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 9,095,559
`_____________________
`
`DECLARATION OF NEAL SONDHEIMER, M.D., Ph.D.
`
`
`
`
`
`
`
`
`

`

`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`TABLE OF CONTENTS
`
`I.
` 
`II.
` 
`
`INTRODUCTION ........................................................................................... 1 
`BACKGROUND ............................................................................................. 6 
`A. 
`The ’559 Patent ..................................................................................... 8 
`B. 
`The Urea Cycle .................................................................................... 15 
`C. 
`Prior Art Treatment Protocols Using Nitrogen Scavenging Drugs .... 20 
`III.
`  LEVEL OF SKILL IN THE ART ................................................................. 22 
`IV.
`INTERPRETATIONS OF THE ’559 PATENT ........................................... 23 
` 
`LEGAL PRINCIPLES ................................................................................... 24 
`V.
` 
`VI.
`  GROUND 1: FERNANDES IN VIEW OF THE ’859 PUBLICATION,
`OPTIONALLY IN VIEW OF BLAU, SIMELL AND/OR LEE
`(INDEPENDENT CLAIMS 1-2; DEPENDENT CLAIMS 4, 7-10, 12, 13) 26 
`A. 
`The Prior Art and Its Holdings ............................................................ 28 
`1. 
`Fernandes .................................................................................. 28 
`2. 
`The ’859 Publication ................................................................. 32 
`3. 
`Blau ........................................................................................... 38 
`4. 
`Simell ........................................................................................ 39 
`5. 
`Lee ............................................................................................. 39 
`Independent Claims 1 and 2 and Dependent Claims 4, 7-10, 12 and 13
`are Obvious over Fernandes in View of the ‘859 Publication,
`Optionally in View of Blau, Simell and/or Lee .................................. 43 
`1. 
`Independent Claims 1 and 2 Are Obvious ................................ 43 
`C.  Obviousness of Dependent Claims 4, 7-10, 12, and 13 ...................... 54 
`D.  Motivation to Combine the Prior Art .................................................. 58 
`VII.
`  GROUND 2: FERNANDES IN VIEW OF THE ’859 PUBLICATION AND
`LEE OR LICHTER-KONECKI, OPTIONALLY IN VIEW OF BLAU OR
`SIMELL (CLAIM 5) ..................................................................................... 60 
`A. 
`The Prior Art and Its Holdings ............................................................ 60 
`1. 
`Lichter-Konecki ........................................................................ 60 
`B.  Obviousness of Dependent Claim 5 .................................................... 61 
`
`B. 
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`B. 
`
`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`C.  Motivation to Combine ....................................................................... 67 
`VIII.
`  GROUND 3: THE ‘859 PUBLICATION IN VIEW OF PANDYA AND/OR
`LEE (INDEPENDENT CLAIM 3; DEPENDENT CLAIMS 7-9, 11, 14) ... 67 
`A. 
`The Prior Art and Its Holdings ............................................................ 68 
`1. 
`Pandya ....................................................................................... 68 
`Independent Claim 3 and Dependent Claims 7-9, 11 and 14 are
`Obvious over the ’859 Publication in View of Pandya and/or Lee .... 69 
`1. 
`Independent Claim 3 ................................................................. 69 
`2. 
`Dependent Claims 7-9, 11 and 14 ............................................. 75 
`C.  Motivation to Combine ....................................................................... 77 
`  GROUND 4: THE ’859 PUBLICATION IN VIEW OF FERNANDES,
`OPTIONALLY IN FURTHER VIEW OF PANDYA, BLAU, SIMELL
`AND/OR LEE (DEPENDENT CLAIMS 6 AND 15) .................................. 77 
`A. 
`The Prior Art and Its Holdings ............................................................ 77 
`B.  Obviousness of Dependent Claims 6 and 15....................................... 77 
`C.  Motivation to Combine ....................................................................... 79 
`  ADDITIONAL REMARKS .......................................................................... 79 
`
`IX.
`
`X.
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`Inter Partes Review of USPN 9,095,559
`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
`
`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
`
`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. 9,095,559 (which I refer
`
`to as the ’559 Patent) (Ex. 1001) and the other documents that are exhibits to the
`
`petition, and to provide my opinions on what those documents disclose.
`
`4.
`
`I have reviewed and am familiar with, among others, the following
`
`documents:
`
`a. U.S. Patent No. 9,095,559 to Scharschmidt et al. (“’559
`
`Patent”), filed February 22, 2013, issued August 4, 2015 is
`
`marked as Ex. 1001.
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`1
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`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.
`
`g. Scientific Discussion for Ammonaps, EMEA 2005, available at
`
`http://www.ema.europa.eu/docs/en_GB/document_library/EPA
`
`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`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
`
`Neonate at Risk of Hyperammonaemia Due to a Urea Cycle
`
`Disorder, 167 Eur. J. Pediatr. 305-309 (2008) (“Leonard”),
`
`which is marked as Ex. 1016.
`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`n. Lichter-Konecki, et al., Ammonia Control in Children with
`
`Urea Cycle Disorders (UCDs): Phase 2 Comparison of Sodium
`
`Phenylbutyrate and Glycerol Phenylbutyrate, 103 Molecular
`
`Genetics and Metabolism, 323-329 (2011) (“Lichter-Konecki”),
`
`which is marked as Ex. 1017.
`
`o. Pandya et al., N-Acetylglutamate Synthetase Deficiency:
`
`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
`
`Urea Cycle Disorders (UCDS), 102 Mol Gen Met 276–277
`
`(2011) (“Diaz”), which is marked as Ex. 1021.
`
`
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`4
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`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 ’559 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
`
`opinions about what a person of skill in the art would understand about the
`
`combinations of documents as of September 30, 2011.
`
`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
` 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
`
`Professor of Paediatrics at The University of Toronto School of Medicine.
`
`10.
`
`I hold relevant specialty certifications including a certification in the
`
`American Academy of Pediatrics (received in 2006), a certification in the
`
`American Board of Medical Genetics - Clinical Genetics (received in 2007), and a
`
`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
`
`treatment of urea cycle defects (“UCD”). In this regard, I have been involved in
`
`several research studies on the genetic causes, diagnosis and treatment of UCDs. In
`
`2008, I was co-author of a study that identified a novel genetic mechanism causing
`
`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`a disorder that included a urea cycle defect (Deardorff et al., MGM, 2008). In
`
`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
`
`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
`
`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
`
`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,
`
`as set forth below, is based on my personal experience and what was known, and in
`
`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
`
`Ammonul, Sodium Phenylbutyrate (both as Pheburane and Buphenyl), glyceryl tri-
`
`[4-phenylbutyrate] as well as sodium benzoate. 1 I continue to use these
`
`
`1 I will collectively refer to the phenylacetate component of Ammonul, sodium
`
`phenylbutyrate and glyceryl tri-[4-phenylbutyrate] as “PAA prodrugs.” Some
`
`
`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`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
`
`response to elevated plasma ammonia values, both fasted and non-fasted, and did
`
`so prior to 2011. I have adjusted PAA prodrug dosages for various reasons
`
`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.
`
`A. The ’559 Patent
`
`15. According to the face of the patent, the ’559 Patent is a divisional
`
`patent of U.S. Patent 8,204,215 (known as the ’215 Parent Patent). It is titled
`
`“Methods of Therapeutic Monitoring of Nitrogen Scavenging,” and provides a
`
`method for administering and adjusting the dosage of a nitrogen scavenging drug
`
`in a patient with a nitrogen retention disorder. (The ’559 Patent at Abstract.) I
`
`understand that the ’559 Patent claims a filing date back to September 30, 2011
`
`
`references will refer to glyceryl tri-[4-phenylbutyrate] as either RAVICTI, HPN-
`
`100, glycerol PBA, glycerol phenylbutyrate, GT4P, or GPB.
`
`
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`8
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`

`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`(“the priority date”), which is when Provisional Application No. 61/542,100 was
`
`filed.
`
`16.
`
`In essence, the ’559 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 1-3
`
`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 for adjusting the dosage of glyceryl tri-[4-phenylbutyrate]
`in a subject being treated for 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 ULN for plasma ammonia
`level, the method comprising:
`(a) measuring a fasting plasma ammonia level for the subject;
`(b) comparing the fasting plasma ammonia level to the ULN for
`plasma ammonia level; and
`tri-[4-
`glyceryl
`of
`dosage
`(c) administering
`an
`adjusted
`phenylbutyrate], wherein the adjusted dosage is greater than the
`initial dosage if the fasting plasma ammonia level is greater than
`half the ULN for plasma ammonia level.
`
`
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`9
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`

`

`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`17. Claim 2 is functionally indistinguishable, exchanging the term
`
`“treating a subject” for “adjusting the dosage” and rearranging other words. The
`
`dependent claims that depend from claims 1 and 2 also add the same limitations to
`
`both claims 1 and 2. Therefore, claims 1 and 2 are essentially identical.
`
`18. Claim 3 is an independent claim and recites:
`
`A method of administering glyceryl tri-[4-phenylbutyrate] to a subject
`having a urea cycle disorder, the method comprising:
`
`(a) measuring a first fasting plasma ammonia level for the
`subject;
`
`(b) comparing the first fasting plasma ammonia level to the
`upper limit of normal for plasma ammonia level; and
`tri-[4-
`
`(c) administering an
`initial dosage of glyceryl
`phenylbutyrate] to the subject if the fasting plasma ammonia level is
`greater than half the upper limit of normal for plasma ammonia level
`and less than the upper limit of normal for plasma ammonia level.
`Unlike claims 1 and 2, claim 3 is not limited to patients who have previously been
`
`administered glyceryl tri-[4-phenylbutyrate] or to dose adjustment, and covers the
`
`initial use of the medication. In addition, the concept of having plasma ammonia
`
`levels less than the ULN is found in step (c) of claim 3 instead of in the preamble,
`
`as it is in claims 1 and 2.
`
`19. Claim 4 depends from claim 1 or 2, wherein the adjustment produces
`
`a normal average daily ammonia level in the subject.
`
`
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`10
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`20. Claim 5 depends from claim 4 (and thus claims 1 and 2) and provides
`
`for iterative measurements of fasting plasma ammonia level and adjustment.
`
`21. Claim 6 depends from claim 3, in which the patient has a “second”
`
`fasted plasma ammonia level, with comparison and adjustment of medication.
`
`22. Claim 7 depends from claims 1-3 and further requires that the ULN is
`
`35µM. Claim 8 depends from claims 1-3 and requires that the ULN is “specific to
`
`the laboratory in which the fasting plasma ammonia level is measured.” Claim 9
`
`depends from claims 1-3 and requires that the ULN is “determin[ed]…for the
`
`subject prior to step (b).”
`
`23. Claim 10 depends from either claims 1 or 2 wherein the adjusted
`
`dosage “is calculated by (i) measuring urinary phenylacetyl glutamine (P AGN)
`
`[sic] output; and (ii) calculating an effective adjusted dosage of glyceryl tri-[4-
`
`phenylbutyrate] based on the urinary PAGN output, wherein the effective adjusted
`
`dosage is calculated based on a mean conversion of glyceryl tri-[4-phenylbutyrate]
`
`to urinary PAGN of 60-75%.”
`
`24. Claim 11 depends from claim 3 and, like claim 10, recites “wherein
`
`the initial dosage is calculated by (i) determining a target urinary phenylacetyl
`
`glutamine (PAGN) output; and (ii) calculating and effective adjusted dosage of
`
`glyceryl tri-[4-phenylbutyrate] based on the urinary PAGN output, wherein the
`
`
`
`11
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`effective adjusted dosage is calculated based on a mean conversion of glyceryl tri-
`
`[4-phenylbutyrate] to urinary PAGN of 60-75%.”
`
`25. Claims 12-16 depend from claims 1-3 and 6, respectively, where
`
`glyceryl tri-[4-phenylbutyrate] is provided orally.
`
`26. The ’559 Patent marks the third 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.
`
`27. The ’559 Patent claims contain trivial differences from the ’215
`
`Parent Patent:
`
`Unpatentable ’215 Parent Patent,
`Exemplary Claim 1
`
`’559 Patent,
`Exemplary Claim 1
`
`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 method for adjusting the dosage
`of [GPB] in a subject being treated
`for a urea cycle disorder who has
`previously been administered an
`initial dosage of [GPB] 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 blood
`ammonia level for the subject;
`
`a) measuring a fasting plasma
`ammonia level for the subject;
`
`b) comparing the fasting blood
`ammonia level to the upper limit
`
`b) comparing the fasting plasma
`ammonia level to the upper limit
`
`12
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`

`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`Unpatentable ’215 Parent Patent,
`Exemplary Claim 1
`of normal for blood ammonia
`level; and
`
`’559 Patent,
`Exemplary Claim 1
`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], wherein the adjusted
`dosage 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.
`
`
` The ’559 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 ’559 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.
`
`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
` The ’559 Patent corrects an error in the ’215 Parent Patent where “blood
`
`ammonia levels” were used as a measurement rather than “plasma
`
`ammonia levels.”2
`
` The ’559 Patent incorporates iterative steps in claims 5 and 6, which are
`
`also disclosed in the prior art to the ’215 Parent Patent and cited by the
`
`Board in the ’215 Final Written Decision, including at least Fernandes
`
`and ’859 Publication.
`
` Dependent claims 12-15 of the ’559 Patent require oral administration,
`
`but this limitation is also disclosed in the prior art to the ’215 Parent
`
`Patent and cited by the Board in the ’215 Final Written Decision,
`
`including at least Fernandes and ’859 Publication.
`
`
`2 The technical measurement of ammonia occurs in a plasma sample after removal
`
`of the blood cells. Some older references and the ’215 and ’559 Patents refer to
`
`“blood” ammonia levels which is a less preferred term. The terminology makes
`
`little difference to a POSA as it would be clear that plasma is derived from a
`
`sample of blood and ammonia could only be measured in a plasma sample as cells
`
`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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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`28. There is one substantive difference in the ’559 Patent as compared to
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`the ’215 Parent Patent. Unlike the claims of the ’215 Parent Patent, the claims of
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`the ’559 Patent recite the limitation “who have a fasting plasma ammonia level
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`below the ULN,” or similar language. As discussed below, the prior art discloses
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`administering nitrogen scavenging drugs to patients “who have a fasting plasma
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`ammonia level below the ULN,” and this limitation does not distinguish the ’559
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`Patent claims from the prior art.
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`29.
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`In summary, the ’559 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.
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`30.
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`The Urea Cycle
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`In the human body, the urea cycle is the major pathway for the
`
`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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`15
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`31. Nitrogen enters the body principally in the amino acids in dietary
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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 represents
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`the removal of two atoms of nitrogen. The two figures below illustrate how the
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`urea cycle works:
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`
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`16
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`32.
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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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`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`In these patients, excess dietary amino acids are converted into ammonia that
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`accumulates, causing toxicity.
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`33. 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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`
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`18
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`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
`
`
`
`of benzoate.
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`34. Glyceryl tri-[4-phenylbutyrate] is a pre-pro-drug of phenylacetic acid
`
`(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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`
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`19
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`35. There is no known consequence of having low levels of plasma
`
`ammonia, and physicians use therapeutically acceptable doses of nitrogen
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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.
`
`C.
`
`36.
`
`Prior Art Treatment Protocols Using Nitrogen Scavenging Drugs
`
`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 ’559 Patent. (See e.g.,
`
`Brusilow ’91.) PAA prodrugs known prior to the priority date included glyceryl tri-
`
`[4-phenyl-butyrate].
`
`37.
`
`It was well-known before the priority date of the ’559 Patent that
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`when treating UCD patients, plasma ammonia levels should be measured regularly
`
`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
`
`vary depending exactly on how it is measured, but that some clinical tests showed
`
`a normal range of <35 µM, which would place the ULN at 35 µM. (See e.g., ’859
`
`Publication at [0063] & Fig. 13, [0094], [0201].) Various ULNs may be
`
`established based on age, and ULNs are not identical between different testing
`
`laboratories and clinics or between individuals.
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`
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`20
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`In practice, when measuring a patient’s plasma ammonia levels to
`
`38.
`
`compare to a ULN, it is recommended to measure a fasting plasma ammonia level.
`
`(Blau at Table 11.9; Barsotti at S11.) The fasting plasma ammonia level tends to
`
`be the lowest value over the course of the day and to be the value with the least
`
`variation. (Moser at 9; Lee at Fig. 2; Lichter-Konecki at Fig. 2.) The prior art
`
`confirms that for patients on treatment with PAA prodrugs, plasma ammonia levels
`
`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
`
`Fig. 2; Yajima at 214 (Fig. 1); Batshaw at 1086 (Fig. 2).) Diurnal variation would
`
`cause one of a set of repeated daily measurements to regularly have the lowest or
`
`highest value. Due to diurnal variation, a POSA would know that the ammonia
`
`levels in a fasted state would be reliably lower than those at other times and that
`
`the maintenance of normal ammonia over the course of the day would require a
`
`fasted plasma ammonia level that was in the lower half of the normal range.
`
`39.
`
`It was also well-recognized that the conversion of PAA prodrugs to
`
`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
`
`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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`
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`Inter Partes Review of USPN 9,095,559
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`40. The ’559 Patent specification uses data from prior art references Lee,
`
`Lichter-Konecki and Diaz. All of these studies were in the prior art at the earliest
`
`priority date.
`
`41. For example, the ’559 Patent specification states that “[b]ased on
`
`well-controlled clinical trials with repeated blood sampling over 24 hours, the
`
`maximum blood ammonia has been observed to occur following the third major
`
`meal of the day in the early to mid evening hours” and cites Lee and Lichter-
`
`Konecki. (Ex. 1001 at 12:5-10.) In a second example, the ’559 Patent specification
`
`states that the data evaluated in Example 1 of the specification was obtained from
`
`“two Phase 2 studies and one Phase 3 study comparing ammonia control assessed
`
`by 24-hour sampling during steady state treatment with HPN-100 versus NaPBA in
`
`65 UCD patients . . ..” (Id. at 15:16-22.) The three studies cited are Lee, Lichter-
`
`