`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner.
`
`_____________________
`
`Case IPR: Unassigned
`U.S. Patent No. 9,561,197
`_____________________
`
`DECLARATION OF NEAL SONDHEIMER, M.D., Ph.D.
`
`EXHIBIT 1002
`
`

`

`
`
`
`
`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`TABLE OF CONTENTS
`Overview .......................................................................................................... 1
` My background and qualifications .................................................................. 3
` List of documents considered in formulating my opinion .............................. 6
` Person of ordinary skill in the art .................................................................... 8
`State of the art before April 20, 2012 .............................................................. 9
`
`The urea cycle ....................................................................................... 9
` Nitrogen scavenging drugs .................................................................. 12
`
`PAA was well-known to cause neurotoxicity when present at
`excessive levels in plasma. .................................................................. 15
`PAA-to-PAGN conversion was known to be saturable. ..................... 16
`Determining a therapeutic window was well-known in the art
`by April 20, 2012. ................................................................................ 20
` The ’197 patent and its claims ....................................................................... 21
`
`Independent claims 1 and 2 ................................................................. 21
`
`Claim construction .............................................................................. 22
` The basis of my analysis with respect to obviousness .................................. 25
` A person of ordinary skill in the art reading Lee, Praphanphoj,
`Thibault, and Carducci would have had a reason and the
`knowledge to arrive at the methods of claims 1 and 2 with a
`reasonable expectation of success. ...................................................... 26
`
`A person of ordinary skill in the art would have had a
`reason to administer GPB. ........................................................ 27
`A person of ordinary skill in the art would have had a
`reason to determine a patient’s PAA:PAGN plasma ratio........ 28
`
`
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`A person of ordinary skill in the art would have had a
`reason to adjust a patient’s dose of GPB based on the
`patient’s PAA:PAGN plasma ratio being outside a target
`range of 1 to 2 or 2.5. ................................................................ 35
`A person of ordinary skill in the art would have had a
`reasonable expectation of success in practicing the
`methods of claims 1 and 2. ....................................................... 36
` Objective indicia of non-obviousness ................................................. 38
`
`No unexpectedly superior results .............................................. 39
`
`No long-felt, but unmet need or failure of others ..................... 40
`
`No teaching away ...................................................................... 41
` Conclusion ..................................................................................................... 41
`
`
`ii
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`I, Neal Sondheimer, do hereby declare as follows:
`
`
`
`Overview
`1.
`I am over the age of 18 and otherwise competent to make this
`
`declaration. I am a medical doctor with specialties in Pediatrics, Clinical Genetics
`
`and Clinical Biochemical Genetics. 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 Inter Partes Review (“IPR”) proceeding or the content of my
`
`opinions. I am not employed by, nor receiving grant support from Par
`
`Pharmaceutical, Inc. (“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. 9,561,197 (“the ’197
`
`Patent”) (EX1001) and other documents that are exhibits to Par’s Petition, and to
`
`provide my opinions on what those documents disclose. I understand that the ’197
`
`patent issued on February 7, 2017 and resulted from U.S. Application No.
`
`13/610,580, filed on September 11, 2012, which claims the benefit of U.S.
`
`Provisional Application No. 61/636,256, filed on April 20, 2012. I understand
`
`that, based on that April 20, 2012 date, the earliest possible date to which the ’197
`
`1
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`

`

`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`patent may claim priority is April 20, 2012. I have been asked to provide my
`
`analysis of the ’197 patent based on prior art and the knowledge in the art before
`
`April 20, 2012. I also understand that the face page of the ’197 patent states that
`
`the ’197 patent is currently assigned to Horizon Therapeutics, LLC (“Horizon”).
`
`4.
`
`I have also relied upon my experience in the relevant art and
`
`considered the viewpoint of a person of ordinary skill in the art before April
`
`20, 2012.
`
`5.
`
`Independent claims 1 and 2 of the ’197 patent generally recite a
`
`method of treating a subject with a urea cycle disorder (“UCD”) comprising
`
`administering to the subject a dose of the nitrogen scavenging drug glyceryl tri-[4-
`
`phenylbutyrate] (“GPB”) in an amount effective to achieve a specific plasma ratio
`
`of phenylacetic acid (“PAA”)1 and phenylacetylglutamine (“PAGN”), if the
`
`subject’s PAA:PAGN plasma ratio is outside a specific range.
`
`
`1 The ’197 patent defines PAA as “phenylacetic acid.” (EX1001, 2:4-10, 2:38-55.)
`
`A person of ordinary skill in the art would have understood that “phenylacetic
`
`acid” includes phenylacetic acid or its conjugate base, phenylacetate. As used
`
`herein, PAA means either phenylacetic acid or phenylacetate. Similarly, a person
`
`of ordinary skill in the art would understand that “phenylbutyric acid”
`
`2
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`

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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`Broadly, this declaration sets forth my opinion that claims 1 and 2 of
`
`6.
`
`the ’197 patent would have been obvious over the prior art. First, this declaration
`
`sets forth my opinion that a person of ordinary skill in the art would have had a
`
`reason to arrive at the subject matter recited in claims 1 and 2, with a reasonable
`
`expectation of success, by combining the disclosures of Lee (EX1004),
`
`Praphanphoj (EX1005), Thibault (EX1006), Carducci (EX1007), and a person of
`
`ordinary skill in the art’s knowledge of the prior state of the art, as discussed in this
`
`declaration below.
`
`7.
`
`Second, this declaration describes how, in reaching my conclusions
`
`regarding obviousness, I have considered potential objective indicia of
`
`nonobviousness and concluded that there are none that I am aware of that would
`
`support a claim of nonobviousness.
`
` My background and qualifications
`8.
`A copy of my curriculum vitae is attached as EX1003.
`
`9.
`
`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
`
`
`encompasses either phenylbutyric acid or its conjugate base, phenylbutyrate. As
`
`used herein, PBA means either phenylbutyric acid or phenylbutyrate.
`
`3
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`2002. I also completed a postdoctoral fellowship at the University of Pennsylvania
`
`in Genetics in 2009.
`
`10.
`
`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 Associate
`
`Professor of Paediatrics and Molecular Genetics at The University of Toronto
`
`School of Medicine.
`
`11.
`
`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.
`
`12. Among my research interests are the genetic causes, diagnosis and
`
`treatment of UCDs. 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 a disorder that
`
`included a urea cycle defect (See EX1003, 9 (citing Deardorff et al., MGM, 2008).)
`
`In 2013, I was co-author of a study of methods for emergency management of
`
`neonates with UCDs (see id., 8 (citing Spinale et al., Peds. Neph., 2013).) Also in
`
`2013, I was the senior author on a study for early detection methods for infants
`
`4
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`with UCDs (see id. (citing 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.
`
`13. 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 April 20, 2012. 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 April 20, 2012.
`
`14.
`
`In my clinical practice, I have in the past treated patients with
`
`Ammonul, sodium PBA (both as Pheburane and Buphenyl), GPB, and sodium
`
`benzoate.2 I continue to use these medications today. I have adjusted PAA-
`
`prodrug dosages for various reasons including ammonia control, alterations in diet,
`
`and weight gain.
`
`
`2 I will collectively refer to Ammonul, sodium phenylbutyrate and GPB as “PAA-
`
`prodrugs.” PAA-prodrugs are drugs that the body metabolizes into PAA upon
`
`administration. Some references will refer to glyceryl tri-[4-phenylbutyrate] as
`
`either RAVICTI, HPN-100, glycerol PBA, glycerol phenylbutyrate, GT4P, or
`
`GPB.
`
`5
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`15. 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 herein.
`
` List of documents considered in formulating my opinion
`16.
`In formulating my opinion, I have considered all documents cited
`
`herein, including the following:
`
`Exhibit
`No.
`
`1001
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`Description
`
`Scharschmidt, B. and Mokhtarani, M., U.S. Patent No. 9,561,197 (filed
`Sept. 11, 2012; issued Feb. 7, 2017) (“the ’197 patent”)
`Lee, B., 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,
`MOLECULAR GENETICS METABOLISM, 100: 221-28 (2010) (“Lee”)
`Praphanphoj, V., et al., Three Cases of Intravenous Sodium Benzoate
`and Sodium Phenylacetate Toxicity Occurring in the Treatment in the
`Treatment of Acute Hyperammonaemia, J. INHERIT. METAB. DIS., 23:
`129-36 (2000) (“Praphanphoj”)
`Thibault, A., et al., A Phase I and Pharmacokinetic Study of
`Intravenous Phenylacetate in Patients with Cancer, CANCER
`RESEARCH, 54: 1690-94 (1994) (“Thibault”)
`Carducci, M.A., et al., A Phase I Clinical and Pharmacological
`Evaluation of Sodium Phenylbutyrate on an 120-h Infusion Schedule,
`CLINICAL CANCER RESEARCH, 7: 3047-55 (2001) (“Carducci”)
`Msall, M., et al., Neurologic Outcome in Children with Inborn Errors
`of Urea Synthesis — Outcome of Urea-Cycle Enzymopathies, NEW
`ENGLAND JOURNAL OF MEDICINE, 310: 1500-05 (1984)
`File History for U.S. Patent No. 9,561,197
`
`6
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`

`

`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`Exhibit
`No.
`
`Description
`
`1010
`
`1011
`
`MacArthur, R.B., et al., Pharmacokinetics of Sodium Phenylacetate
`and Sodium Benzoate Following Intravenous Administration As Both a
`Bolus and Continuous Infusion to Healthy Adult Volunteers,
`MOLECULAR GENETICS AND METABOLISM, 81: S67-S73 (2004)
`McGuire, B.M., et al., Pharmacology and Safety of Glycerol
`Phenylbutyrate in Healthy Adults and Adults with Cirrhosis,
`HEPATOLOGY, 51: 2077-85 (2010)
`1012 Buxton, I.L.O., Goodman & Gilman’s: The Pharmacological Basis of
`Therapeutics, 1-39 (L. Brunton et al., eds., 11th ed. 2006)
`1013 Ravicti Product Label, Revised: Apr. 2017
`1014 Buphenyl Label, Revised: Apr. 2008
`1015 Ammonul Label, Revised: Feb. 2005
`1017 Feillet, F. and Leonard, J.V., Alternative Pathway Therapy for Urea
`Cycle Disorders, J. INHER. METAB. DIS., 21: 101-11 (1998).
`1018 Fernandes, J., et al., Inborn Metabolic Diseases Diagnosis and
`Treatment, 214-222 (J. Fernandes et al., eds., 3d ed. 2000)
`1019 Scientific Discussion for Ammonaps, EMEA, 1-12 (2005)
`1020 Scharschmidt, B., U.S. Patent Appl. Pub. No. 2010/0008859 (filed Jan.
`7, 2009; published Jan. 14, 2010)
`1021 Scharschmidt, B., U.S. Patent Appl. Pub. No. 2012/0022157 (filed
`Aug. 27, 2009; published Jan. 26, 2012)
`1022 Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for
`Waste Nitrogen Excretion, PEDIATRIC RESEARCH, 29: 147-50 (1991)
`1023 Brusilow, S.W., U.S. Patent No. 5,968,979 (filed Jan. 13, 1998; issued
`Oct. 19, 1999)
`Yang, D., et al., Assay of the Human Liver Citric Acid Cycle Probe
`Phenylacetylglutamine and of Phenylacetate in Plasma by Gas
`Chromatography-Mass Spectrometry, ANALYTICAL BIOCHEMISTRY,
`212: 277-82 (1993)
`
`1024
`
`7
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`Exhibit
`No.
`
`Description
`
`1025
`
`1026
`
`Yamaguchi, M. and Nakamura, M., Determination of Free and Total
`Phenylacetic Acid in Human and Rat Plasma by High-Performance
`Liquid Chromatography with Fluorescence Detection, CHEM. PHARM.
`BULL., 35: 3740-45 (1987)
`Laryea, M.D., et al., Simultaneous LC-MS/MS Determination of
`Phenylbutyrate, Phenylacetate Benzoate and their Corresponding
`Metabolites Phenylacetylglutamine and Hippurate in Blood and
`Urine, J. INHERITED METABOLIC DISEASES, 33: S321-S328 (2010)
`PubChem Open Chemistry Database, Compound Summary for CID
`999, Phenylacetic Acid, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/phenylacetic_acid (last
`accessed August 16, 2018)
`PubChem Open Chemistry Database, Compound Summary for CID
`92258, Phenylacetylglutamine, available at
`https://pubchem.ncbi.nlm.nih.gov/compound/Phenylacetylglutamine
`(last accessed August 16, 2018)
`Buphenyl Approval Information, available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=
`overview.process&ApplNo=020573 (last accessed August 16, 2018)
`Ammonul Approval Information, available at
`https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=
`overview.process&ApplNo=020645 (last accessed August 16, 2018)
`1032 Biochemistry, 426-59 (Reginald H. Garrett & Charles M. Grisham,
`eds., 2nd ed. 1999)
`
`1028
`
`1029
`
`1030
`
`1031
`
` Person of ordinary skill in the art
`17.
`I understand that one of the relevant factors in this proceeding is the
`
`level of skill in the pertinent art. In my opinion, a person of ordinary skill in the art
`
`as of April 20, 2012 (the date of the alleged invention) would have been a
`
`physician with an M.D. degree and specialized training in the diagnosis and
`
`treatment of inherited metabolic disorders, such as UCDs and other nitrogen
`
`8
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`retention disorders. Today, such a person may have post-graduate training to
`
`fulfill the requirements of the American Board of Medical Genetics and Genomics
`
`in the disciplines of Clinical Genetics, Clinical Biochemical Genetics, or Medical
`
`Biochemical Genetics. A person of ordinary skill in the art would have easily
`
`understood the prior art references referred to herein and would have been capable
`
`of drawing the inferences herein from them.
`
`
`
`State of the art before April 20, 2012
`18. Before April 20, 2012, the state of the art included the teachings
`
`provided by the references discussed in this Declaration. Additionally, a person of
`
`ordinary skill in the art, based on then-existing literature, would also have had
`
`general knowledge of the diagnostic methods used to treat UCDs, as well as
`
`various courses of treatment of UCDs.
`
` The urea cycle
`19.
`In the human body, the urea cycle is the major pathway for the
`
`removal of waste nitrogen. (EX1017, 101.) Enzymes and transporters within the
`
`urea cycle synthesize urea from ammonia, which is then excreted in urine to
`
`remove excess nitrogen. (Id., 101-02; EX1004, 221.) In a patient with a UCD, an
`
`enzyme or transporter supporting or participating in the urea cycle is deficient and
`
`the patient has an impaired ability to generate urea and remove waste nitrogen.
`
`(EX1001, 1:19-47; EX1004, 221; EX1017, 101-03; EX1018, 215-17.) UCDs
`
`9
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`

`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`occur in newborn, child, and adult patients often due to genetic conditions.
`
`(EX1017, 102-03; EX1018, 215-17.) The inability to remove excess nitrogen in
`
`these patients can lead to elevated ammonia (hyperammonemia), which in turn can
`
`lead to lethargy, brain damage, and death. (EX1008, 1500; EX1019, 1.)
`
`20. Nitrogen enters the body principally in the amino acids in dietary
`
`protein. Excess amino acids – amino acids that are beyond those necessary for
`
`ordinary bodily function and not used for endogenous protein synthesis – are
`
`broken down and form pools of free amino acids, including glutamine and glycine.
`
`(EX1018, 214.) Ammonia is liberated during the breakdown of free amino acids
`
`and its nitrogen is incorporated into urea through the sequential actions of
`
`carbamoyl phosphate synthetase and the enzymes of the urea cycle. (EX1018, 214,
`
`216-17; EX1017, 101.) Urea is then excreted in urine. (EX1018, 214; EX1017,
`
`102.) Thus, each urea molecule excreted represents the removal of two atoms of
`
`nitrogen. The two figures below describe how the urea cycle works:
`
`
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`10
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`
`
`21.
`
`In a patient with a UCD, a defect is present in either a required
`
`enzyme of the urea cycle itself or in a transporter that supports urea cycle function.
`
`(EX1004, 221; EX1017, 101-03; EX1018, 215-17.) In these patients, excess
`
`dietary amino acids are converted into ammonia that accumulates, causing toxicity
`
`(EX1019, 5), as shown in the unshaded pathway below:
`
`11
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`
`
`
`22. There is no known consequence of having low levels of plasma
`
`ammonia. Physicians use therapeutically acceptable doses of nitrogen scavenging
`
`medications to achieve normal plasma ammonia levels to reduce the risk of a
`
`hyperammonemic event. In doing so, physicians attempt to strike a balance
`
`between required protein intake and nitrogen excretion to achieve a desired amount
`
`of ammonia control. If the dose of nitrogen scavenging drug, such as GPB, was
`
`less effective than desired for controlling a patient’s ammonia levels, then the dose
`
`of the nitrogen scavenging drug could be appropriately adjusted.
`
` Nitrogen scavenging drugs
`23. Along with dietary modifications, medications that are metabolized to
`
`PAA (including GPB) provide an alternative mechanism for the clearance of
`
`glutamine in the form of PAGN, which contains two moles of nitrogen, like urea.
`
`12
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`(EX1014, 1; EX1018, 219; EX1020, ¶¶22-23.) The unshaded pathway below
`
`describes this process:
`
`
`
`Unlike PAA, benzoate operates as a nitrogen scavenging drug by being conjugated
`
`with glycine to form hippurate, which is excreted in urine. Through this reaction
`
`to form hippurate, benzoate results in the excretion of one mole of nitrogen per
`
`mole of benzoate.
`
`24. PAA was well-known to have an offensive odor. (EX1022, 147.)
`
`Due to this drawback, Horizon developed sodium PBA (“NaPBA”), which is a
`
`prodrug of PAA, and marketed it under the brand name Buphenyl. (EX1014.)
`
`NaPBA was known to rapidly metabolize to PAA after its administration. (Id., 1.)
`
`NaPBA, however, was known to have several drawbacks. For example, UCD
`
`patients typically ingested forty tablets of 0.5 g NaPBA per day. (EX1023, 3:48-
`
`51.) As such, these patients would intake approximately 2363 mg of sodium per
`
`13
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`

`

`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`day, on top of the sodium contained in the patient’s dietary intake. (EX1004, 222.)
`
`Dietary guidelines recommended a maximum daily sodium intake of 2300 mg/day
`
`in the general population and of 1500 mg/day in individuals with hypertension.
`
`(Id.)
`
`25. GPB is a pre-prodrug of PAA comprised of three molecules of PBA
`
`esterified to a molecule of glycerol. (EX1004, 222; EX1020, ¶23.) GPB is
`
`metabolized by pancreatic lipases to produce three moles of PBA per mole of
`
`GPB. (EX1004, 222, 224; EX1023, 4:66-5:2.) PBA is further metabolized by
`
`beta-oxidation to produce PAA. (EX1004, 222; EX1013, 12; EX1019, 6.) PAA-
`
`prodrugs greatly simplify the process of balancing dietary intake of nitrogen with
`
`bodily demand in patients with UCDs. They act prior to the release of free
`
`ammonia, shunting it away from its formation.
`
`26. GPB was known to overcome the limitations of PBA and PAA by
`
`(1) providing the same amount of active ingredient in a smaller dose (GPB four
`
`teaspoonfuls instead of forty tablets); (2) decreasing the amount of sodium intake
`
`for patients; (3) avoiding PBA’s unpleasant taste; and (4) providing the active
`
`component of the drug at a more constant level. (EX1020, ¶65; EX1023, 3:48-55;
`
`EX1004, 222, 224.)
`
`14
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`PAA was well-known to cause neurotoxicity
`when present at excessive levels in plasma.
`27. By April 20, 2012, it was well-known that at a certain plasma
`
`
`
`concentration, PAA begins to cause neurotoxicity. For example, Thibault
`
`disclosed that cancer patients receiving a continuous infusion of PAA presented
`
`with PAA-induced neurotoxicity that reversed upon discontinuation, stating:
`
`Drug-related toxicity was clearly related to the serum
`phenylacetate concentration. Three episodes of CNS
`toxicity, limited to confusion and lethargy and often
`preceded by emesis, occurred in patients treated at dose
`levels 3 and 4. They were associated with drug
`concentrations of 906, 1044, and 1285 μg/mL (1078 ± 192
`μg/mL), respectively.
`(EX1006, 1693.)
`
`28. Similarly to Thibault, Praphanphoj disclosed fatal PAA-induced
`
`toxicity in two UCD patients that received inadvertent overdoses of PAA.
`
`(EX1005, Summary, 130-33.) Praphanphoj reports that one of the patients that
`
`died had PAA values that peaked at a level of 9.07 mM, i.e., 1235 µg/mL3, at 9
`
`hours post-infusion and that ranged from 7.59 to 8.16 mM, i.e., 1026.4 to
`
`
`3 Praphanphoj reports its PAA values in mmol/L. The molecular weight of PAA is
`
`136.15 g/mol. (EX1028, 1.) Praphanphoj’s values have been converted to µg/mL,
`
`herein.
`
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`1111 µg/mL, at 13 to 19 hours post-infusion, before dropping to 1.79 mM, i.e.,
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`243.7 µg/mL, after discontinuation of PAA administration. (Id., Table 1.)
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`29. Labels for Buphenyl (NaPBA) and Ammonul (PAA and benzoate)
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`also provide warnings about PAA-induced toxicity. (EX1014, 3-4; EX1015, 8.)
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`The Buphenyl label states: “Neurotoxicity was reported in cancer patients
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`receiving intravenous phenylacetate, 250-300 mg/kg/day for 14 days, repeated at
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`4-week intervals.” (EX1014, 4.) The Ammonul label similarly states:
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`“Neurotoxicity was reported in cancer patients receiving intravenous
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`phenylacetate, 250-300 mg/kg/day for 14 days, repeated at 4-week intervals.
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`Manifestations were predominantly somnolence, fatigue, and lightheadedness,
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`with-less frequent headaches, dysgeusia, hypoacusis, disorientation, impaired
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`memory, and exacerbation of a pre-existing neuropathy.” (EX1015, 8.) And it
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`cites to Thibault for this statement. (Id.)
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`PAA-to-PAGN conversion was known to be saturable.
`30. PAA’s conversion to PAGN in the body was also well-known to be
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`saturable, by April 20, 2012. For instance, in measuring the pharmacokinetics of
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`PBA administered by infusion, Carducci found that PAA accumulated in one out
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`of four patients administered 76.87 µmol/h/kg PBA and in four out of six patients
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`administered 91.35 µmol/h/kg. (EX1007, 3052.) From this, Carducci determined
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`that “92% of the population would be expected to have Vmax values less than the
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`highest dosing rate in this study, 91.35 µmol/h/kg” and “[i]n any individual whose
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`Vmax is less than his or her drug-dosing rate, PA[A] can be expected to accumulate
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`progressively.”4 (Id.) Carducci also found that PAGN plasma level plateaued at
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`~320 µg/mL5 when PBA was continuously infusion at 515 mg/kg/d. (Id., Fig. 2)
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`As such, Carducci demonstrated that PAA’s conversion to PAGN was saturable.
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`Of note, Carducci reported that the patient whose PAGN plasma level plateaued
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`experienced grade 3 neuro-cortical toxicity that reversed 10-12 hours after
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`discontinuation of PBA dosing. (Id., 3051.)
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`31. Similar to Carducci, Thibault reported on the “saturable
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`pharmacokinetics of phenylacetate.” (EX1006, 1693-94.) For instance, Thibault
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`disclosed the kinetics of PAA is nonlinear and that the Km of PAA, i.e., the
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`concentration at which the conversion of PAA to PAGN is half-maximal, is only
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`105 µg/mL. (EX1006, Abstract, 1692-93; EX1032, 437.) Because this
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`concentration is relevant to the plasma concentrations seen in therapeutic use of
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`4 Vmax represents the maximum rate of an enzymatic reaction. (EX1032, 434-37.)
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`5 Carducci reports his values as µmol/L. The molecular weight of PAGN is 264.3
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`g/mol. (EX1029, 1.) Carducci reports that PAGN plateaued at ~1200-1250
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`µmol/L, i.e., ~317-330 µg/mL.
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`PAA-prodrugs, a person of ordinary skill in the art would recognize the limited
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`ability of PAA to convert to PAGN at higher concentrations.
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`32. Other prior art also pointed to the saturability of PAA-to-PAGN
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`conversion. MacArthur et al. stated that “[t]he clearance of phenylacetate appears
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`to be much slower and, unlike benzoate, clearance can become saturated at the
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`plasma levels attained with doses used to treat hyperammonemia.” (EX1010,
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`S72.)
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`33.
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`In view of the above, a person of ordinary skill in the art would have
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`known about the saturability of the PAA-to-PAGN conversion process, which
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`would have further bolstered concerns about the well-known toxicity of PAA.
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`This is because the saturability of the PAA-to-PAGN conversion process could
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`cause unwanted accumulation of PAA in the body. (EX1006, 1692; EX1032, 436-
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`37.) And further, a person of ordinary skill in the art would have expected PAA’s
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`efficacy in removing waste nitrogen could not be increased once there was
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`saturation of PAA’s conversion to PAGN.
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`34. As such, a person of ordinary skill in the art would have sought to
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`monitor the plasma ratio of PAA to PAGN to (1) make sure PAA-to-PAGN
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`conversion was proceeding at an acceptable rate to avoid neurotoxicity due to PAA
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`buildup and (2) avoid a plateau in PAGN formation that would reduce GPB’s
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`efficacy. To that end, the prior art disclosed “maintaining the plasma levels of
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`phenylacetate and benzoate below the levels associated with toxicity, while
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`providing enough of these scavenging agents to maximize waste nitrogen removal”
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`and also changing the dosing to “lessen the risk of attaining inappropriately high
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`plasma phenylacetate levels, while maximizing its conversion to PAG[N].”
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`(EX1010, S72.) The art further disclosed that “[d]ose optimization will require
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`both plasma and urine measurement of the metabolites, and phenylacetate and
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`benzoate.” (Id., S73.)
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`35. The art also reported methods for determining plasma PAA and
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`PAGN levels. (See generally EX1024; EX1025.) In fact, Laryea et al. stated that
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`“[k]nowledge regarding concentrations of . . . PAA[] and PBA and their
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`metabolite[] . . . PAG[N] in urine and blood is a prerequisite for detailed studies on
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`their metabolism and for pharmacokinetic and evaluation studies.” (EX1026,
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`S322.) Laryea further reported that “individual dosage and therapy optimization
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`are highly important in children with inborn errors of urea synthesis.” (Id.) Laryea
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`also disclosed that his method provided “rapid, accurate, and clinically useful
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`means of monitoring the therapeutic course.” (Id., S327.) A person of ordinary
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`skill in the art, therefore, would have easily known to measure a patient’s plasma
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`PAA:PAGN ratio. And a person of ordinary skill in the art would have had a
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`reason to make such measurements in order to determine GPB’s therapeutic
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`window. In fact, as discussed below, the prior art recommended making such
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`determinations.
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` Determining a therapeutic window was
`well-known in the art by April 20, 2012.
`36. A person of ordinary skill in the art would also have been aware of the
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`concept of the therapeutic window, which is an important principal of medical
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`pharmacology. A commonly used textbook of medical pharmacology, available
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`prior to the earliest priority date and widely used in medical schools defines this
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`term: “a therapeutic window . . . reflect[s] a concentration range that provides
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`efficacy without unacceptable toxicity.” (EX1012, 18 (emphasis in original).) The
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`figure below, graphically depicts this concept and relates the plasma drug
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`concentration (Cp) to the minimum effective concentration (MEC) for both desired
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`and adverse responses.
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`(Id., 19.)
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`Inter Partes Review of USPN 9,561,197
`Declaration of Neal Sondheimer, M.D., Ph.D. (Exhibit 1002)
`37. The text further notes that “[t]he therapeutic goal is to obtain and
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`maintain concentrations within the therapeutic window for the desired response
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`with a minimum of toxicity.” (Id.) Thus, a person of ordinary skill in the art
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`would have been well aware of the core concept of the ’197 patent claims, which
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`merely parrot the well-understood concept that some concentrations of PAA would
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`be undesirably low because of poor effectiveness, some would have been desirable,
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`and some would have been unacceptable due to toxicity.
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` The ’1