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 9,254,278
`_____________________
`
`DECLARATION OF NEAL SONDHEIMER, M.D., Ph.D.
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`TABLE OF CONTENTS
`
`I. 
`II. 
`
`INTRODUCTION ........................................................................................... 1 
`BACKGROUND ............................................................................................. 6 
`A. 
`The ’278 Patent ...................................................................................... 8 
`B. 
`The Urea Cycle ..................................................................................... 17 
`C. 
`Prior Art Treatment Protocols Using Nitrogen Scavenging
`Drugs .................................................................................................... 22 
`III.  LEVEL OF SKILL IN THE ART ................................................................. 24 
`IV. 
`INTERPRETATIONS OF THE ’278 PATENT ........................................... 25 
`V. 
`LEGAL PRINCIPLES ................................................................................... 26 
`VI.  GROUND 1: THE ’859 PUBLICATION (INDEPENDENT CLAIM 1
`AND DEPENDENT CLAIMS 2-3) .............................................................. 28 
`A. 
`The Prior Art and Its Holdings ............................................................. 28 
`1. 
`The ’859 Publication ................................................................. 28 
`Independent Claim 1 and Dependent Claims 2 and 3 Are
`Anticipated by the ’859 Publication ..................................................... 34 
`1. 
`Independent Claim 1 ................................................................. 34 
`2. 
`Dependent Claims 2 and 3 ........................................................ 36 
`VII.  GROUND 2: FERNANDES
`IN VIEW OF THE
`’859
`PUBLICATION
`AND
`LEE
`OR
`LICHTER-KONECKI,
`OPTIONALLY IN VIEW OF BLAU OR SIMELL (INDEPENDENT
`CLAIM 1 AND DEPENDENT CLAIMS 2-3) ............................................. 37 
`A. 
`The Prior Art and Its Holdings ............................................................. 37 
`1. 
`The ’859 Publication ................................................................. 37 
`2. 
`Fernandes .................................................................................. 37 
`3. 
`Blau ........................................................................................... 41 
`4. 
`Simell ........................................................................................ 42 
`5. 
`Lee ............................................................................................. 42 
`6. 
`Lichter-Konecki ........................................................................ 46 
`Independent Claim 1 and Dependent Claims 2 and 3 Are
`Obvious Under 35 U.S.C. § 103(a) Over Fernandes in View of
`
`B. 
`
`B. 
`
`
`
`i
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`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`the ’859 Publication and Lee or Lichter-Konecki, Optionally in
`View of Blau or Simell ......................................................................... 47 
`1. 
`Independent Claim 1 ................................................................. 47 
`2. 
`Dependent Claims 2 and 3 ........................................................ 52 
`C.  Motivation to Combine ........................................................................ 53 
`VIII.  GROUND 3:
` FERNANDES
`IN VIEW OF THE
`’859
`PUBLICATION, OPTIONALLY IN VIEW OF BLAU, SIMELL
`AND/OR LEE (INDEPENDENT CLAIMS 4, 8 AND 12 AND
`DEPENDENT CLAIMS 6, 7, 10, 11, 14 AND 15) ...................................... 54 
`A. 
`The Prior Art and Its Holdings ............................................................. 54 
`B. 
`Independent Claims 4, 8 and 12 and Dependent Claims 6, 7, 10,
`11, 14 and 15 Are Obvious Under 35 U.S.C. § 103(a) Over
`Fernandes in View of the ’859 Publication, Optionally in View
`of Blau, Simell and/or Lee ................................................................... 54 
`1. 
`Independent Claims 4, 8 and 12 Are Obvious .......................... 55 
`2. 
`Dependent Claims 6, 7, 10, 11, 14 and 15 ................................ 69 
`C.  Motivation to Combine ........................................................................ 69 
`IX.  GROUND 4:
` FERNANDES
`IN VIEW OF THE
`’859
`PUBLICATION
`AND
`LEE
`OR
`LICHTER-KONECKI,
`OPTIONALLY IN VIEW OF BLAU OR SIMELL (DEPENDENT
`CLAIMS 5, 9 AND 13) ................................................................................. 71 
`X.  ADDITIONAL REMARKS .......................................................................... 77 
`
`
`
`ii
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`

`

`Inter Partes Review of USPN 9,254,278
`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. 9,254,278 (which I refer
`
`to as the ’278 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:
`
`
`
`1
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`a. U.S. Patent No. 9,254,278 to Scharschmidt et al. (“’278
`
`Patent”), filed August 3, 2015, issued February 9, 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
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`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
`
`Neonate at Risk of Hyperammonaemia Due to a Urea Cycle
`
`
`
`3
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`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`Disorder, 167 Eur. J. Pediatr. 305-309 (2008) (“Leonard”),
`
`which is marked as Ex. 1016.
`
`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
`
`
`
`4
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`Urea Cycle Disorders (UCDS), Mol Gen Met 102:276–277
`
`(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 ’278 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
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`opinions about what a person of skill in the art would understand about the
`
`combinations of documents as of September 30, 2011.
`
`II. BACKGROUND
`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
`
`
`
`6
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`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
`
`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-
`
`
`
`7
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`[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
`
`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 ’278 Patent
`15. According to the face of the patent, the ’278 Patent is a continuation
`
`of U.S. Patent No. 9,095,559, which 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
`
`
`1 I will collectively refer to the phenylacetate component of Ammonul, sodium
`
`phenylbutyrate and glyceryl tri-[4-phenylbutyrate] as “PAA prodrugs.” Some
`
`references will refer to glyceryl tri-[4-phenylbutyrate] as either RAVICTI, HPN-
`
`100, glycerol PBA, glycerol phenylbutyrate, GT4P, or GPB.
`
`
`
`8
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`the dosage of a nitrogen scavenging drug in a patient with a nitrogen retention
`
`disorder. (The ’278 Patent at Abstract.) I understand that the ’278 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 ’278 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,
`
`4, 8 and 12 are the independent claims. Claims 4, 8 and 12 each comprised a
`
`preamble, which describes the intended type of patients for the claimed methods.
`
`For example, claim 4 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 upper limit
`of normal 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 upper limit of
`normal for plasma ammonia level; and
`
`
`
`9
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate], 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, and
`wherein the method further comprises restricting the subject's dietary
`protein intake.
`17. Claim 8 is similar to claim 4 except that the method further comprises
`
`monitoring the subject's ammonia levels if the glyceryl tri-[4-phenylbutyrate] is not
`
`being adequately digested by the subject's pancreatic lipases. The dependent
`
`claims that depend from claims 4 and 8 also add the same limitations to both
`
`claims 4 and 8. Therefore, claims 4 and 8 are similar.
`
`18. Claim 1 is an independent claim and recites:
`
`A method of treating a subject with a urea cycle disorder, the method
`comprising: administering to the subject in need thereof glyceryl tri-
`[4-phenylbutyrate] in an amount sufficient to produce a fasting plasma
`ammonia level that is less than half the upper limit of normal for
`plasma ammonia level.
`Unlike claims 4 and 8, claim 1 is not limited to patients who have previously been
`
`administered glyceryl tri-[4-phenylbutyrate] or to dose adjustment.
`
`19. Claim 12 is an independent claim and recites:
`
`A method for adjusting the dosage of glyceryl tri-[4-phenylbutyrate]
`in a subject being treated for a urea cycle disorder who has previously
`
`
`
`10
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`been administered an initial dosage of sodium 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;
`(b) comparing the fasting plasma ammonia level to the upper limit of
`normal for plasma ammonia level;
`(c) administering an initial dosage of glyceryl tri-[4-phenylbutyrate],
`wherein the initial dosage is determined by the amount of the initial
`dosage of sodium phenylbutyrate, and
`(d) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate],
`wherein the adjusted dosage is greater than the initial dosage of
`glyceryl tri-[4-phenylbutyrate] if the fasting plasma ammonia level is
`greater than half the upper limit of normal for plasma ammonia level.
`Unlike Claims 4 and 8, claim 12 is limited to patients who have previously been
`
`administered sodium phenylbutyrate. In addition, the claim further requires that the
`
`initial dose of glyceryl tri-[4-phenylbutyrate] is determined by the amount of the
`
`initial dose of sodium phenylbutyrate.
`
`20. Claim 2 depends from claim 1 and further requires the upper limit of
`
`normal for plasma ammonia level to be 35 µmol/L.
`
`21. Claim 3 depends from claim 1 and further requires the adjusted
`
`dosage of glyceryl tri-[4-phenylbutyrate] be administered orally.
`
`
`
`11
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`22. Claims 5, 9 and 13 depend from claims 4, 8 and 12, respectively, and
`
`further require 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.
`
`23. Claims 6, 10 and 14 depend from claims 4, 8 and 12, respectively, and
`
`further require the initial dosage of glyceryl tri-[4-phenylbutyrate] to be
`
`administered orally.
`
`24. Claims 7, 11 and 15 depend from claims 4, 8 and 12 respectively, and
`
`further require
`
`the adjusted dosage of glyceryl
`
`tri-[4-phenylbutyrate]
`
`is
`
`administered orally.
`
`25. The ’278 Patent marks the fourth 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.
`
`26. The ’278 Patent claims contain trivial differences from the ’215
`
`Parent Patent:
`
`
`
`12
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`Unpatentable ’215 Parent Patent,
`Exemplary Claim 1
`
`’278 Patent,
`Exemplary Claims 4, 8 and 122
`
`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] {sodium
`phenylbutyrate} and who has a
`fasting plasma ammonia level less
`than the upper limit of normal for
`plasma ammonia level, the method
`comprising:
`
`measuring a fasting blood ammonia
`level for the subject;
`
`measuring a fasting plasma
`ammonia level for the subject;
`
`comparing the fasting blood
`ammonia level to the upper limit of
`normal for blood ammonia level;
`and
`
`comparing the fasting plasma
`ammonia level to the upper limit of
`normal for plasma ammonia level;
`and
`
`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.
`
`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,
`and {administering an initial
`dosage of [GPB], wherein the
`
`
`2 Bolded text found in curly brackets is found in claim 4 only. Bolded and
`
`italicized text in curly brackets is only found in claim 8. Bolded and underlined
`
`text in curly brackets is found only in claim 12.
`
`
`
`13
`
`

`

`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`Unpatentable ’215 Parent Patent,
`Exemplary Claim 1
`
`
`
`’278 Patent,
`Exemplary Claims 4, 8 and 122
`initial dosage is determined by the
`amount of the initial dosage of
`sodium phenylbutyrate}
`
`wherein the method further
`comprises restricting the subject's
`dietary protein intake {wherein the
`method further comprises
`monitoring the subject’s ammonia
`levels if the [GPB] is not being
`adequately digested by the subject’s
`pancreatic lipases}
`{d) administering an adjusted
`dosage of [GPB], wherein the
`adjusted dosage is greater than the
`initial dosage of {GPB} if the
`fasting plasma ammonia level is
`greater than half the upper limit of
`normal for plasma ammonia
`level.}.
`
`
` The ’278 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 ’278 Patent require that the subject have “a fasting plasma ammonia
`
`level less than the upper limit of normal.” The same prior art that
`14
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`
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`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`invalidated the ’215 Parent Patent claims discloses initial and adjusted
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`doses of nitrogen scavenging drugs in UCD patients having fasted plasma
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`ammonia levels less than the upper limit of normal.
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` The ’278 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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` The ’278 Patent Claims recite a method of treating UCD that includes
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`restricting the subject’s dietary protein intake. The same prior art that
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`invalidated the ’215 Parent Patent) claims, such as Fernandes (Fernandes
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`at 218, 219) and the ’859 Publication (’859 Publication at [0083]),
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`disclose these additional steps.
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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 ’278 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 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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` The ‘278 Patent Claims recite a method of treating UCD that include the
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`monitoring of ammonia levels if glyceryl tri-[4-phenylbutyrate] is not
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`being adequately digested by the subject’s pancreatic lipases. The idea
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`that lipases are required for activation of glyceryl tri-[4-phenylbutyrate]
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`was well known. The original patent covering the compound glyceryl tri-
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`[4-phenylbutyrate] described that “[p]ancreatic lipase is able to hydrolyse
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`the triglyceride compounds of the invention to produce glycerol and
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`phenylalkanoic acids or phenylalkenoic acids.” (’979 patent at 4:66-5:2;
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`see also ’859 Publication at [0022]; Lee at 224.). Phenylbutyrate is the
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`phenylalkanoic acid released from glyceryl tri-[4-phenylbutyrate] after
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`hydrolysis. This concept is also directly referenced in the discussion of
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`glyceryl tri-[4-phenylbutyrate] by prior art. McGuire and colleagues
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`stated that their “findings are consistent with the gradual release of PBA
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`by pancreatic lipases when delivered in the form of glyceryl tri-[4-
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`phenylbutyrate] compared with NaPBA, and the absence of intact
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`glyceryl tri-[4-phenylbutyrate] in blood or urine suggests that intestinal
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`breakdown of glyceryl tri-[4-phenylbutyrate] is complete.” (McGuire at
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`2084.)
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` The ’278 Patent Claims recite a method of treating UCD wherein the
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`subject was previously administered sodium phenylbutyrate and then
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`16
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`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`switched to glyceryl tri-[4-phenylbutyrate]. It was well-known that UCD
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`subjects can be switched from sodium phenylbutyrate to glyceryl tri-[4-
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`phenylbutyrate]. (See generally Lee and the ’859 Publication.)
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`27.
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`In summary, the ’278 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.
`28.
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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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`29. 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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`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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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 illustrate how the
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`urea cycle works:
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`18
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`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`30.
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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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`19
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`Inter Partes Review of USPN 9,254,278
`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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`31. 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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`20
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`Inter Partes Review of USPN 9,254,278
`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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`32. 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. A person of ordinary skill in the art would have
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`been concerned that patients in whom pancreatic lipase activity was low would
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`21
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`Inter Partes Review of USPN 9,254,278
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
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`convert glyceryl tri-[4-phenylbutyrate] to PBA at too slow a rate to provide clinical
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`efficacy. Accordingly, a POSA would have monitored such patients’ plasma
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`ammonia levels closely, to ensure that the administered doses of glyceryl tri-[4-
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`phenylbutyrate] was sufficient to provide a therapeutic nitrogen-scavenging effect.
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`33. There is no known consequence of having low levels of plasma
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`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.
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`C.
`34.
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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 ’278 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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`35.
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`It was well-known before the priority date of the ’278 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 10;
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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, b