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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`PAR PHARMACEUTICAL, INC.
`Petitioner
`v.
`HYPERION THERAPEUTICS, INC.
`Patent Owner
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,642,012
`PURSUANT TO §§ 35 U.S.C. 311–319 AND 37 C.F.R. § 42
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`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313–1450
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`Table of Contents
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`Page
`
`I.
`II.
`
`INTRODUCTION ........................................................................................... 1
`OVERVIEW .................................................................................................... 1
`A.
`Summary of the ’012 Patent .................................................................. 1
`B.
`Summary of the Prosecution History of the ’012 Patent ...................... 3
`III. BACKGROUND ON THE UREA CYCLE, UREA CYCLE
`DISORDER, AND NITROGEN SCAVENGING DRUGS ........................... 4
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................. 6
`V.
`PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................... 6
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................... 7
`A.
`Real-Parties-in-Interest .......................................................................... 7
`B.
`Related Matters ...................................................................................... 7
`C.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) .................................................... 8
`VII. PERSON OF ORDINARY SKILL IN THE ART .......................................... 8
`VIII. CLAIM CONSTRUCTION ............................................................................ 9
`A.
`Broadest Reasonable Interpretation Standard ....................................... 9
`B.
`Terms of the ’012 Patent ..................................................................... 10
`IX. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) & 42.104(b)) ................. 12
`A. Ground 1: Independent Claims 1 and 8 and Dependent Claims 3, 4,
`7, 10, and 12 Are Obvious under § 103(a) over Brusilow ’91 in
`View of Sherwin and Shiple ................................................................ 15
`1.
`Overview of Prior Art Applied in Ground 1 ............................. 15
`2. Motivation to Combine Art Applied in Ground 1 .................... 16
`3.
`Independent Claim 1 ................................................................. 18
`(a) Determining – Part (a) of Independent Claim 1 ............. 18
`(b) Calculating – Part (b) of Independent Claim 1 ............... 18
`(c) Administering – Part (c) of Independent Claim 1 .......... 23
`
`i
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`

`

`B.
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`Independent Claim 8 ................................................................. 23
`(a) Administering – Part (a) of Independent Claim 8 .......... 23
`(b) Measuring – Part (b) of Independent Claim 8 ................ 24
`(c) Calculating - Part (c) of Independent Claim 8 ............... 24
`(d) Administering – Part (d) of Independent Claim 8 .......... 26
`Dependent Claims 3, 4, 7, 10, and 12 ....................................... 27
`5.
`Ground 2: Dependent Claim 5 Is Obvious under § 103(a) over
`Brusilow ’91 in view of Sherwin, Shiple, and Fernandes ................... 28
`1.
`Overview of Prior Art Applied in Ground 2 ............................. 29
`2. Motivation to Combine Art Applied in Ground 2 .................... 29
`3.
`Dependent Claim 5 ................................................................... 30
`Ground 3: Dependent Claims 2 and 9 Are Obvious under § 103(a)
`over Brusilow ’91 in view of Sherwin, Shiple, and the ʼ647 Patent ... 31
`1.
`Overview of Prior Art Applied in Ground 3 ............................. 31
`2. Motivation to Combine Prior Art Applied in Ground 3 ........... 32
`3.
`Dependent Claims 2 and 9 ........................................................ 33
`D. Ground 4: Dependent Claims 6 and 11 Are Obvious under § 103(a)
`over Brusilow ’91 in view of Sherwin, Shiple, Kasumov, and the
`’979 Patent .......................................................................................... 34
`1.
`Overview of Prior Art Applied in Ground 4 ............................. 34
`2. Motivation to Combine Prior Art Applied in Ground 4 ........... 35
`3.
`Dependent Claims 6 and 11 ...................................................... 35
`Ground 5: Independent Claims 1 and 8 and Dependent Claims 3, 4,
`7, 10, and 12 Are Obvious under § 103(a) over Brusilow ’91 in
`view of Simell ...................................................................................... 36
`Ground 6: Dependent Claims 5 Is Obvious under § 103(a) over
`Brusilow ’91 in view of Simell and Fernandes ................................... 45
`1.
`Overview of Prior Art Applied in Ground 6 ............................. 45
`2. Motivation to Combine Art Applied in Ground 6 .................... 46
`3.
`Dependent Claim 5 ................................................................... 46
`
`C.
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`E.
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`F.
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`4.
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`ii
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`G. Ground 7: Dependent Claims 2 and 9 Are Unpatentable under 35
`U.S.C. § 103(a) as Obvious over Brusilow ’91 in view of Simell,
`and the ʼ647 Patent .............................................................................. 47
`1.
`Overview of Prior Art Applied in Ground 7 ............................. 47
`2. Motivation to Combine Prior Art Applied in Ground 7 ........... 48
`3.
`Dependent Claims 2 and 9 ........................................................ 48
`H. Ground 8: Dependent Claims 6 and 11 are Obvious under 35
`U.S.C. § 103(a) over Brusilow ’91 in view of Simell, Kasumov, and
`the ’979 Patent ..................................................................................... 49
`1.
`Overview of Prior Art Applied in Ground 8 ............................. 50
`2. Motivation to Combine Prior Art Applied in Ground 8 ........... 50
`3.
`Dependent Claims 6 and 11 ...................................................... 51
`Ground 9: Claims 1–4, 7, 9, 10, and 12 Are Obvious under §
`103(a) over Brusilow ’91 ..................................................................... 51
`5.
`Dependent Claims 2 and 9 ........................................................ 59
`Ground 10: Claims 6 and 11 Are Obvious under § 103(a) over
`Brusilow ’91 in view of Kasumov and the ’979 Patent ....................... 59
`CONCLUSION .............................................................................................. 60
`
`J.
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`I.
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`
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`iii
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`X.
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`List of Exhibits
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`Ex. 1001: U.S. Patent No. 8,642,012 to Scharschmidt (“the ’012 patent), filed
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`January 7, 2009, issued February 4, 2014.
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`Ex. 1002: Declaration of Dr. Neal Sondheimer.
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`Ex. 1003: Curriculum vitae of Dr. Neal Sondheimer.
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`Ex. 1004: Reserved.
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`Ex. 1005: Simell, et al.., Waste Nitrogen Excretion Via Amino Acid Acylation:
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`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20
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`Pediatric Research, 1117–1121 (1986). (“Simell”).
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`Ex. 1006: Reserved.
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`Ex. 1007: Reserved.
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`Ex. 1008: Reserved.
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`Ex. 1009: Reserved.
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`Ex. 1010: Reserved.
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`Ex. 1011: Fernandes, Saudubray Berghe (editors), Inborn Metabolic Diseases
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`Diagnosis and Treatment, 219–220 (3d ed. 2000). (“Fernandes”).
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`Ex. 1012: Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for
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`Waste Nitrogen Excretion, 29 Pediatric Research, 147–150 (1991).
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`(“Brusilow ’91”).
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`Ex. 1013: Reserved.
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`iv
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`Ex. 1014: Reserved.
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`Ex. 1015: Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
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`Humans and Rats, 32 Drug Metabolism and Disposition, 10–19
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`(2004). (“Kasumov”).
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`Ex. 1016: Sherwin, et al., The Maximum Production of Glutamine by the Human
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`Body as Measured by the Output of Phenylacetylglutamine, 37 J. Biol.
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`Chem., 113–119 (1919). (“Sherwin”).
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`Ex. 1017: Shiple, et al.., Synthesis of Amino Acids in Animal Organisms. I.
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`Synthesis of Glycocoll and Glutamine in the Human Organism, 44 J.
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`American Chem. Society, 618–624 (1922). (“Shiple”).
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`Ex. 1018: U.S. Patent No. 4,284,647 to Brusilow et al., filed March 31, 1980,
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`issued August 18, 1981 (“the ’647 patent”).
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`Ex. 1019: Reserved.
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`Ex. 1020: Reserved.
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`Ex. 1021: Prosecution History of the ’012 patent.
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`Ex. 1022:
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`Joint Claim Construction filed March 13, 2015 in Eastern District of
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`Texas District Court, Case 2:14-cv-00384.
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`Ex. 1023: Piscitelli, et al., Disposition of Phenylbutyrate and its Metabolites,
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`Phenylacetate and Phenylacetylglutamine, 35 J. Clin. Pharmacol.,
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`368–373 (1995). (“Piscitelli”).
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`Ex. 1024: Reserved.
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`Ex. 1025: Comte, et al., Identification of phenylbutyrylglutamine, a new
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`metabolite of phenylbutyrate metabolism in humans, J. Mass.
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`Spectrom. 2002:37:581–90. (“Comte”).
`
`Ex. 1026: U.S. Patent No. 5,968,979 to Brusilow, filed Feb. 7, 1995, issued Oct.
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`19, 1999 (“the ’979 patent”).
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`Ex. 1027: Collins et al., Oral Sodium Phenylbutyrate Therapy in Homozygous β
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`Thalassemia: A Clinical Trial, 85 Blood 43 (1995). (“Collins”).
`
`
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`
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`vi
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`I.
`
`INTRODUCTION
`Par Pharmaceutical, Inc. (“Petitioner” or “Par”) petitions for Inter Partes
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`Review (“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42 of Claims 1 to 12
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`of U.S. Patent No. 8,642,012 (“the ’012 patent”).1 (Ex. 1001.)
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`II. OVERVIEW
`A.
`Summary of the ’012 Patent
`The ’012 patent is directed to a method of treating a subject with a urea
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`cycle disorder (“UCD”)—an inherited disease causing elevated waste nitrogen
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`levels—by administering prodrugs of phenylacetic acid (“PAA”), a type of
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`nitrogen scavenging drug. The patent describes a way to calculate an effective
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`dosage of the PAA prodrug by measuring urinary phenylacetyl glutamine
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`(“PAGN”), a natural metabolite of PAA prodrugs.
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`PAA prodrugs have been used as nitrogen scavenging drugs to treat UCD
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`for decades, including phenylbutyric acid (“PBA”), sodium phenylbutyrate
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`(“NaPBA”), and glycerol phenylbutyrate (“HPN-100”). The uses of PAA
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`prodrugs to treat UCD are old and not novel.
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`1 The ʼ012 patent was filed on January 7, 2009 and claims benefit to U.S.
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`Provisional Application No. 61/093,234, filed August 29, 2008. It is assigned
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`to Hyperion Therapeutics, Inc. (“Hyperion” or “Patent Owner”).
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`
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`1
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`The ’012 patent purports to disclose a novel method comprising steps of
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`measuring, calculating, determining, and administering. For example, independent
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`claims 1 and 8 comprise the common steps of administering a PAA prodrug,
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`measuring urinary PAGN, calculating an effective dose of PAA prodrug based on a
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`target urinary PAGN, and administering the new dose. These methods were
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`known in the art.
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`The patentee, however, alleges to have discovered an improved calculation
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`of an effective dose of PAA prodrug based on the assumption that a mean
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`conversion of about 60% of the PAA prodrug should be converted to urinary
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`PAGN in a UCD subject. For example, if a treating physician measures urinary
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`PAGN of a UCD subject to be 30%, the physician is supposed to reduce the
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`amount of PAA prodrug by an amount calculated that would produce a mean
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`conversion of about 60%. If she measures the urinary PAGN to be 90%, the
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`physician is supposed to increase the amount of PAA prodrug.2
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`The claims of the ʼ012 patent describe nothing more than what was
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`disclosed and known in the prior art long before August 29, 2008, the earliest
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`2 Example 9 of the ’012 patent, the only example of the claimed calculation,
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`erroneously states this in reverse, which is biologically implausible. (Ex. 1002
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`¶ 17 n. 1.)
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`2
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`possible priority date (“priority date”) of the ʼ012 patent. Accordingly, this
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`Petition should be granted.
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`Summary of the Prosecution History of the ’012 Patent
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`B.
`The application leading to the ’012 patent was filed on January 7, 2009.
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`(Ex. 1001.) The prosecution focused on the percent conversion of PAA prodrug to
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`urinary PAGN. The Applicant originally sought a method wherein the effective
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`dose of PAA prodrug was based on a mean conversion of “about 60% to about
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`75%.” (Ex. 1021 at 3–6 (original claims 6, 12, & 18).) Because the prior art
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`teaches a conversion of 80%, the applicant narrowed the range to a “mean
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`conversion . . . of about 60%.”
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`The U.S. Patent and Trademark Office (“PTO”) issued a notice of allowance
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`on September 30, 2013, primarily based on the Applicant’s data purporting to
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`measure the conversion of a PAA prodrug to PAGN in UCD patients. (Ex. 1021 at
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`718; see id. at 682–83.) The Applicant erroneously characterized the prior art cited
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`by the examiner as assuming 100% conversion (see, e.g., Ex. 1001 at 2:57–59),
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`which the examiner accepted without question, and relied upon to issue the patent.
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`The following is an examiner’s statement of reasons for allowance:
`The closest prior art is considered to be the Brusilow references of
`record. The prior art teaches an about 80% (Brusilow ’91) and about
`92% (Brusilow ’93) prodrug conversion of PAA to urinary PAGN
`when administered to patients having nitrogen retention disorders
`including urea cycle disorder. The prior art assumes a near 100%
`
`3
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`conversion of the drug while applicant has found that only “about
`60%” of the drug is converted. Applicants Declaration filed
`11/12/2012 contains data drawn to an about 60% conversion rate of
`PAA to urinary PAGN as disclosed in the specification, which
`supports applicants disclosed drug conversion in the as filed
`specification, which supports applicants disclosed drug conversion in
`the as filed specification. Applicant discloses that urea cycle disorder
`patients have an “about 60%” mean conversion rate.
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`(Ex. 1021 at 719.)
`
`The “mean conversion of PAA prodrug to urinary PAGN of about 60%”
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`purportedly comes from the Applicant’s measurement of PAA prodrug
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`conversion to PAGN in a number of UCD patients and calculating the mean.
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`(Ex. 1021 at 718–19; see id. at 682–83.) Such data is not included in the ’012
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`patent specification, although the Applicant submitted a declaration during
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`prosecution (discussed infra) reporting 130 measurements from 65 UCD
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`patients purportedly showing a mean conversion of 67%. (Ex. 1021 at 682–83.)
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`As shown below, the steps of the method that the Examiner believed
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`were absent from the prior art were in fact known.
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`III. BACKGROUND ON THE UREA CYCLE, UREA CYCLE
`DISORDER, AND NITROGEN SCAVENGING DRUGS
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`Healthy individuals have an intrinsic capacity to excrete waste nitrogen in
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`the form of urea through the urea cycle at a rate that exceeds the production of
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`4
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`waste nitrogen by the body, and therefore, nitrogen does not normally build up and
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`ammonia does not rise to harmful levels. (Ex. 1018 at 1:10–12.) UCDs occur
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`when enzymes or transporters in the urea cycle are deficient, resulting in the
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`accumulation of waste nitrogen. (Ex. 1018 at 1:16–22, 38–45.) Before and after
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`the priority date of the ʼ012 patent, the treatment options for UCDs included low
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`protein diets (because protein produces waste nitrogen) and the use of nitrogen
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`scavenging drugs. (Ex. 1012 at 147–49.)
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`Nitrogen scavenging drugs promote nitrogen excretion via alternative
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`pathways. (Ex. 1012 at 147–48; Ex. 1011 at 219–20; Ex. 1018 at 1:46–63.) For
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`example, PAA is converted to PAGN by an enzymatic reaction that conjugates
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`PAA to the amino acid glutamine. (Ex. 1012 at 147–48; Ex. 1011 at 219; Ex. 1018
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`at 1:57–61, 64–66, 3:49–53.)3 PAGN is excreted in urine, bypassing the urea
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`cycle. (Ex. 1002 ¶ 21; Ex. 1012 at 147; Ex. 1011 at 219.) Because PAA and its
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`prodrugs (NaPBA, HPN-100) provide the body with an alternate pathway to urea
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`for excretion of waste nitrogen, they are referred to as “alternative pathway
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`medications.” (Ex. 1011 at 219; Ex. 1012 at 147; Ex. 1016 at 113, 116; Ex. 1017
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`at 623; Ex. 1018 at 1:57–61.)
`
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`3 NaPBA and HPN-100 undergo beta oxidation in the body to produce PAA.
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`(Ex. 1012 at 147–48.)
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`5
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`The conversion rate of PAA, PBA, and NaPBA to PAGN has been measured
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`in various clinical settings since at least 1919. For example, as discussed infra,
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`around 50–67% (Sherwin) of administered PAA is converted to urinary PAGN in
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`healthy subjects (Ex. 1016 at 114, 116 (Table I)), and around 51–54% (Simell) in
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`UCD patients. The conversion of PAA prodrug to urinary PAGN exhibits inter-
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`individual variability. (Ex. 1001 at 31:32–34.) Based on the prior art, the person
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`of ordinary skill in the art knew that the conversion of a PAA prodrug to urinary
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`PAGN would fall within the range 53–67% for individuals with UCD. (Ex. 1002
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`¶¶ 27, 51, 58, 96.) Therefore, the ʼ012 patent merely describes well known
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`methods of treating UCD patients.
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`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Petitioner certifies that (1) the ʼ012 patent, issued on February 4, 2014, is
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`available for IPR; (2) Petitioner is not barred or estopped from requesting an IPR
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`on the grounds identified in this Petition; and (3) Petitioner has not filed any
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`complaint relating to the ʼ012 patent. This Petition is filed in accordance with 37
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`C.F.R. § 42.106(a). Concurrently filed herewith is a Power of Attorney and an
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`Exhibit List per 37 C.F.R. §§ 42.10(b) and 42.63(e), respectively.
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`V.
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`PAYMENT OF FEES (37 C.F.R. § 42.103)
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`Petitioner authorizes required fees to be charged to Deposit Acct. 02-1818.
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`6
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`VI. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real-Parties-in-Interest
`Petitioner certifies that Par Pharmaceutical, Inc., with its principal place of
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`business at One Ram Ridge Road, Chestnut Ridge, New York 10977, and
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`Hyperion Therapeutics, Inc., with its principal place of business at 2000 Sierra
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`Point Parkway, Suite 400, Brisbane, California 94005, are the real-parties-in-
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`interest.4
`
`B. Related Matters
`On April 23, 2014, Hyperion filed a complaint in District Court for the
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`Eastern District of Texas (Case No. 14-cv-00384) alleging that Petitioner is
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`infringing two U.S. Patents, including the ’012 patent (“the Texas action”).
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`Hyperion served the complaint on April 29, 2014.
`
` Petitioner is filing
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`contemporaneously a second petition for IPR of Hyperion’s U.S. Patent 8,404,215,
`
`although that patent is not related to the ’012 patent.
`
`
`4 Par Pharmaceutical, Inc. is a wholly owned subsidiary of Par Pharmaceutical
`
`Companies, Inc., which
`
`itself
`
`is a wholly owned subsidiary of Par
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`Pharmaceutical Holdings, Inc., which has no parent corporation and no publicly
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`held company owns 10% or more of the stock of Par Pharmaceutical Holdings,
`
`Inc.
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`7
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`C. Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4))
`
`Lead Counsel
`
`Backup Counsel
`
`Michael J. Freno
`Reg. No. 57,163
`K&L Gates LLP
`925 Fourth Avenue, Suite 2900
`Seattle, WA 98104
`michael.freno@klgates.com
`T: 206.370.7947
`F: 206.623.7022
`
`David H. Silverstein
`Reg. No. 61,948
`Par Pharmaceutical, Inc.
`300 Tice Blvd.
`Woodcliff Lake, NJ 07677
`david.silverstein@parpharm.com
`T: 201.802.4605
`F: 201.802.4600
`
`Sanjay K. Murthy
`Reg. No. 45,976
`K&L GATES LLP
`70 W. Madison Street, Suite 3100
`Chicago, IL 60602
`sanjay.murthy@klgates.com
`T: 312.807.4416
`F: 312.827.8138
`
`Please address all correspondence and service to counsel listed above.
`
`
`
`Petitioner consents to service by email.
`
`VII. PERSON OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the art (“POSA”) is a hypothetical person who
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`is presumed to know the relevant prior art. (See IPR2013-00116 at 9, 37). A
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`POSA has ordinary creativity, is not an automaton, and is capable of combining
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`teachings of the prior art. (Id. (citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
`
`420–21 (2007)).) With respect to the ʼ012 patent, Petitioner submits that a POSA
`
`is a physician or scientist with a Ph.D. or M.D. degree and specialized training in
`
`8
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`the diagnosis or treatment of inherited metabolic disorders, such as UCD and other
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`nitrogen retention disorders. (Ex. 1002 ¶ 24.) Today, such a person may have
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`post-graduate training to fulfill the requirements of the American Board of Medical
`
`Genetics and Genomics in Clinical Genetics, Clinical Biochemical Genetics, or
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`Medical Biochemical Genetics. (Ex. 1002 ¶ 24.) A POSA would easily have
`
`understood the prior art references referred to herein and would have the capability
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`to draw inferences from them.
`
`VIII. CLAIM CONSTRUCTION
`A. Broadest Reasonable Interpretation Standard
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
`
`given their broadest reasonable interpretation in light of the specification of the
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`’012 patent. The Patent Trial and Appeal Board (“Board”) interprets claims using
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`the “broadest reasonable construction in light of the specification of the patent in
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`which [they] appear[].” 37 C.F.R. § 42.100(b); Office Patent Trial Practice Guide,
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`77 Fed. Reg. 48756, 48766 (Aug. 14, 2012).
`
`Under this broadest reasonable interpretation standard, claim terms are
`
`generally given their ordinary and customary meaning, as would be understood by
`
`a POSA in the context of the entire disclosure. In re Translogic Tech., Inc. 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007). If a special definition for a claim term is
`
`proffered, it must be described in the specification “with reasonable clarity,
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`9
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`deliberateness, and precision.” In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`Absent such a special definition, limitations are not to be read from the
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`specification into the claims. See In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir.
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`1993).
`
`Terms of the ’012 Patent
`
`B.
`The term “mean conversion . . . of about 60%” should be construed to
`
`include at least 53–67%, which is how a person of ordinary skill in the art would
`
`interpret it. (Ex. 1002 ¶ 27.) “[T]he word ‘about’ does not have a universal
`
`meaning in patent claims, . . . the meaning depends upon the technological facts of
`
`the particular case.” Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Labs, Ltd., 476
`
`F.3d 1321, 1326 (Fed. Cir. 2007) (holding that for a ratio of ingredients, “about
`
`1:5” encompasses ratios up to and including 1:7.1 and ratios down to and including
`
`1:3.6 (quoting Pall Corp. v. Micron Separations, Inc., 66 F.3d 1211, 1217 (Fed.
`
`Cir. 1995))).
`
`In this case, the conversion of a PAA prodrug to PAGN varies with
`
`individual patients, and even from time to time in those patients. (Ex. 1002 ¶ 20.)
`
`Example 3 of the ’012 patent describes ten adult UCD patients switched from
`
`sodium PBA to HPN-100. (Ex. 1001 at 32–35.) Although the ’012 patent does not
`
`provide individual data, the inventors conclude that “the findings demonstrate
`
`considerable inter-individual variability in the percentage of both sodium PBA and
`
`10
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`HPN-100 that is converted to urinary PAGN.” (Ex. 1001 at 31:32–34.) This
`
`statement is consistent with the November 20, 2012 Declaration of Bruce
`
`Scharschmidt, a named inventor, submitted during prosecution of the ’012 patent.
`
`(Ex. 1021 at 682–83.)
`
`During prosecution of the ’012 patent, Scharschmidt stated that the
`
`calculated mean percent conversion of 65 UCD patients was 67%. (Ex. 1021 at
`
`683 ¶ 4.) Although Scharschmidt does not provide individual data points, at a 95%
`
`confidence interval, he stated that the mean conversion is within the range 64–
`
`70%. (Ex. 1021 at 683 ¶ 4.) At a 99% confidence interval, the mean conversion is
`
`even broader, 63–71%. (Id.) During prosecution, Hyperion could not amend its
`
`claims to read “a mean conversion of . . . about 67%” for UCD patients because the
`
`’012 patent does not disclose a mean conversion of 67%. The patent merely
`
`mentions 60% for UCD patients (Ex. 1001 at col. 9, ll. 30–31), and some of the
`
`data presented by Scharschmidt was not in the ’012 patent specification. (Ex. 1021
`
`(Part 6 of 6) at 683 ¶ 4.)
`
`Because the examiner allowed the claims based on the understanding that “a
`
`mean conversion of . . . about 60%” encompasses 67%, and because the patentee
`
`acknowledged considerable inter-individual variability in the actual ’012 patent, a
`
`person of ordinary skill in the art would reasonably construe the term “mean
`
`11
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`conversion of . . . about 60%” as encompassing a range of mean conversion
`
`between 53–67%. (Ex. 1002 ¶ 24.)5
`
`IX. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) & 42.104(b))
`Petitioner requests inter partes review and cancellation of claims 1–12 on
`
`the following grounds.6
`
`Ground
`
`35 U.S.C.
`
`Index of References
`
`1
`
`2
`
`3
`
`4
`
`§ 103
`
`§ 103
`
`§ 103
`
`§ 103
`
`Brusilow ’91 in view of Sherwin, Comte,
`and Shiple
`Brusilow ’91 in view of Sherwin, Shiple,
`and Fernandes
`Brusilow ’91 in view of Sherwin, Shiple,
`and the ʼ647 patent
`Brusilow ’91 in view of Sherwin, Shiple,
`and Kasumov
`
`ʼ012 Patent
`Claims
`1, 3, 4, 7, 8,
`10, & 12
`5
`
`2 & 9
`
`6 & 11
`
`Separately, claims 1–12 should be cancelled on the following grounds.
`
`Ground 35 U.S.C.
`
`Index of References
`
`5
`
`§ 103
`
`Brusilow ’91 in view of Simell’86
`
`ʼ012 Patent
`Claims
`1, 3, 4, 7, 8,
`10, & 12
`Brusilow ’91 in view of Simell’86, and 5
`§ 103
`6
`
`5 In the related Texas action, Hyperion construed certain terms, and Par requests
`
`that the challenged claims be construed at least as broadly as Hyperion
`
`proposed in the attached joint claim construction statement. (Ex. 1022.)
`
`6 Sherwin and Fernandes were not considered by the PTO during the
`
`examination of the ʼ012 patent.
`
`12
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`7
`
`8
`
`§ 103
`
`§ 103
`
`Fernandes
`Brusilow ’91 in view of Simell’86, and the
`ʼ647 patent
`Brusilow ’91 in view of Simell’86 and
`Kasumov
`
`2 & 9
`
`6 & 11
`
`In addition, claims 1–4, 6, 7, and 9–12 should be cancelled on the following
`
`grounds.
`
`Ground 35 U.S.C.
`
`Index of References
`
`9
`
`§ 103
`
`Brusilow ’91
`
`10
`
`§ 103
`
`Brusilow ’91 in view of Kasumov and the
`’979 patent
`
`ʼ012 Patent
`Claims
`1–4, 7, 9, 10,
`& 12
`6 & 11
`
`Copies of the references are filed herewith. 37 C.F.R. § 42.6(c). Petitioner
`
`provides the declaration of Dr. Neal Sondheimer in support of the grounds for
`
`challenging the claims. (Ex. 1002.)7
`
`Claims 1 and 8 are the two independent claims of the ʼ012 patent.
`
`Independent claim 1 recites:
`
`A method of treating a patient having a urea cycle disorder
`comprising
`(a) determining a target urinary phenylacetyl glutamine (PAGN)
`output
`(b) calculating an effective initial dosage of a phenylacetic acid
`(PAA) prodrug selected from glyceryl tri-[4-phenylbutyrate]
`(HPN-100)
`and
`phenylbutyric
`acid
`(PBA)
`or
`a
`
`7 Dr. Sondheimer is an expert in the field. (Ex. 1002 ¶ 8-14.)
`
`13
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`pharmaceutically acceptable salt of PBA, wherein the effective
`dosage of PAA prodrug is calculated based on a mean
`conversion of PAA prodrug to urinary PAGN of about 60%;
`and
`(c) administering the effective initial dosage of PAA prodrug to
`the patient.
`
`
`(Ex. 1001 at 42:16–25.) Independent claim 8 recites:
`
`A method of administering a phenylacetic acid (PAA)
`prodrug selected from glyceryl tri-[4-phenylbutyrate] (HPN-100)
`and phenylbutyric acid (PBA) or a pharmaceutically acceptable salt
`of PBA to a patient having a urea cycle disorder comprising
`(a) administering a first dosage of the PAA prodrug;
`(PAGN)
`(b) determining urinary phenylacetyl glutamine
`excretion following administration of the first dosage of the
`PAA prodrug;
`(c) determining an effective dosage of the PAA prodrug based
`on the urinary PAGN excretion, wherein the effective
`dosage is based on a mean conversion of PAA prodrug to
`urinary PAGN of about 60%; and
`(d) administering the effective dosage to the patient.
`
`
`(Ex. 1001 at 42:41–52.)
`
`14
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`A. Ground 1: Independent Claims 1 and 8 and Dependent Claims 3,
`4, 7, 10, and 12 Are Obvious under § 103(a) over Brusilow ’91 in
`View of Sherwin and Shiple
`
`Independent claims 1 and 8 and dependent claims 3, 4, 7, 10, and 12 are
`
`obvious in view of Brusilow ’91, Sherwin, and Shiple. (Ex. 1002 ¶¶ 42-69.)
`
`1. Overview of Prior Art Applied in Ground 1
`Brusilow ’91 (Ex. 1012) provides a method for calculating an effective
`
`dosage of PAA prodrug (NaPBA) to treat UCD. (Ex. 1012 at 147–48.) Brusilow
`
`’91 started by using the daily protein intake of a patient to calculate dietary
`
`nitrogen intake. (Ex. 1012 at 147.) This dietary nitrogen was used to calculate the
`
`required waste nitrogen excretion, which was used as a basis for determining the
`
`target amount of urinary PAGN to be excreted. (Id.) Brusilow ’91 used this target
`
`amount of urinary PAGN to calculate the dose of NaPBA to be administered to the
`
`patient. (Id.) Brusilow ’91 began by assuming 100% conversion, but he later
`
`measured 90% and 80% following subsequent doses of PAA prodrugs. (Id.)
`
`Sherwin (Ex. 1016), published in 1919, studied the conversion of PAA into
`
`PAGN by administering varying doses of PAA to a normal man (i.e., healthy
`
`subject). (Ex. 1016 at 114.) The man ingested varying doses of PAA ranging from
`
`2.5–15.0 grams, and each dose was taken all at once over 3–5 minutes. (Id.) His
`
`urine was collected in 24 hour periods beginning at the time of ingestion of the
`
`dose. (Id.) Urinary PAGN was measured and a percent conversion from PAA to
`
`15
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`PAGN was calculated. (Id. at 114, 116 (Table I).) The conversion ranged from
`
`about 50–67%. (Id.; Ex. 1002 ¶ 52.) A POSA reviewing Sherwin would further
`
`understand that the conversions observed in Sherwin are low because the subject
`
`was not dosed throughout the day, but instead, given a single dose of PAA.
`
`Sherwin itself acknowledges this: “It is probable that more of the [PAGN] would
`
`have appeared in the urine after each dose of the acid, had the acid been ingested at
`
`regular intervals covering a period of 10 or 12 hours.” (Id.; Ex. 1016 at 118.)
`
`Shiple (Ex. 1017), published in 1922, found that when the subject consumed
`
`PAA, urea production was substantially suppressed. (Ex. 1017 at 620 (Table II),
`
`623–24.) Shiple studied the effect that varying doses of PAA had on urea
`
`production in a single man. (Id. at 619–20, 623–24.) A POSA would understand
`
`that the percentage conversion of a UCD patient would be higher than a normal
`
`patient. (Ex. 1002 ¶ 39.) Because UCD patients experience elevated glutamine
`
`levels (i.e., nitrogen), there is more glutamine for a PAA prodrug to scavenge,
`
`resulting in a higher conversion. (Ex. 1002 ¶ 39.)
`
`2. Motivation to Combine Art Applied in Ground 1
`A POSA considering UCD treatment with PAA prodrugs before the priority
`
`date of the ʼ012 patent would have been motivated to combine the teachings of
`
`Brusilow ’91 with Sherwin and Shiple to arri