`
`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
`_____________________
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,561,197
`UNDER 35 U.S.C. §§ 311-319 AND 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`

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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1 
`GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................. 4 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE ............................................................................... 5 
`  OVERVIEW .................................................................................................... 5 
`POSA ..................................................................................................... 5 
`Scope and Content of the Prior Art Before April 20, 2012 ................... 6 
`The Urea Cycle and UCDs ......................................................... 6 
`Nitrogen Scavenging Drugs ........................................................ 8 
`PAA Was Known to Cause Neurotoxicity At High
`Levels. ....................................................................................... 11 
`PAA’s Conversion to PAGN Was Known to Be
`Saturable. ................................................................................... 14 
`Summary of the ’197 Patent ................................................................ 16 
`Brief Description of the ’197 Patent ......................................... 16 
`The ’197 Patent Claims ............................................................. 16 
`Prosecution Background and Summary of Arguments ............ 17 
`CLAIM CONSTRUCTION .......................................................................... 23 
`The Preambles ..................................................................................... 24 
`“a plasma PAA to PAGN ratio within the target range of 1 to 2”
`and “a plasma PAA to PAGN ratio within the target range of 1
`to 2.5” .................................................................................................. 28 
`IDENTIFICATION OF THE CHALLENGE (37 C.F.R. § 42.104(b)) ........ 31 
`  Ground 1: Claims 1 and 2 Would Have Been Obvious Over
`Lee, Praphanphoj, Thibault, and Carducci. ......................................... 32 
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`Administering GPB to Treat UCD Patients Was Well-
`Known In the Art. ..................................................................... 32 
`A POSA Would Have Had a Reason to Determine a
`Subject’s PAA:PAGN Ratio. .................................................... 33 
`A POSA Would Have Had a Reason to Determine if a
`Subject’s Plasma PAA:PAGN Ratio Was Outside a
`Target Range of 1 to 2 or 2.5 and Adjust the Dose of
`GPB Accordingly. ..................................................................... 40 
`A POSA Would Have Had a Reasonable Expectation of
`Successfully Practicing the Claimed Methods.......................... 42 
`Objective Indicia of Nonobviousness Do Not Weigh In Favor
`of Patentability of Claims 1 and 2. ...................................................... 44 
`No Unexpected Superior Results. ............................................. 45 
`No Long-Felt Need or Failure of Others. ................................. 47 
`No Commercial Success. .......................................................... 48 
`Alleged Copying By Generic Drug Makers Is Irrelevant. ........ 50 
`No Teaching Away. .................................................................. 50 
`  CONCLUSION .............................................................................................. 50 
`  MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................. 51 
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`EXHIBIT LIST
`
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`Exhibit
`Description
`No.
`1001 Scharschmidt, B. and Mokhtarani, M., U.S. Patent No. 9,561,197 (filed
`Sept. 11, 2012; issued Feb. 7, 2017) (“the ’197 patent”)
`1002 Declaration of Neal Sondheimer, M.D., Ph.D.
`1003 Curriculum Vitae of Neal Sondheimer, M.D., Ph.D.
`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)
`1009 File History for U.S. Patent No. 9,561,197
`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)
`
`1010
`
`1011
`
`iii
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`Description
`
`Exhibit
`No.
`1013 Ravicti Product Label, Revised: Apr. 2017
`1014 Buphenyl Label, Revised: Apr. 2008
`1015 Ammonul Label, Revised: Feb. 2005
`1016 Center for Drug Evaluation and Research, NDA No. 203284, Summary
`Review
`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)
`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)
`
`1024
`
`1025
`
`1026
`
`iv
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`Exhibit
`No.
`
`Description
`
`1027
`
`Ravicti Orange Book Entry, available at
`https://www.accessdata.fda.gov/scripts/cder/ob/patent_info.cfm?
`Product_No=001&Appl_No=203284&Appl_type=N (last accessed
`June 19, 2018)
`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
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
`
`
`
`INTRODUCTION
`Pursuant to 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42, Par Pharmaceutical,
`
`Inc. submits this Petition for Inter Partes Review (“IPR”) seeking cancellation of
`
`claims 1 and 2 of U.S. Patent No. 9,561,197 (EX1001) as unpatentable under
`
`35 U.S.C. § 103(a).
`
`In patients with urea cycle disorders (“UCDs”), the clinical benefit of
`
`glyceryl tri-[4-phenylbutyrate] (“GPB”) derives from the ability of GPB to
`
`metabolize into phenylacetic acid (“PAA”)1, which conjugates with nitrogen to
`
`form phenylacetylglutamine (“PAGN”) and replace urea as a vehicle for carrying
`
`waste nitrogen out of the body. (EX1001, 2:58-62.) This conjugation avoids the
`
`buildup of toxic ammonia in patients with defective urea cycle functionality. (Id.)
`
`The challenged claims generally recite methods of administering a dose of
`
`GPB in an amount effective to achieve a specific ratio of PAA to PAGN in the
`
`subject’s plasma, in subjects whose PAA:PAGN plasma ratio is outside a specific
`
`
`1 The ’197 patent defines PAA as “phenylacetic acid.” (EX1001, 2:4-10, 2:38-55.)
`
`A person of ordinary skill in the art (“POSA”) would understand that “phenylacetic
`
`acid” encompasses either phenylacetic acid or its conjugate base, phenylacetate.
`
`(EX1002, ¶5 n.1.) As used herein, PAA means either phenylacetic acid or
`
`phenylacetate.
`
`1
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`range. (Id., 32:9-20.) But in doing so, the ’197 patent merely claims the long-
`
`known concept of a therapeutic window, and is, thus, not inventive.
`
`First, GPB dosages that result in a plasma PAA:PAGN ratio below the low
`
`end of the target range, i.e., PAA:PAGN values <1, were recognized in the art as
`
`being less than effective because the PAA levels need to be sufficiently high in
`
`order to be available for conjugation with glutamine. Second, GPB dosages that
`
`result in a plasma PAA:PAGN ratio above the high end of the target range, i.e.,
`
`PAA:PAGN values >2 (or >2.5), were recognized in the art as being too high
`
`because such PAA levels result in undesirable PAA-dependent toxicity. Therefore,
`
`the doses of GPB that achieve safe and effective amounts of PAA were well-
`
`known in the art.
`
`More particularly, the prior art disclosed every part of the challenged claims.
`
`For instance, GPB was a well-known pro-drug of PAA used to control ammonia
`
`levels in patients with UCDs. GPB was also known to be preferable over the
`
`standard UCD treatment with sodium phenylbutyrate2 (“NaPBA”) because:
`
`(1) GPB provides the same amount of active ingredient in a smaller dose (four
`
`
`2 A POSA would understand that “phenylbutyric acid” refers to phenylbutyric acid
`
`and/or its conjugate base, phenylbutyrate. (EX1002, ¶5 n.1.) As used herein, PBA
`
`refers to phenylbutyric acid and/or phenylbutyrate.
`
`2
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`teaspoonfuls instead of forty tablets); (2) decreases the amount of sodium intake
`
`for patients; (3) avoids the unpleasant taste of NaPBA; and (4) and provides PAA
`
`at a more constant level. Lee (EX1004), for example, disclosed these aspects of
`
`GPB treatment well-before the ’197 patent. Lee also taught that UCD patients
`
`with a mean plasma PAA:PAGN ratio of about 0.52, did not have proper ammonia
`
`control. To that end, prior art such as Praphanphoj disclosed that a patient properly
`
`treated with PAA had an initial PAA plasma level of 462.4 µg/mL that decreased
`
`to 204 µg/mL, resulting in a plasma PAA:PAGN ratio range of 1.7-4.5, with the
`
`initial elevation of PAA:PAGN due to the delayed onset of PAA’s conversion to
`
`PAGN.
`
`Further, high plasma PAA levels were well-known to cause neurotoxicity
`
`and even death. For example, Thibault (EX1006) noted reversible neurotoxicity at
`
`PAA plasma concentrations of 906 µg/mL and higher. And Praphanphoj reported
`
`that two patients died after receiving inadvertent overdoses of PAA that resulted in
`
`plasma PAA values in excess of 1000 µg/mL and plasma PAA:PAGN ratios of
`
`13.7 and 14.4. (EX1005, 130-133.)
`
`Lastly, PAA’s conversion to PAGN was well-known to be saturable, which
`
`leads to PAA buildup and toxicity. For instance, Carducci (EX1007) found that
`
`the maximum PAGN plasma level achieved from continuous infusion of various
`
`dosages of PAA was ~320 µg/mL. Taken together with Thibault’s report of
`
`3
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`toxicity at a PAA plasma level of 906 µg/mL, a POSA would have understood that
`
`PAA toxicity could begin to appear at a plasma PAA:PAGN ratio of around 2.8
`
`due to PAA’s buildup and lack of conversion to PAGN. Thus, a POSA would
`
`have expected the benefit of increasing the dose of GPB would be increased PAA
`
`plasma levels, but that such benefit would become outweighed by PAA’s toxicity
`
`at around the point of saturation of PAA to PAGN conversion.
`
`The challenged claims merely apply known techniques to a known method
`
`of using GPB to treat UCDs, achieving predictable results; as illustrated in this
`
`petition and evidenced by the supporting Declaration of Dr. Neal Sondheimer
`
`(EX1002), an internationally-renowned expert in the genetic causes, diagnosis, and
`
`treatment of UCDs. Each of the challenged claims, therefore, are fatally obvious
`
`under the Supreme Court’s KSR decision and its extensive progeny. KSR Int’l Co.
`
`v. Teleflex Inc., 550 U.S. 398, 416 (2007). Further, no publicly available evidence
`
`of objective indicia of nonobviousness weighs in favor of patentability.
`
`Accordingly, as explained in detail below, Par is reasonably likely to prevail with
`
`respect to each of the challenged claims.
`
` GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Par certifies that the ’197 patent is available for IPR and Par is not barred or
`
`estopped from requesting IPR of any of the challenged claims.
`
`4
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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` STATEMENT OF THE PRECISE RELIEF
`REQUESTED AND THE REASONS THEREFORE
`The Office should institute IPR under 35 U.S.C. §§ 311-319 and 37 C.F.R.
`
`§§ 42.1-.80 and 42.100-42.123, and cancel claims 1 and 2 of the ’197 patent as
`
`unpatentable under pre-AIA 35 U.S.C. § 103(a) for the reasons explained below.
`
`Par’s detailed, full statement of the reasons for relief requested is provided in
`
`Section VI.
`
` OVERVIEW
`
`POSA
`A POSA is a hypothetical person who is presumed to be aware of all
`
`pertinent art, thinks along conventional wisdom in the art, and is a person of
`
`ordinary creativity. With respect to the ’197 patent, a POSA would have been a
`
`physician with an M.D. and specialized training in the diagnosis and treatment of
`
`inherited metabolic disorders, such as UCDs and other nitrogen retention disorders.
`
`(EX1002, ¶17.) Today, such a person may also have post-graduate training to
`
`fulfill the requirements of the American Board of Medical Genetics and Genomics
`
`in Clinical Genetics, Clinical Biochemical Genetics, or Medical Biochemical
`
`Genetics. (Id.)
`
`5
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`Before April 20, 2012,3 a POSA would have been aware of the teachings
`
`provided by the references discussed in this Petition and by Dr. Sondheimer, who
`
`also discusses prior art teachings confirming the general knowledge of a POSA.
`
`See Abbott Labs. v. Andrx Pharm., Inc., 452 F.3d 1331, 1336 (Fed. Cir. 2006)
`
`(stating that a person of ordinary skill possesses the “understandings and
`
`knowledge reflected in the prior art”); see also Randall Mfg. v. Rea, 733 F.3d
`
`1355, 1362 (Fed. Cir. 2013) (“[T]he knowledge of [a person of ordinary skill in the
`
`art] is part of the store of public knowledge that must be consulted when
`
`considering whether a claimed invention would have been obvious”). A POSA,
`
`based on then existing literature, would also have had general knowledge of the
`
`methods used to diagnose and treat UCDs. (EX1002, ¶17.)
`
`
`
`Scope and Content of the Prior Art Before April 20, 2012
`
`The Urea Cycle and UCDs
`Protein is an essential part of everybody’s diet. Most people can consume a
`
`reasonable excess of protein without any adverse health problems. The body
`
`metabolizes dietary protein into amino acids. In healthy people, excess amino
`
`acids (such as glutamine) are metabolized into, among other things, waste nitrogen
`
`
`3 Par does not concede that the ’197 patent is entitled to an effective filing date of
`
`April 20, 2012, rather that it is not entitled to any earlier date.
`
`6
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`in the form of ammonia.4 (EX1017, 101-02; EX1018, 214; EX1002, ¶¶19-20.)
`
`The action of enzymes then processes that ammonia into urea, via the urea cycle.
`
`(EX1017, 101; EX1004, 221; EX1002, ¶19.) The body readily eliminates urea
`
`through urine. (EX1017, 102; EX1002, ¶19.) The following schematic figure
`
`illustrates how the urea cycle contributes to the elimination of ammonia, following
`
`the unshaded pathway:
`
`
`
`(EX1002, ¶20.)
`The urea cycle is the major pathway for the metabolism and excretion of
`
`waste nitrogen. (EX1017, 101; EX1002, ¶19.) UCDs occur in newborn, child, and
`
`adult patients due to deficient enzymes or transporters in the urea cycle, often due
`
`to genetic conditions. (EX1001, 1:19-47; EX1017, 102-03; EX1018, 215-17;
`
`
`4 Excess amino acids refer to amino acids beyond those necessary for ordinary
`
`bodily functions. (EX1002, ¶20.)
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`7
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`EX1002, ¶19.) A breakdown in the urea cycle significantly reduces the body’s
`
`ability to process excess ammonia, leading to elevated plasma ammonia levels and
`
`hyperammonemia. (EX1008, 1500; EX1019, 1; EX1002, ¶¶19, 21.) The
`
`following figure illustrates how a disorder in the urea cycle causes toxic ammonia
`
`to build up in the unshaded pathway:
`
`
`(EX1002, ¶21.) Ammonia results in toxicity to the body’s nerve cells. Thus,
`
`prolonged or severe hyperammonemia can cause lethargy, coma, irreversible brain
`
`defects and death. (EX1008, 1500; EX1019, 1; EX1002, ¶19.)
`
`
`Nitrogen Scavenging Drugs
`In addition to diet modifications, the prior art standard of care was to
`
`administer nitrogen scavenging drugs to patients having UCDs. (EX1014, 1;
`
`EX1018, 219; EX1002, ¶23.) Such drugs were known, and were primarily based
`
`on the archetypical nitrogen scavenging drug, PAA.
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`8
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`PAA and PBA
`In the body, PAA conjugates to glutamine to form PAGN, which can be
`
`easily eliminated through urine. (EX1014, 1; EX1020, ¶22; EX1002, ¶23.) Each
`
`molecule of glutamine converted to PAGN removes two nitrogen atoms that would
`
`form two molecules of toxic ammonia. (EX1020, ¶¶22-23; EX1002, ¶23.)
`
`One drawback of PAA is its offensive odor. (EX1022, 147; EX1002, ¶24.)
`
`Therefore, NaPBA, a prodrug of PAA5, was developed. In 1996, Horizon began
`
`marketing NaPBA under the brand name Buphenyl. (EX1014; EX1002, ¶24.) The
`
`body rapidly metabolizes NaPBA to PAA after its administration. (EX1014, 1;
`
`EX1002, ¶24.) The following figure illustrates this process and how it was known
`
`in the prior art that PAA and PAA-prodrugs, such as NaPBA, remove free
`
`glutamine and thereby reduce the risk of toxic ammonia build-up in a UCD patient:
`
`
`5 PAA-prodrugs are drugs that the body metabolizes into to PAA after
`
`administering the PAA-prodrug to a subject. (EX1002, ¶14 n.2.)
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`(EX1002, ¶23.) NaPBA was also known to have certain drawbacks. (Id., ¶24.)
`
`For instance, NaPBA was typically administered in the form of forty 0.5g tablets
`
`per day. (EX1023, 3:48-51; EX1002, ¶24.) This results in an intake of
`
`approximately 2363 mg of sodium, in addition to the UCD patient’s sodium intake
`
`through his or her diet, which can be excessive in view of the recommended daily
`
`intake of 1500 and 2300 mg/day for sodium in individuals with hypertension and
`
`the general population, respectively. (EX1004, 222; EX1002, ¶24.)
`
`
`GPB
`A few years after development of NaPBA, the pre-prodrug GPB was
`
`developed, a.k.a. HPN-100–the drug recited in the Asserted Claims–which is made
`
`up of three PBA molecules esterified to one glycerol molecule. (EX1004, 222;
`
`EX1020, ¶23; EX1023, 4:66-5:2; EX1002, ¶25.) After GPB administration,
`
`pancreatic lipases cleave the PBA from GPB; the released PBA then metabolizes
`
`into PAA. (EX1004, 224; EX1002, ¶25.) GPB was known to overcome the
`
`limitations of PBA and PAA by (1) providing the same amount of active ingredient
`
`in a smaller dose (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; EX1002, ¶26.)
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`10
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`
`PAA Was Known to Cause Neurotoxicity At High Levels.
`The prior art also disclosed that high plasma levels of PAA resulted in
`
`neurotoxicity and even death. (EX1002, ¶27.) For example, Thibault reported that
`
`following continuous infusions of PAA in cancer patients,6 reversible neurotoxicity
`
`due to PAA accumulation was observed:
`
`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; EX1002 ¶27.) Praphanphoj reported that two patients died after
`
`receiving inadvertent overdoses of PAA that resulted in plasma PAA values in
`
`excess of 1000 µg/mL.7 (EX1005, Summary, Table 1; EX1002, ¶28.)
`
`
`6 As discussed herein, a POSA would expect PAA toxicity in cancer patients and
`
`UCD patients alike. (See Section VI.A.2.; EX1002, ¶60.) As such, PAA toxicity
`
`reported in studies on cancer patients would have been relevant to a POSA
`
`developing a method of dosing GPB to UCD patients that avoids PAA-dependent
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`toxicity. (See Section VI.A.2.; EX1002, ¶60.)
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`7 The PAA and PAGN values reported in Praphanphoj are in units of mmol/L,
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`which have been converted to µg/mL, herein. (EX1002, ¶28 n.3.) The molecular
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`FDA-approved labels for commercially-available, prior art nitrogen
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`scavenging drugs used in UCD patients contained warnings about PAA toxicity.
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`For example, the Buphenyl label states: “Neurotoxicity was reported in cancer
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`patients receiving intravenous phenylacetate, 250-300 mg/kg/day for 14 days,
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`repeated at 4-week intervals.” (EX1014, 3-4; EX1002 ¶29.) The Ammonul label
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`cites to Thibault to report the exact same information. (EX1015, 8; EX1002, ¶29.)
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`In fact, the prior art recommends “maintaining the plasma levels of
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`phenylacetate . . . below the levels associated with toxicity, while providing
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`enough of these scavenging agents to maximize waste nitrogen removal” and also
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`changing the dosing to “lessen the risk of attaining inappropriately high plasma
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`phenylacetate [PAA] levels, while maximizing its conversion to PAG[N].”
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`(EX1010, S72; EX1002, ¶34.)
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`Moreover, a POSA would have understood the concept of the therapeutic
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`window, which is an important principal of medical pharmacology. (EX1002,
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`¶36.) “[A] therapeutic window . . . reflect[s] a concentration range that provides
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`efficacy without unacceptable toxicity.” (EX1012, 18 (emphasis removed);
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`EX1002, ¶36.) This concept is graphically depicted below, which relates the
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`weight of PAA is 136.15 g/mol. (EX1028, 1; EX1002, ¶28 n.3.) The molecular
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`weight of PAGN is 264.3 g/mol. (EX1029, 1; EX1002, ¶30 n.5.)
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`plasma drug concentration (Cp) to the minimum effective concentration (MEC) for
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`both desired and adverse responses. (EX1012, 19; EX1002, ¶36.)
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`As such, a POSA’s “therapeutic goal is to obtain and maintain
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`concentrations within the therapeutic window for the desired response with a
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`minimum of toxicity.” (EX1012, 19; EX1002, ¶37.) Accordingly, the core
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`concept of the ’197 patent claims merely applies the well-understood concept that
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`some concentrations of PAA would be undesirably low because of poor
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`effectiveness, some would have been desirable, and some would have been
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`unacceptable due to toxicity. (EX1002, ¶37.)
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`In addition, the art reported various methods for determining plasma PAA
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`and PAGN levels. (See generally EX1024; EX1025; EX1002, ¶35.) For instance,
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`Laryea et al. taught that “[k]nowledge regarding concentrations of . . . PAA[] and
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`PBA and their metabolite[] . . . PAG[N] in urine and blood is a prerequisite for
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`detailed studies on their metabolism and for pharmacokinetic and evaluation
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`studies.” (EX1026, S322; EX1002, ¶35.) Laryea also disclosed that “individual
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`dosage and therapy optimization are highly important in children with inborn
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`errors of urea synthesis.” (EX1026, S322; EX1002, ¶35.) Further, Laryea
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`concluded that his method provided “rapid, accurate, and clinically useful means of
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`monitoring the therapeutic course.” (EX1026, S327; EX1002, ¶35.) As such, a
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`POSA would have readily been able to measure a patient’s plasma PAA:PAGN
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`ratio and would have had a reason to do so in order to determine GPB’s therapeutic
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`window. (EX1002, ¶¶35-37.)
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`PAA’s Conversion to PAGN Was Known to Be Saturable.
`By April 20, 2012, PAA’s known toxicity would also have been a concern to
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`a POSA because it was known that the metabolic step that converts PAA to PAGN
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`can become saturated, leading to unwanted accumulation of PAA in the body.
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`(EX1002, ¶¶30-33.) For example, MacArthur et al. reported that “[t]he clearance
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`of phenylacetate appears to be much slower and . . . can become saturated at the
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`plasma levels attained with doses used to treat hyperammonemia.” (EX1010, S72;
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`EX1002, ¶32.)
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`Carducci reported PAA accumulation in one out of four patients dosed with
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`PBA at a rate of 76.87 µmol/h/kg and four out of six patients dosed with
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`91.35 µmol/h/kg. (EX1007, 3052; EX1002, ¶30.) And Carducci concluded that
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`“[i]n any individual whose Vmax is less than his or her drug-dosing rate, PA[A] can
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`be expected to accumulate progressively.”8 (EX1007, 3052; EX1002, ¶30.)
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`Carducci further reported that the maximum PAGN plasma level achieved from
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`continuous infusion of 515 mg/kg/d PBA was ~320 µg/mL,9 and PAA’s
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`conversion to PAGN was, thus, saturable. (EX1007, Figure 2; EX1002, ¶30.)
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`Carducci noted that a patient whose PAGN plasma level plateaued experienced
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`grade 3 neuro-cortical toxicity that reversed 10-12 hours after discontinuation of
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`PBA dosing. (EX1007, 3051; EX1002, ¶30.)
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`Thibault also reported the “saturable pharmacokinetics of phenylacetate.”
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`(EX1006, 1693-94; EX1002, ¶31.) In fact, Thibault taught that PAA has nonlinear
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`pharmacokinetics with the Km of PAA, i.e., the concentration at which the
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`conversion of PAA to PAGN is half-maximal, being only 105 µg/mL, showing the
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`limited ability of PAA to convert to PAGN at higher concentrations. (EX1006,
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`Abstract, 1692-93; EX1032, 437; EX1002, ¶31.) A POSA would have, therefore,
`
`recognized the limited ability of PAA to convert to PAGN at higher concentrations
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`because this Km concentration is relevant to the plasma concentrations seen in
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`8 Vmax represents the maximum rate of an enzymatic reaction. (EX1032, 434-37.)
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`9 Carducci reports that PAGN plateaued at ~1200-1250 µmol/L, i.e., ~317-330
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`µg/mL. (EX1007, Figure 2; EX1002, ¶30 n.5.)
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`therapeutic use of PAA-prodrugs. (EX1002, ¶31.) And a POSA would have
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`expected PAA’s efficacy in removing waste nitrogen could not be increased once
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`there was saturation of PAA’s conversion to PAGN. (Id., ¶33.)
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`
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`Summary of the ’197 Patent
`
`Brief Description of the ’197 Patent
`Against this background, Scharschmidt and Mokhtarani filed a patent
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`application, which issued as the ’197 patent on February 7, 2017, providing
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`methods of treating UCDs by measuring a patient’s plasma PAA to PAGN ratio
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`and adjusting the dose of GPB administered to the patient based on that ratio. The
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`’197 patent asserts its earliest priority claim to April 20, 2012. According to the
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`Office’s electronic assignment records, Horizon Therapeutics, LLC (“Horizon”)
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`owns the ’197 patent by assignment.
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`
`The ’197 Patent Claims
`The ’197 patent has two issued claims, each of which is independent.
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`Claim 1 is reproduced below:
`
`A method of treating a urea cycle disorder in a subject
`comprising administering to a subject having a plasma
`PAA to PAGN ratio outside the target range of 1 to 2, a
`dosage of glyceryl tri-[4-phenylbutyrate] (HPN-100)
`effective to achieve a plasma PAA to PAGN ratio within
`the target range of 1 to 2.
`(EX1001, 32:9-14.) Claim 2 is substantially similar to claim 1, except it recites a
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`“target range of 1 to 2.5.” (Id., 32:15-20.)
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`Petition for Inter Partes Review of U.S. Patent No. 9,561,197
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`Prosecution Background and Summary of Arguments
`As originally filed, the application that issued as the ’197 patent contained
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`independent claims generally reciting methods of treating a nitrogen retention
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`disorder by measuring a subject’s plasma PAA and PAGN levels, and determining
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`whether the dosage of a nitrogen scavenging drug needs to be adjusted based on
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`whether the plasma PAA:PAGN ratio falls within a “target range,” which was not
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`numerically defined. (EX1009, 44-46.)
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`After issuing a Restriction Requirement and Horizon electing claims reciting
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`methods of treating UCDs with GPB, the Examiner rejected the claims as obvious
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`over U.S. Patent Appl. Pub. No. 2012/0022157 (EX1021; “Scharschmidt”) in view
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`of McGuire et al. (EX1011). (EX1009, 95-98, 101-102, 601-07.) According to the
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`Examiner, Scharschmidt discloses a method for treating a nitrogen retention
`
`disorder comprising administering a PAA prodrug and measuring urinary PAGN
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`levels, but not measuring PAA or PAGN levels in plasma or calculating a plasma
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`PAA:PAGN ratio. (Id., 602-03.) The Examiner also asserted that McGuire
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`discloses measuring plasma PAA and PAGN after administering a PAA prodrug,
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`and teaches that urinary testing is not as complete and thorough as plasma testing.
`
`(Id., 603.) According