvious over Fernandes in View of
`the ’859 Publication, Optionally in View of Blau, Simell and/or Lee 45
`1.
`
`Independent Claims 1, 6 and 9 Are Obvious ............................ 45
`
` 2.
`Obviousness of Dependent Claims 2, 3, 5, 8 and 11 ................ 58
`
` Motivation to Combine the Prior Art ........................................ 59 3.
`
`
`Claims 12, 14 and 15 are Anticipated by the ’859 Publication .......... 61
`A.
` 1.
`
`Independent Claim 12 ............................................................... 61
`
` 2.
`Dependent Claims 14 and 15 .................................................... 66
`
` GROUND 1: FERNANDES IN VIEW OF THE ’859 PUBLICATION, VII.
`
` GROUND 2: THE ’859 PUBLICATION (Claims 12, 14 and 15) ............... 61 VIII.
`
`
`
`i
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`
`IX.
`
`X.
`
` Ground 3: the ’859 Publication, Optionally In Further View of Blau and
`Simell (Claims 12, 14 and 15) ....................................................................... 66
` Ground 4: Fernandes in View of the ’859 Publication and Lee or Lichter-
`Konecki, Optionally in View of Blau or Simell (Dependent Claims 4, 7, 10
`and 13) ........................................................................................................... 68
` ADDITIONAL REMARKS .......................................................................... 74
`
`XI.
`
`
`
`ii
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`INTRODUCTION
`
`
`
`I.
`I, Dr. Neal Sondheimer, M.D., Ph.D., do hereby declare and say:
`
`1.
`
`I am a medical doctor with specialties in Pediatrics, Clinical Genetics
`
`and Clinical Biochemical Genetics. I am over the age of twenty-one (21) and
`
`competent to make this declaration. I am also qualified to give testimony under
`
`oath. The facts and opinions listed below are within my personal knowledge.
`
`2.
`
`I am being compensated for my time in this proceeding at my standard
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`consulting rate of $650/hour. My compensation in no way depends on the outcome
`
`of this IPR proceeding or the content of my opinions. I am not employed by, nor
`
`receiving grant support from Par Pharmaceutical, Inc., which I refer to as “Par,” or
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`any related companies. I am receiving compensation from Par solely for my time
`
`spent working on this matter and based only on my standard hourly consulting
`
`fees.
`
`3.
`
`I have been asked to review U.S. Patent No. 9,326,966 (which I refer
`
`to as the ’966 Patent) (Ex. 1001) and the other documents that are exhibits to the
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`petition, and to provide my opinions on what those documents disclose.
`
`4.
`
`I have reviewed and am familiar with, among others, the following
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`documents:
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`
`
`1
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`a. U.S. Patent No. 9,326,966 to Scharschmidt et al. (“’966
`
`Patent”), filed December 3, 2015, issued May 3, 2016 is
`
`marked as Ex. 1001.
`
`b. U.S. Patent Publication No. 2010/0008859, filed January 7,
`
`2009, published January 14, 2010 (“’859 Publication”), which
`
`is marked as Ex. 1004.
`
`c. Moser, et al., Argininosuccinic Aciduria Report of Two New
`
`Cases and Demonstration of Intermittent Elevation of Blood
`
`Ammonia, 42 American Journal of Medicine, 9-26 (1967)
`
`(“Moser”) which is marked as Ex. 1005.
`
`d. Blau, Duran, Blaskovics, Gibson (editors), Physician’s Guide to
`
`the Laboratory Diagnosis of Metabolic Diseases, 261-276 (2d
`
`ed. 1996) (“Blau”), which is marked as Ex. 1006.
`
`e. Simell, et al., Waste Nitrogen Excretion Via Amino Acid
`
`Acylation: Benzoate and Phenylacetate in Lysinuric Protein
`
`Intolerance, 20 Pediatric Research, 1117-1121
`
`(1986)
`
`(“Simell”), which is marked as Ex. 1007.
`
`f. Feillet, Alternative Pathway Therapy for Urea Cycle Disorders,
`
`21 Journal of Inherited Metabolic Disease Suppl. 1, 101-111
`
`(1998) (“Feillet”), which is marked as Ex. 1008.
`
`2
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`g. Scientific Discussion for Ammonaps, EMEA 2005, available at
`
`http://www.ema.europa.eu/docs/en_GB/document_library/EPA
`
`R_-_Scientific_Discussion/human/000219/WC500024748.pdf
`
`(“Ammonaps”), which is marked as Ex. 1009.
`
`h. Lee, et al., Phase 2 comparison of a novel ammonia scavenging
`
`agent with sodium phenylbutyrate in patients with urea cycle
`
`disorders: Safety, pharmacokinetics and ammonia control, 100
`
`Molecular Genetics and Metabolism, 221-228 (2010) (“Lee”)
`
`which is marked as Ex. 1010.
`
`i. Buphenyl Label, which is marked as Ex. 1011.
`
`j. Prosecution History of U.S. Patent No. 8,404,215 (“’215 Parent
`
`Patent), which is marked as Ex. 1012.
`
`k. Assignment History of U.S. Patent 8,642,012, which is marked
`
`as Ex. 1013.
`
`l. Fernandes, Saudubray, Berghe (editors), Inborn Metabolic
`
`Diseases Diagnosis and Treatment, 215-222 (3d ed. 2000)
`
`(“Fernandes”), which is marked as Ex. 1015.
`
`m. Leonard et al., Hypothesis: Proposals for the Management of a
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`Neonate at Risk of Hyperammonaemia Due to a Urea Cycle
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`3
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`Disorder, 167 Eur. J. Pediatr. 305-309 (2008) (“Leonard”),
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`which is marked as Ex. 1016.
`
`n. Lichter-Konecki, et al., Ammonia Control in Children with
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`Urea Cycle Disorders (UCDs): Phase 2 Comparison of Sodium
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`Phenylbutyrate and Glycerol Phenylbutyrate, 103 Molecular
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`Genetics and Metabolism, 323-329 (2011) (“Lichter-Konecki”)
`
`which is marked as Ex. 1017.
`
`o. Pandya et al., N-Acetylglutamate Synthetase Deficiency:
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`Clinical and Laboratory Observations, 14 J. Inher. Metab. Dis.
`
`685-690 (1991) (“Pandya”), which is marked as Ex. 1018.
`
`p. U.S. Patent No. 5,968,979 (“the ’979 patent”), which is marked
`
`as Ex. 1019.
`
`q. McGuire et al., Pharmacology and Safety of Glycerol
`
`Phenylbutyrate in Healthy Adults and Adults with Cirrhosis,
`
`51(6) Hepatology 2077-2085 (2010) (“McGuire”), which is
`
`marked as Ex. 1020.
`
`r. Diaz, G. A., et al., Phase 3 Blinded Randomized, Crossover
`
`Comparison of Sodium Phenylbutyrate (NaPBA) and Glycerol
`
`Phenylbutyrate (GPB): Ammonia (NH3) Control in Adults with
`
`4
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`Urea Cycle Disorders (UCDS), 102 Mol Gen Met 276–277
`
`(2011) (“Diaz”) which is marked as Ex. 1021.
`
`s. Barsotti, Measurement of Ammonia in Blood, 138 J. Pediatrics,
`
`S11-S20 (2001) (“Barsotti”), which is marked as Ex. 1022.
`
`t. Yajima, et al. Diurnal Fluctuations of Blood Ammonia Levels
`
`in Adult-Type Citrullinemia, 137 Tokohu J. Ex/ Med, 213-220
`
`(1982) (“Yajima”), which is marked as Ex. 1023.
`
`u. Batshaw, et al., Treatment of Carbamyl Phosphate Synthetase
`
`Deficiency with Keto Analogues of Essential Amino Acids, 292
`
`The New England J. Medicine, 1085−90 (1975) (“Batshaw”),
`
`which is marked as Ex. 1024.
`
`v. Brusilow, Phenylacetylglutamine May Replace Urea as a
`
`Vehicle for Waste Nitrogen Excretion, 29 Pediatric Research,
`
`147-150 (1991) (“Brusilow ’91”), which is marked as Ex. 1025.
`
`5.
`
`I provide my conclusions regarding the disclosures of the documents I
`
`reviewed as applied to the ’966 Patent below as viewed from the perspective of
`
`one of ordinary skill in the art (“POSA”) as of September 30, 2011.
`
`6.
`
`I was also asked to provide my opinion on the technical feasibility of
`
`combining certain exhibits, and offer my opinion on the feasibility of these
`
`combinations as of September 30, 2011 in this declaration. I have also offered my
`
`
`
`5
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`
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
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`opinions about what a person of skill in the art would understand about the
`
`combinations of documents as of September 30, 2011.
`
` BACKGROUND
`II.
`7.
`A copy of my curriculum vitae is attached as Ex. 1003.
`
`8.
`
`I received my A.B. in Biology from Harvard University in 1994, my
`
`Ph.D. in Molecular Genetics and Cell Biology from the University of Chicago in
`
`2000, and my M.D. from the University of Chicago Pritzker School of Medicine in
`
`2002. I also completed a postdoctoral fellowship at the University of Pennsylvania
`
`in Genetics in 2009.
`
`9.
`
`I am currently a Staff Physician at The Hospital for Sick Children in
`
`the Division of Clinical and Metabolic Genetics. I am also currently an Assistant
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`Professor of Paediatrics at The University of Toronto School of Medicine.
`
`10.
`
`I hold relevant specialty certifications including a certification in the
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`American Academy of Pediatrics (received in 2006), a certification in the
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`American Board of Medical Genetics - Clinical Genetics (received in 2007), and a
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`certification in the American Board of Medical Genetics - Clinical Biochemical
`
`Genetics (received in 2009). I have held an academic practice license in Ontario
`
`since 2015.
`
`11. Among my research interests are the genetic causes, diagnosis and
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`treatment of urea cycle defects (“UCD”). In this regard, I have been involved in
`
`
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`6
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
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`several research studies on the genetic causes, diagnosis and treatment of UCDs. In
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`2008, I was co-author of a study that identified a novel genetic mechanism causing
`
`a disorder that included a urea cycle defect (Deardorff et al., MGM, 2008). In
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`2013, I was co-author of a study of methods for emergency management of
`
`neonates with UCDs (Spinale et al., Peds. Neph., 2013). Also in 2013, I was the
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`senior author on a study for early detection methods for infants with UCDs
`
`(Vergano et al., MGM, 2013). Although these studies discuss the use of ammonia-
`
`scavenging medications, I have never received funding from a pharmaceutical
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`company for research relating to the use of nitrogen scavenging medications for
`
`the treatment of UCDs.
`
`12. Based upon my extensive knowledge and years of experience in this
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`field, I have an understanding of how nitrogen scavenging drugs were being used
`
`in medical treatment on or before September 30, 2011. My analysis on this matter,
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`as set forth below, is based on my personal experience and what was known, and in
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`fact, considered to be standard, by one skilled in the art prior to September 30,
`
`2011.
`
`13.
`
`In my clinical practice, I have in the past treated patients with
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`Ammonul, Sodium Phenylbutyrate (both as Pheburane and Buphenyl), glyceryl tri-
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`
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`7
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`[4-phenylbutyrate] as well as sodium benzoate.1 I continue to use these
`
`medications today. I have obtained fasted and non-fasted plasma ammonia levels
`
`in patients. I have compared fasted and non-fasted plasma ammonia levels to the
`
`upper limit of normal (“ULN”). I have adjusted the dosage of these medications in
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`response to elevated plasma ammonia values, both fasted and non-fasted, and did
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`so prior to 2011. I have adjusted PAA prodrug dosages for various reasons
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`including ammonia control, alterations in diet and weight gain.
`
`14. My opinions, explained below, are based on my education,
`
`experience, and background in the field discussed above, as well as my review of
`
`the references cited above.
`
` The ’966 Patent
`A.
`15. According to the face of the patent, the ’966 Patent is a continuation
`
`of U.S. patent No. 9,254,278, which is a continuation of U.S. Patent No. 9,095,559,
`
`which is a continuation of U.S. Patent 8,204,215 (known as the ’215 Parent
`
`Patent). It is titled “Methods of Therapeutic Monitoring of Nitrogen Scavenging,”
`
`
`1 I will collectively refer to the phenylacetate component of Ammonul, sodium
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`phenylbutyrate and glyceryl tri-[4-phenylbutyrate] as “PAA prodrugs.” Some
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`references will refer to glyceryl tri-[4-phenylbutyrate] as either RAVICTI, HPN-
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`100, glycerol PBA, glycerol phenylbutyrate, GT4P, or GPB.
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`
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`8
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`and provides a method for administering and adjusting the dosage of a nitrogen
`
`scavenging drug in a patient with a nitrogen retention disorder. (The ’966 Patent at
`
`Abstract.) I understand that the ’966 Patent claims a filing date back to September
`
`30, 2011 (“the priority date”), which is when Provisional Application No.
`
`61/542,100 was filed.
`
`16.
`
`In essence, the ’966 Patent provides a method of measuring the
`
`patient’s fasting plasma ammonia levels and then comparing the fasting plasma
`
`ammonia level to the ULN for plasma ammonia level. In some embodiments, if the
`
`patient’s fasting plasma ammonia level is greater than half the ULN for plasma
`
`ammonia level and less than the ULN, then a nitrogen scavenging drug is either
`
`administered or the dose is increased if it was previously administered. Claims 1,
`
`6, 9 and 12 are the independent claims. Each is comprised of a preamble, which
`
`describes the intended type of patients for the claimed methods. For example,
`
`Claim 1 states:
`
`A method of treating a subject with a urea cycle disorder
`who has previously been administered an initial dosage
`of glyceryl tri-[4-phenylbutyrate] and who has a fasting
`plasma ammonia level less than the upper limit of normal
`for plasma ammonia level, the method comprising:
`(a) measuring a fasting plasma ammonia level for the
`subject;
`
`
`
`9
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`comparing the fasting plasma ammonia level to the
`(b)
`upper limit of normal for plasma ammonia level; and
`(c)
`administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate] that is greater than the initial dosage if
`the fasting plasma ammonia level is greater than half the
`upper limit of normal for plasma ammonia level,
`wherein the upper limit of normal for plasma ammonia
`level is in the range of 26-64 μmol/L.
`17. Claim 6 is an independent claim and recites:
`
`A method of treating a pediatric subject with a urea cycle disorder
`who has previously been administered an initial dosage of glyceryl tri-
`[4-phenylbutyrate] and who has a fasting plasma ammonia level less
`than the upper limit of normal for plasma ammonia level, the method
`comprising:
`
`(a) measuring a fasting plasma ammonia level for the pediatric
`subject;
`
`(b) comparing the fasting plasma ammonia level to the upper
`limit of normal for plasma ammonia level; and
`
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate] that is greater than the initial dosage if the fasting
`plasma ammonia level is greater than half the upper limit of normal
`for plasma ammonia level.
`18. Claim 9 is functionally indistinguishable, exchanging the term
`
`“pediatric subject” for “adult subject.” The dependent claims that depend from
`
`
`
`10
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
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`claims 6 and 9 also add the same limitations to both claims 6 and 9. Therefore,
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`claims 6 and 9 are essentially identical.
`
`19. Claim 12 is an independent claim and recites:
`
`A method of treating a patient having a urea cycle disorder
`comprising:
`
`(a) administering an initial effective dosage of glyceryl tri-[4-
`phenylbutyrate] (HPN-100) to the patient, wherein the initial effective
`dosage is calculated based on body surface area of the patient;
`
`(b) measuring the patient's urinary PAGN and/or fasting plasma
`ammonia level to determine whether to change the dosage of the
`glyceryl tri-[4-phenylbutyrate] (HPN-100); and
`
`(c) administering a subsequent effective dosage of glyceryl tri-
`[4-phenylbutyrate] (HPN-100) to the patient that is either the same as
`the initial effective dosage or is an increased dosage, wherein said
`increased dosage, if any, is calculated based on the patient's urinary
`PAGN and/or fasting plasma ammonia level.
`20. Claim 2 depends from claim 1 and further requires that the upper limit
`
`of normal for plasma ammonia level be in the range of 32-38 μmol/L.
`
`21. Claim 3 depends from claim 2 and further requires that the upper limit
`
`of normal for plasma ammonia level be in the range of 34-36 μmol/L.
`
`22. Claim 4 depends from claim 1 and further requires repeating steps (a)
`
`to (c) until the subject exhibits a fasting plasma ammonia level at or below half the
`
`upper limit of normal for plasma ammonia level.
`
`
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`11
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`23. Claim 5 depends from claim 1 and further requires the adjusted
`
`
`
`dosage of glyceryl tri-[4-phenylbutyrate] be administered orally.
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`24. Claim 7 depends from claim 6 and further requires repeating steps (a)
`
`to (c) until the pediatric subject exhibits a fasting plasma ammonia level at or
`
`below half the upper limit of normal for plasma ammonia level.
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`25. Claim 8 depends from claim 6 and further requires the adjusted
`
`dosage of glyceryl tri-[4-phenylbutyrate] be administered orally.
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`26. Claim 10 depends from claim 9 and further requires repeating steps
`
`(a) to (c) until the adult subject exhibits a fasting plasma ammonia level at or
`
`below half the upper limit of normal for plasma ammonia level.
`
`27. Claim 11 depends from claim 9 and further requires the adjusted
`
`dosage of glyceryl tri-[4-phenylbutyrate] be administered orally.
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`28. Claim 13 depends on claim 12 and further requires repeating steps (b)
`
`to (c) until the subject exhibits a fasting plasma ammonia level at or below half the
`
`upper limit of normal for plasma ammonia level.
`
`29. Claim 14 depends from claim 12 and further requires the initial
`
`effective dosage of glyceryl tri-[4-phenylbutyrate] be administered orally.
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`30. Claim 15 depends from claim 12 and further requires the subsequent
`
`effective dosage of glyceryl tri-[4-phenylbutyrate] be administered orally.
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`12
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`31. The ’966 Patent marks the last of five patents, all directed to dosage
`
`
`
`adjustment of nitrogen scavenging drugs, that have been filed by Dr. Scharschmidt
`
`with or without Dr. Mokhtarani. Glyceryl tri-[4-phenylbutyrate] itself remains
`
`under orphan drug protected status, and is marketed by Horizon.
`
`32. The ’966 Patent claims contain trivial differences from the ’215
`
`Parent Patent:
`
`Unpatentable ’215 Parent Patent,
`Exemplary Claim 1
`
`’966 Patent,
`Exemplary Claims 1, 6 and 92
`
`A method for adjusting the dosage
`of a nitrogen scavenging drug in
`a subject who has previously been
`administered an initial dosage of
`the nitrogen scavenging drug,
`comprising:
`
`
`
`a) measuring a fasting blood
`ammonia level for the subject;
`
`A method of treating {a subject} {a
`pediatric subject} {an adult
`subject} with a urea cycle disorder
`who has previously been
`administered an initial dose of
`[GPB] and who has a fasting
`ammonia level less than the upper
`limit of normal for plasma
`ammonia level, the method
`comprising:
`
`a) measuring a fasting plasma
`ammonia level for {the subject}
`{the pediatric subject} {the
`adult subject};
`
`
`2 Bolded text found in curly brackets is found in claim 1 only. Bolded and
`
`italicized text in curly brackets is only found in claim 6. Bolded and underlined
`
`text in curly brackets is found only in claim 9.
`
`
`
`13
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`
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`Unpatentable ’215 Parent Patent,
`Exemplary Claim 1
`
`’966 Patent,
`Exemplary Claims 1, 6 and 92
`
`b) comparing the fasting blood
`ammonia level to the upper limit
`of normal for blood ammonia
`level; and
`
`b) comparing the fasting plasma
`ammonia level to the upper limit
`of normal for plasma ammonia
`level; and
`
`c) administering an adjusted dosage
`of the nitrogen scavenging
`drug, wherein the adjusted
`dosage is greater than the initial
`dosage if the fasting blood
`ammonia level is greater than
`half the upper limit of normal for
`blood ammonia level.
`
`c) administering an adjusted dosage
`of [GPB] that is greater than the
`initial dosage if the fasting
`plasma ammonia level is greater
`than half the upper limit of
`normal for plasma ammonia
`level,
`{wherein the upper limit of
`normal for plasma ammonia level
`is in the range of 26-64 µmol/L.}
`
`
` The ’966 Patent restricts the claims to glyceryl tri-[4-phenylbutyrate].
`
`The same prior art that invalidated the ’215 Parent Patent claims also
`
`discloses glyceryl tri-[4-phenylbutyrate] for treating UCD, including at
`
`least the ’859 Publication.
`
` The ’966 Patent limits the claims to patients with urea cycle disorders.
`
`The same prior art that invalidated the ’215 Parent Patent claims also
`
`discloses treating patients with urea cycle disorders, including at least
`
`Fernandes,’859 Publication, and Blau.
`
`14
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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` The ’966 Patent corrects an error in the ’215 Parent Patent where “blood
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`ammonia levels” were used as a measurement rather than “plasma
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`ammonia levels.”3
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` Claims 6 and 9 require “pediatric” and “adult” subjects respectively.
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`Treatment of these groups of patients with nitrogen scavenging drugs,
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`including glycerol phenylbutyrate are disclosed in the prior art, including
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`Fernandes, the ’859 Publication, Lee, Lichter-Konecki and Blau.
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` Claim 1 requires the upper limit of normal for plasma ammonia to be in
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`the range of 26-64 µmol/L and this limitation is also disclosed in the
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`prior art to the ’215 Parent Patent.
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`3 The technical measurement of ammonia occurs in a plasma sample after removal
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`of the blood cells. Some older references and the ’215 and ’966 Patents refer to
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`“blood” ammonia levels which is a less preferred term. The terminology makes
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`little difference to a POSA as it would be clear that plasma is derived from a
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`sample of blood and ammonia could only be measured in a plasma sample as cells
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`would interfere with analysis. Furthermore, as recognized by the Patent Trial and
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`Appeal Board in the ’215 Final Written Decision, the terms “blood” and “plasma”
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`are interchangeable in the context of these patents and the prior art to the patents.
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`15
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`33. There is one substantive difference in the ’966 Patent as compared to
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`
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`the ’215 Parent Patent. Unlike the claims of the ’215 Parent Patent, the claims of
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`the ’966 Patent recite the limitation “who has a fasting plasma ammonia level less
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`than the upper limit of normal,” or similar language. As discussed below, the prior
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`art discloses administering nitrogen scavenging drugs to patients “who have a
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`fasting plasma ammonia level below the ULN,” and this limitation does not
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`distinguish the ’966 Patent claims from the prior art.
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`34.
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`In summary, the ’966 Patent claims do not cover any invention that
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`was not already covered by the ’215 Parent Patent claims, which have been held
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`unpatentable.
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`B.
`35.
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`The Urea Cycle
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`In the human body, the urea cycle is the major pathway for the
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`removal of waste nitrogen. Enzymes and transporters within the urea cycle
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`synthesize urea from ammonia, which is then excreted in urine to remove excess
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`nitrogen. In a patient with a UCD, an enzyme or transporter supporting or
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`participating in the urea cycle is deficient and the patient has an impaired ability to
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`generate urea and remove waste nitrogen. The inability to remove excess nitrogen
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`in these patients can lead to elevated ammonia (hyperammonemia), which in turn
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`can lead to lethargy, brain damage, and death.
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`16
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`36. Nitrogen enters the body principally in the amino acids in dietary
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`
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`protein. Excess amino acids – amino acids that are beyond those necessary for
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`ordinary bodily function and not used for endogenous protein synthesis – are
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`broken down and form pools of free amino acids, including glutamine and glycine.
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`Ammonia is liberated during the breakdown of free amino acids and through the
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`sequential actions of carbamoyl phosphate synthetase and the enzymes of the urea
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`cycle. In normal patients, through these processes, waste nitrogen is converted into
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`urea. Urea is then excreted in urine. Thus, each urea molecule excreted represented
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`the removal of two atoms of nitrogen. The two figures below describe how the urea
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`cycle works:
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`17
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`37.
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`In a patient with a urea cycle disorder, a defect in either a required
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`enzyme of the urea cycle itself or a transporter for urea cycle substrate is present.
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`18
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`In these patients, excess dietary amino acids are converted into ammonia that
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`accumulates, causing toxicity.
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`38. Medications that are metabolized to phenylacetate (including glyceryl
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`tri-[4-phenylbutyrate]) provide an alternative mechanism for the clearance of
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`glutamine in the form of phenylacetylglutamine, which contains two moles of
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`nitrogen, like urea.
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`19
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`Unlike PAA, benzoate operates as a nitrogen scavenging drug by being conjugated
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`with glycine to form hippurate, which is excreted in urine. Through this reaction to
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`form hippurate, benzoate results in the excretion of one mole of nitrogen per mole
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`of benzoate.
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`39. Glyceryl tri-[4-phenylbutyrate] is a pre-pro-drug of phenylacetic acid
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`(PAA). It is metabolized by pancreatic lipases to produce three moles of
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`phenylbutyrate per mole of glyceryl tri-[4-phenylbutyrate]. Phenylbutyrate is
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`further metabolized by beta-oxidation to produce PAA. PAA prodrugs greatly
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`simplify the process of balancing dietary intake of nitrogen with bodily demand in
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`patients with UCDs. They act prior to the release of free ammonia, providing a
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`shunt away from its formation.
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`40. There is no known consequence of having low levels of plasma
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`ammonia, and physicians use therapeutically acceptable doses of nitrogen
`20
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`scavenging medications to achieve normal plasma ammonia levels to reduce the
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`risk of a hyperammonemic event, attempting to strike a balance between required
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`protein intake and nitrogen excretion. If the dose of nitrogen scavenging drug,
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`such as glyceryl tri-[4-phenylbutyrate], was less effective, then the dose could be
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`appropriately adjusted.
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`C.
`41.
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`Prior Art Treatment Protocols Using Nitrogen Scavenging Drugs
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`In practice, using PAA prodrugs to treat urea cycle disorders was
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`well-known in the art before the priority date of the ’966 Patent. (See e.g.,
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`Brusilow ’91.) PAA prodrugs known prior to the priority date included glyceryl tri-
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`[4-phenyl-butyrate].
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`42.
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`It was well-known before the priority date of the ’966 Patent that
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`when treating UCD patients, plasma ammonia levels should be measured regularly
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`and compared to ULN. (See e.g., ’859 Publication at [0094]; Ammonaps at 1;
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`Fernandes at 219.) It was also well-known that the ULN of plasma ammonia levels
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`vary depending exactly on how it is measured, but that some clinical tests showed
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`a normal range of <35 µM, which would place the ULN at 35 µM. (See e.g., ’859
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`Publication at [0063] & Fig. 13, [0094], [0201].) Various ULNs may be
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`established based on age, and ULNs are not identical between different testing
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`laboratories and clinics or between individuals.
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`21
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`43.
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`In practice, when measuring a patient’s plasma ammonia levels to
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`
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`compare to a ULN, it is recommended to measure a fasting plasma ammonia level.
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`(Blau at Table 11.9; Barsotti at S11.) The fasting plasma ammonia level tends to
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`be the lowest value over the course of the day and to be the value with the least
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`variation. (Moser at 9; Lee at Fig. 2; Lichter-Konecki at Fig. 2.) The prior art
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`confirms that for patients on treatment with PAA prodrugs, plasma ammonia levels
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`are “lowest after overnight fasting and peak(ed) postprandially.” (Diaz at 276.)
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`This variation was well recognized in the art. (Lee at Fig. 2; Lichter-Konecki at
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`Fig. 2; Yajima at 214 (Fig. 1); Batshaw at 1086 (Fig. 2).) Diurnal variation would
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`cause one of a set of repeated daily measurements to regularly have the lowest or
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`highest value. Due to diurnal variation, a POSA would know that the ammonia
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`levels in a fasted state would be reliably lower than those at other times and that
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`the maintenance of normal ammonia over the course of the day would require a
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`fasted plasma ammonia level that was in the lower half of the normal range.
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`44.
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`It was also well-recognized that the conversion of PAA prodrugs to
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`PAGN is incomplete. (’859 Publication at claim 6; Brusilow ’91 at 148.) The
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`conversion rate of PAA prodrugs into PAGN is one means to determine the dose of
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`PAA prodrug to administer to the UCD patient. (’859 Publication at claim 18;
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`Brusilow ’91 at 147-48.)
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`22
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`Inter Partes Review of USPN 9,326,966
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`45. The ’966 Patent specification uses data from prior art references Lee,
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`
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`Lichter-Konecki and Diaz. All of these studies were in the prior art at the earliest
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`priority date.
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`46. For example, the ’966 Patent specification states that “[b]ased on
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`well-controlled clinical trials with repeated blood sampling over 24 hours, the
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`maximum blood ammonia has been observed to occur following the third major
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`meal of the day in the early to mid evening hours” and cites Lee and Lichter-
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`K