`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`__________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, INC.
`
`Patent Owner.
`
`__________________
`
`IPR2016-00283
`
`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
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`TABLE OF CONTENTS
`
`Page
`
`I.
`II.
`
`III.
`
`INTRODUCTION .............................................................................................................. 1
`OVERVIEW ....................................................................................................................... 1
`A.
`Summary of the ‘012 Patent ................................................................................... 1
`B.
`Summary of the Prosecution History of the ‘012 Patent ........................................ 3
`BACKGROUND ON THE UREA CYCLE, UREA CYCLE DISORDER, AND
`NITROGEN SCAVENGING DRUGS ............................................................................... 5
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) .................................................... 6
`V.
`PAYMENT OF FEES (37 C.F.R. § 42.103) ...................................................................... 7
`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
`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 ............................. 19
`(c)
`Administering – Part (c) of Independent Claim 1 ......................... 23
`Independent Claim 8 ................................................................................. 23
`(a)
`Administering – Part (a) of Independent Claim 8 ......................... 24
`(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 ........................ 27
`
`IX.
`
`4.
`
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`5.
`Dependent Claims 3, 4, 7, 10, and 12 ....................................................... 28
`B.
`Ground 2: Dependent Claim 5 Is Obvious under § 103(a) over Brusilow ‘91 in
`view of Sherwin, Shiple, and Fernandes .......................................................................... 29
`1.
`Overview of Prior Art Applied in Ground 2 ............................................. 29
`2.
`Motivation to Combine Art Applied in Ground 2 .................................... 30
`3.
`Dependent Claim 5 ................................................................................... 30
`C.
`Ground 3: Dependent Claims 2 and 9 Are Obvious under § 103(a) over Brusilow
`‘91 in view of Sherwin, Shiple, and the ‘647 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 ...................................................................... 36
`CONCLUSION ................................................................................................................. 37
`
`X.
`
`
`
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`ACTIVE/84217394.3
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`ii
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`List of Exhibits
`
`Ex. 1001: U.S. Patent No. 8,642,012 to Scharschmidt (“the ‘012 patent), filed
`January 7, 2009, issued February 4, 2014.
`
`Ex. 1002: Declaration of Dr. Neal Sondheimer.
`
`Ex. 1003: Curriculum vitae of Dr. Neal Sondheimer.
`
`Ex. 1004: Reserved.
`
`Ex. 1005: Simell, et al.., Waste Nitrogen Excretion Via Amino Acid Acylation:
`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20
`Pediatric Research, 1117-1121 (1986). (“‘Simell”‘).
`
`Ex. 1006: Reserved.
`
`Ex. 1007: Reserved.
`
`Ex. 1008: Reserved.
`
`Ex. 1009: Reserved.
`
`Ex. 1010: Reserved.
`
`Ex. 1011: Fernandes, Saudubray Berghe (editors), Inborn Metabolic Diseases
`Diagnosis and Treatment, 219-220 (3d ed. 2000). (“‘Fernandes’”).
`
`Ex. 1012: Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle for
`Waste Nitrogen Excretion, 29 Pediatric Research, 147-150 (1991).
`(“Brusilow ‘91”).
`
`Ex. 1013: Reserved.
`
`Ex. 1014: Reserved.
`
`Ex. 1015: Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
`Humans and Rats, 32 Drug Metabolism and Disposition, 10-19
`(2004). (“‘Kasumov”).
`
`Ex. 1016: Sherwin, et al., The Maximum Production of Glutamine by the Human
`Body as Measured by the Output of Phenylacetylglutamine, 37 J. Biol.
`Chem., 113-119 (1919). (“Sherwin”).
`
`
`ACTIVE/84217394.3
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`iii
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`Ex. 1017: Shiple, et al.. , Synthesis of Amino Acids in Animal Organisms. I.
`Synthesis of Glycocoll and Glutamine in the Human Organism, 44 J.
`American Chem. Society, 618-624 (1922). (“‘Shiple”).
`
`Ex. 1018: U.S. Patent No. 4,284,647 to Brusilow et al., filed March 31, 1980,
`issued August 18, 1981 (“the ‘647 patent”).
`
`Ex. 1019: Reserved.
`
`Ex. 1020: Reserved.
`
`Ex. 1021: Prosecution History of the ‘012 patent.
`
`Ex. 1022: Joint Claim Construction filed March 13, 2015 in Eastern District of
`Texas District Court, Case 2:14-cv-00384.
`
`Ex. 1023: Piscitelli, et al., Disposition of Phenylbutyrate and its Metabolites,
`Phenylacetate and Phenylacetylglutamine, 35 J. Clin. Pharmacol.,
`368-373 (1995). (“Piscitelli”).
`
`Ex. 1025: Comte, et al., Identification of phenylbutyrylglutamine, a new
`metabolite of phenylbutyrate metabolism in humans, J. Mass.
`Spectrom. 2002:37:581-90. (“Comte”).
`
`Ex. 1026: U.S. Patent No. 5,968,979 to Brusilow, filed Feb. 7, 1995, issued Oct.
`19, 1999 (“the ‘979 patent”).
`
`Ex. 1027: Collins et al., Oral Sodium Phenylbutyrate Therapy in Homozygous (3
`Thalassemia: A Clinical Trial, 85 Blood 43 (1995). (“Collins”).
`
`
`
`
`ACTIVE/84217394.3
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`iv
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`I.
`
`INTRODUCTION
`
`Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively “Petitioner” or
`
`“Lupin”) petition for Inter Partes Review (“IPR”) under 35 U.S.C. §§ 311–319
`
`and 37 C.F.R. § 42 of Claims 1 to 12 of U.S. Patent No. 8,642,012 (“the ‘012
`
`patent”).1 (Ex. 1001.)
`
`II. OVERVIEW
`
`A.
`
`Summary of the ‘012 Patent
`
`The ‘012 patent is directed to a method of treating a subject with a urea
`
`cycle disorder (“UCD”)—an inherited disease causing elevated waste nitrogen
`
`levels—by administering prodrugs of phenylacetic acid (“PAA”), a type of
`
`nitrogen scavenging drug. The patent describes a way to calculate an effective
`
`dosage of the PAA prodrug by measuring urinary phenylacetyl glutamine
`
`(“PAGN”), a natural metabolite of PAA prodrugs.
`
`PAA prodrugs have been used as nitrogen scavenging drugs to treat UCD
`
`for decades, including phenylbutyric acid (“PBA”), sodium phenylbutyrate
`
`
`1 The ‘012 patent was filed on January 7, 2009 and claims benefit to U.S.
`
`Provisional Application No. 61/093,234, filed August 29, 2008. At the time of
`
`issuance it was assigned to Hyperion Therapeutics, Inc. (“Hyperion”), which
`
`changed its name to Horizon Therapeutics, Inc. (“Horizon” or “Patent Owner”).
`
`
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`(“NaPBA”), and glycerol phenylbutyrate (“HPN-100”). The uses of PAA
`
`prodrugs to treat UCD are old and not novel.
`
`The ‘012 patent purports to disclose a novel method comprising steps of
`
`measuring, calculating, determining, and administering. For example, independent
`
`claims 1 and 8 comprise the common steps of administering a PAA prodrug,
`
`measuring urinary PAGN, calculating an effective dose of PAA prodrug based on a
`
`target urinary PAGN, and administering the new dose. These methods were
`
`known in the art.
`
`The patentee, however, alleges to have discovered an improved calculation
`
`of an effective dose of PAA prodrug based on the assumption that a mean
`
`conversion of about 60% of the PAA prodrug should be converted to urinary
`
`PAGN in a UCD subject. For example, if a treating physician measures urinary
`
`PAGN of a UCD subject to be 30%, the physician is supposed to reduce the
`
`amount of PAA prodrug by an amount calculated that would produce a mean
`
`conversion of about 60%. If she measures the urinary PAGN to be 90%, the
`
`physician is supposed to increase the amount of PAA prodrug.2
`
`
`2 Example 9 of the ‘012 patent, the only example of the claimed calculation,
`
`erroneously states this in reverse, which is biologically implausible. (Ex. 1002 ¶ 17
`
`n. 1.)
`
`
`
`2
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`The claims of the ‘ 012 patent describe nothing more than what was
`
`disclosed and known in the prior art long before August 29, 2008, the earliest
`
`possible priority date (“priority date”) of the ‘012 patent. Accordingly, this
`
`Petition should be granted.
`
`B.
`
`Summary of the Prosecution History of the ‘012 Patent
`
`The application leading to the ‘012 patent was filed on January 7, 2009.
`
`(Ex. 1001.) The prosecution focused on the percent conversion of PAA prodrug to
`
`urinary PAGN. The Applicant originally sought a method wherein the effective
`
`dose of PAA prodrug was based on a mean conversion of “about 60% to about
`
`75%.” (Ex. 1021 at 3-6 (original claims 6, 12, & 18).) Because the prior art teaches
`
`a conversion of 80%, the applicant narrowed the range to a “mean conversion . . .
`
`of about 60%.”
`
`The U.S. Patent and Trademark Office (“PTO”) issued a notice of allowance
`
`on September 30, 2013, primarily based on the Applicant’s data purporting to
`
`measure the conversion of a PAA prodrug to PAGN in UCD patients. (Ex. 1021 at
`
`718; see id. at 682–83.) The Applicant erroneously characterized the prior art cited
`
`by the examiner as assuming 100% conversion (see, e.g., Ex. 1001 at 2:57–59),
`
`which the examiner accepted without question, and relied upon to issue the patent.
`
`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
`
`
`
`3
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`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% 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.
`
`(Ex. 1021 at 719.)
`
`The “mean conversion of PAA prodrug to urinary PAGN of about 60%”
`
`purportedly comes from the Applicant’s measurement of PAA prodrug conversion
`
`to PAGN in a number of UCD patients and calculating the mean. (Ex. 1021 at
`
`718–19; see id. at 682–83.) Such data is not included in the ‘012 patent
`
`specification, although the Applicant submitted a declaration during prosecution
`
`(discussed infra) reporting 130 measurements from 65 UCD patients purportedly
`
`showing a mean conversion of 67%. (Ex. 1021 at 682–83.)
`
`
`
`4
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`As shown below, the steps of the method that the Examiner believed were
`
`absent from the prior art were in fact known.
`
`III. BACKGROUND ON THE UREA CYCLE, UREA CYCLE
`DISORDER, AND NITROGEN SCAVENGING DRUGS
`
`Healthy individuals have an intrinsic capacity to excrete waste nitrogen in
`
`the form of urea through the urea cycle at a rate that exceeds the production of
`
`waste nitrogen by the body, and therefore, nitrogen does not normally build up and
`
`ammonia does not rise to harmful levels. (Ex. 1018 at 1:10–12.) UCDs occur
`
`when enzymes or transporters in the urea cycle are deficient, resulting in the
`
`accumulation of waste nitrogen. (Ex. 1018 at 1:16–22, 38–45.) Before and after
`
`the priority date of the ‘012 patent, the treatment options for UCDs included low
`
`protein diets (because protein produces waste nitrogen) and the use of nitrogen
`
`scavenging drugs. (Ex. 1012 at 147–49.)
`
`Nitrogen scavenging drugs promote nitrogen excretion via alternative
`
`pathways. (Ex. 1012 at 147–48; Ex. 1011 at 219–20; Ex. 1018 at 1:46–63.) For
`
`example, PAA is converted to PAGN by an enzymatic reaction that conjugates
`
`PAA to the amino acid glutamine. (Ex. 1012 at 147–48; Ex. 1011 at 219; Ex. 1018
`
`at 1:57–61, 64–66, 3:49–53)3. PAGN is excreted in urine, bypassing the urea
`
`
`3 NaPBA and HPN-100 undergo beta oxidation in the body to produce PAA. (Ex.
`
`1012 at 147-48.)
`
`
`
`5
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`cycle. (Ex. 1002 ¶ 21; Ex. 1012 at 147; Ex. 1011 at 219.) Because PAA and its
`
`prodrugs (NaPBA, HPN-100) provide the body with an alternate pathway to urea
`
`for excretion of waste nitrogen, they are referred to as “alternative pathway
`
`medications.” (Ex. 1011 at 219; Ex. 1012 at 147; Ex. 1016 at 113, 116; Ex. 1017
`
`at 623; Ex. 1018 at 1:57–61.)
`
`The conversion rate of PAA, PBA, and NaPBA to PAGN has been measured
`
`in various clinical settings since at least 1919. For example, as discussed infra,
`
`around 50–67% (Sherwin) of administered PAA is converted to urinary PAGN in
`
`healthy subjects (Ex. 1016 at 114, 116 (Table I)), and around 51–54% (Simell) in
`
`UCD patients. The conversion of PAA prodrug to urinary PAGN exhibits inter-
`
`individual variability. (Ex. 1001 at 31:32–34.) Based on the prior art, the person
`
`of ordinary skill in the art knew that the conversion of a PAA prodrug to urinary
`
`PAGN would fall within the range 53–67% for individuals with UCD. (Ex. 1002
`
`¶¶ 27, 51, 58, 96.) Therefore, the ‘012 patent merely describes well known
`
`methods of treating UCD patients.
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`
`Petitioner certifies that (1) the ‘012 patent, issued on February 4, 2014, is
`
`available for IPR; (2) Petitioner is not barred or estopped from requesting an IPR
`
`on the grounds identified in this Petition; and (3) Petitioner has not filed any
`
`complaint relating to the ‘012 patent. This Petition is filed in accordance with 37
`
`
`
`6
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`C.F.R. § 42.106(a). Concurrently filed herewith is a Power of Attorney and an
`
`Exhibit List per 37 C.F.R. §§ 42.10(b) and 42.63(e), respectively.
`
`V.
`
`PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`Petitioner authorizes required fees to be charged to Deposit Acct.06-0923.
`
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`A. Real Parties-in-Interest
`
`Petitioner certifies that Lupin Pharmaceuticals Inc. and Lupin Ltd. are the
`
`real parties-in-interest.
`
`B. Related Matters
`
`Horizon is asserting the ‘012 patent against Par Pharmaceutical, Inc. in Case
`
`No. 14-cv-00384 (E.D. TX).
`
`The ‘012 patent is the subject of IPR2015-01117, filed by Par
`
`Pharmaceutical, Inc.
`
`Par also filed IPR2015-01127 against Horizon’s U.S. Patent 8,404,215,
`
`although that patent is not related to the ‘012 patent.
`
`On October 19, 2015, Horizon filed a complaint in District Court for the
`
`District of New Jersey (Case No. 1:15-cv-07624-RBK-JS) alleging that Petitioner
`
`is infringing three U.S. Patents, including the ‘012 patent. As of the filing of this
`
`petition, Horizon has not yet served the complaint.
`
`
`
`7
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`Petitioner is contemporaneously filing a second petition for IPR of
`
`Horizon’s U.S. Patent 8,404,215, although that patent is not related to the ‘012
`
`patent.
`
`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
`
`Elizabeth J. Holland
`
`Cynthia Lambert Hardman
`
`(Reg. No. 47,657)
`
`(Reg. No. 53,179)
`
`GOODWIN PROCTER LLP
`
`GOODWIN PROCTER LLP
`
`The New York Times Building
`
`The New York Times Building
`
`620 Eighth Avenue
`
`620 Eighth Avenue
`
`New York, NY 10018
`
`New York, NY 10018
`
`(212) 813-8800 (telephone)
`
`(212) 813-8800 (telephone)
`
`(212) 355-3333 (facsimile)
`
`(212) 355-3333 (facsimile)
`
`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
`
`is presumed to know the relevant prior art. (See IPR2013-00116 at 9, 37). A
`
`POSA has ordinary creativity, is not an automaton, and is capable of combining
`
`
`
`8
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`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 ‘012 patent, Petitioner submits that a POSA
`
`is a physician or scientist with a Ph.D. or M.D. degree and specialized training in
`
`the diagnosis or treatment of inherited metabolic disorders, such as UCD and other
`
`nitrogen retention disorders. (Ex. 1002 ¶ 24.) Today, such a person may 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. (Ex. 1002 ¶ 24.) A POSA would easily have
`
`understood the prior art references referred to herein and would have the capability
`
`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
`
`‘012 patent. The Patent Trial and Appeal Board (“Board”) interprets claims using
`
`the “broadest reasonable construction in light of the specification of the patent in
`
`which [they] appear[].” 37 C.F.R. § 42.100(b); Office Patent Trial Practice Guide,
`
`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
`
`
`
`9
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`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`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,
`
`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
`
`specification into the claims. See In re Van Geuns, 988 F.2d 1181, 1184 (Fed. Cir.
`
`1993).
`
`B.
`
`Terms of the ‘012 Patent
`
`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
`
`
`
`10
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
`
`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
`
`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
`
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`11
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`acknowledged considerable inter-individual variability in the actual ‘012 patent, a
`
`person of ordinary skill in the art would reasonably construe the term “mean
`
`conversion of . . . about 60%” as encompassing a range of mean conversion
`
`between 53–67%. (Ex. 1002 ¶ 24.)4
`
`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.5
`
`Ground
`
`35 U.S.C.
`
`Index of References
`
`‘012 patent
`
`1
`
`2
`
`3
`
`§ 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 ‘647
`
`Claims
`
`1, 3, 4, 7, 8, 10,
`& 12
`5
`
`2 & 9
`
`
`4 In the related Texas action, Hyperion, now known as Horizon, construed certain
`
`terms, and Lupin requests that the challenged claims be construed at least as
`
`broadly as Horizon proposed in the attached joint claim construction statement.
`
`(Ex. 1022.)
`
`5Sherwin and Fernandes were not considered by the PTO during the examination
`
`of the ‘ 012 patent.
`
`
`
`12
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`4
`
`§ 103
`
`patent
`Brusilow ‘91 in view of
`Sherwin, Shiple, Kasumov,
`and the ‘979 patent
`
`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.)6
`
`Claims 1 and 8 are the two independent claims of the ‘012 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 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
`
`
`6 Dr. Sondheimer is an expert in the field. (Ex. 1002 ¶ 8-14.)
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`(c)
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`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;
`
`(b) determining urinary phenylacetyl glutamine (PAGN) 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.)
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`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
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`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 ‘012 patent would have been motivated to combine the teachings of
`
`Brusilow ‘91 with Sherwin and Shiple to arrive at the claimed invention. (Ex. 1002
`
`¶¶ 42–45.) A POSA reading Brusilow ‘91’s clinical study using a PAA prodrug
`
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`(Ex. 1012 at 147) would have been motivated to look to both Sherwin and Shiple
`
`because each discusses the conversion of PAA to PAGN. (Ex. 1002 ¶ 42; Ex.
`
`1016 at 113, 116 (Table I), 117–18; Ex. 1017 at 623.)
`
`Because Brusilow ‘91 involved only a single subject and observed a range of
`
`conversion rates (80-90%), a POSA would have been motivated to look to other
`
`references, such as Sherwin, to find more information on conversion rates. (Ex.
`
`1002 ¶ 43.) A POSA would furthermore consider Shiple to ascertain differences
`
`between UCD patients and healthy subjects taking PAA, and to figure out whether
`
`PAA administration impacts urea production in a normal person. (Ex. 1002 ¶ 44.)
`
`Shiple teaches that administering PAA suppresses urea production (Ex. 1017 at
`
`620, 623), and therefore, a POSA reading Shiple and Sherwin would have
`
`understood that the conversion rate of PAA presented in Sherwin would also apply
`
`to the UCD patient in Brusilow ‘91 , because both the normal patient fed PAA and
`
`the UCD patient experience suppressed urea production. (Ex. 1002 ¶ 44.)7
`
`Dr. Sondheimer explains that a POSA interested in UCD treatment with
`
`nitrogen scavenging drugs would have referred to Brusilow ‘91’s clinical study
`
`regarding PAGN production using a PAA prodrug (NaPBA) in combination with
`
`Sherwin and Shiple’s clinical studies regarding the effects of PAA treatment on
`
`7 A POSA reading Sherwin would have also been motivated to look to Shiple as
`
`both have a common author, Carl P. Sherwin. (Ex. 1016; Ex. 1017.)
`
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`Petition for Inter Partes Review of U.S. Patent No. 8,642,012
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`patients. (Ex. 1002 ¶ 45.) See Allergan, Inc. v. Sandoz, Inc., 726 F.3d 1286, 1292
`
`(Fed. Cir. 2013) (holding that motivation to combine can be found in many
`
`different forms, including,