throbber
Trials@uspto.gov
`571-272-7822
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` Paper 13
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`
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` Entered: November 4, 2015
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,1
`Patent Owner.
`
`
`Case IPR2015-01117
`Patent 8,642,012 B2
`
`
`
`Before TONI R. SCHEINER, DEBORAH KATZ, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`
`
`
`1 “[E]ffective May 7, 2015, the name of Hyperion Therapeutics, Inc., was
`changed to Horizon Therapeutics, Inc. . . . Accordingly, Horizon
`Therapeutics, Inc. . . . is the Patent Owner of U.S. Patent No. 8,642,012.”
`Paper 5, 2.
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`I. INTRODUCTION
`
`Par Pharmaceutical, Inc. (“Petitioner”) filed a Petition (Paper 2,
`
`“Pet.”) on April 29, 2015, requesting an inter partes review of claims 1–12
`
`of U.S. Patent No. 8,642,012 B2 (Ex. 1001, “the ’012 patent”). Horizon
`
`Therapeutics, Inc. (“Patent Owner”) filed a Preliminary Response (Paper 8,
`
`“Prelim. Resp.”) on August 5, 2015. We have jurisdiction under 35 U.S.C.
`
`§ 314, which provides that an inter partes review may not be instituted
`
`“unless . . . there is a reasonable likelihood that the petitioner would prevail
`
`with respect to at least 1 of the claims challenged in the petition.”
`
`Upon consideration of the information presented in the Petition and
`
`the Preliminary Response, we conclude that Petitioner has established a
`
`reasonable likelihood that it would prevail in its challenges to claims 1–12 of
`
`the ’012 patent. Accordingly, we institute an inter partes review.
`
`A. Related Proceedings
`
`Patent Owner filed suit against Petitioner, alleging infringement of the
`
`’012 patent and U.S. Patent No. 8,404,215 B1 (“the ’215 patent) in Hyperion
`
`Therapeutics, Inc. v. Par Pharmaceutical, Inc., Case No. 2:14-CV-384-JRG-
`
`RSP (E.D. Tex.). Pet. 7; Paper 5, 3. In addition, concurrently with the
`
`Petition under consideration here, Petitioner filed a petition challenging the
`
`claims of the ’215 patent (IPR2015-01127), but represents that that patent is
`
`not related to the ’012 patent. Pet. 7.
`
`2
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`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`B. The Asserted Grounds of Unpatentability
`
`
`
`Petitioner asserts the challenged claims are unpatentable on the
`
`following grounds. Pet. 12–60:2
`
`References
`
`Basis
`
`Claims Challenged
`
`Brusilow ’91,3 Sherwin,4
`Comte,5 and Shiple6
`
`§ 103
`
`1, 3, 4, 7, 8, 10, 12
`
`
`2 Petitioner supports its challenge with a Declaration, executed April 29,
`2015, by Neal Sondheimer, M.D., Ph.D. (“Sondheimer Declaration”)
`(Ex. 1002).
`3 Saul W. Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle
`for Waste Nitrogen Excretion, 29 PEDIATRIC RESEARCH 147–150 (1991)
`(“Brusilow ’91”) (Ex. 1012).
`4 Carl P. Sherwin at 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”) (Ex. 1016).
`5 Blandine Comte et al., Identification of phenylbutyrylglutamine, a new
`metabolite of phenylbutyrate metabolism in humans, 37 J. MASS SPECTROM.
`581–590 (2002) (“Comte”) (Ex. 1025).
`6 George J. Shiple & Carl P. Sherwin, Synthesis of Amino Acids in Animal
`Organisms. I. Synthesis of Glycocoll and Glutamine in the Human
`Organism, 44 J. AMER. CHEM. SOC. 618–624 (1922) (“Shiple”) (Ex. 1017).
`
`3
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`References
`
`Basis
`
`Claims Challenged
`
`Brusilow ’91 , Sherwin,
`Shiple, and Fernandes7
`Brusilow ’91, Sherwin,
`Shiple, and the ’647 patent8
`Brusilow ’91, Sherwin,
`Shiple, Kasumov,9 and the
`’979 patent10
`Brusilow ’91and Simell11
`
`§ 103
`
`5
`
`§ 103
`
`2, 9
`
`§ 103
`
`6, 11
`
`§ 103
`
`1, 3, 4, 7, 8, 10, 12
`
`Brusilow ’91, Simell, and
`Fernandes
`Brusilow ’91, Simell, and the
`’647 patent
`Brusilow ’91, Simell, and
`Kasumov
`
`§ 103
`
`5
`
`§ 103
`
`2, 9
`
`§ 103
`
`6, 11
`
`
`7 INBORN METABOLIC DISEASES: DIAGNOSIS AND TREATMENT 219–220
`(John Fernandes et al. eds., Springer Verlag 3d ed. 2000) (“Fernandes”)
`(Ex. 1011).
`8 U.S. Patent No. 4,284,647, issued August 18, 1981 to Brusilow et al. (“the
`’647 patent”) (Ex. 1018).
`9 Takhar Kasumov et al., New Secondary Metabolites of Phenylbutyrate in
`Humans and Rats, 32 DRUG METABOLISM AND DISPOSITION 10–19 (2004)
`(“Kasumov”) (Ex. 1015).
`10 U.S. Patent No. 5,968,979, issued October 19, 1999 to Brusilow (“the 979
`patent”) (Ex. 1026).
`11 Olly 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. 1005).
`
`4
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`References
`
`Basis
`
`Claims Challenged
`
`Brusilow ’91
`
`§ 103
`
`1–4, 7, 9, 10, 12
`
`Brusilow ’91, Kasumov, and
`the ’979 patent
`
`§ 103
`
`6, 11
`
`
`
`
`
`C. The ’012 Patent (Ex. 1001)
`
`The ’012 patent, titled “Methods of Treatment Using Ammonia-
`
`Scavenging Drugs,” is directed to “treatment of patients with nitrogen
`
`retention states, in particular urea cycle disorders (UCDs) . . . [by]
`
`administer[ing] compounds that assist in elimination of waste nitrogen from
`
`the body.” Ex. 1001, 1:18–25. These compounds—or “nitrogen scavenging
`
`drugs”12—include glyceryl tri-[4-phenylbutyrate] (HPN-100) and
`
`phenylbutyric acid (PBA)—both of which are prodrugs that are converted in
`
`vivo to phenylacetic acid (PAA). Id. at 3:61–66.
`
`“For patients with nitrogen retention states such as UCD . . . the
`
`body’s intrinsic capacity for waste nitrogen excretion is less than the body’s
`
`waste nitrogen production based on a normal diet that contains significant
`
`amounts of protein.” Id. at 2:22–25. “As a result, nitrogen builds up in the
`
`body . . . and usually results in excess ammonia in the blood . . . [which] has
`
`various toxic effects.” Id. at 2:25–28.
`
`
`12 The terms “ammonia scavenger” and “nitrogen scavenger” are used
`interchangeably in the ’012 patent. Ex. 1001, 4:6–7.
`5
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`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`HPN-100 and PBA “reduce excess waste nitrogen and ammonia by
`
`converting it to readily-excreted forms, such as phenylacetyl glutamine
`
`(PAGN).” Id. at 2:45–47. “The capacity to eliminate excess ammonia in
`
`treated patients can be considered the sum of the patient’s endogenous
`
`capacity for nitrogen elimination (if any) plus the amount of additional
`
`nitrogen-elimination capacity that is provided by a nitrogen scavenging
`
`drug.” Id. at 2:39–44.
`
`According to the ’012 patent, “[i]t has generally been assumed . . .
`
`that a prodrug would be converted with 100% efficiency into PAGN for
`
`elimination” (id. at 9:21–23), but “[i]t has now been found that HPN-100
`
`and phenylbutyrate are both converted into urinary PAGN at an overall
`
`efficiency of about 60% to about 75% on average (about 60% conversion
`
`efficiency was seen in UCD patients and about 75% conversion was seen in
`
`cirrhotic patients, for example)” (id. at 9:27–32). “[C]onsequently, this
`
`efficiency factor can be used to more accurately calculate or determine
`
`initial dosing levels for these drugs, or dietary protein levels acceptable for
`
`patients who use these drugs.” Id. at 9:32–35. Moreover, “urinary PAGN
`
`provides a convenient method for monitoring ammonia elimination induced
`
`by the administered drug, which does not require drawing blood and directly
`
`relates to the actual nitrogen elimination provided by the . . . drug without
`
`being influenced by the many other factors that can affect plasma ammonia
`
`levels.” Id. at 7:24–30.
`
`
`
`
`
`6
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`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`One embodiment of the invention is a method for determining
`and/or adjusting the dose of ammonia scavenging drugs in
`patients with UCDs, whereby the dose would be based on the
`amount of dietary protein the patient is consuming, the
`anticipated conversion of the drug to PAGN, and the patient’s
`residual urea synthetic capacity, if any. Dose adjustments, if
`necessary, would be based on the observed urinary excretion of
`PAGN and/or total urinary nitrogen (TUN), the difference
`between the two reflecting the patient’s endogenous capacity
`for waste nitrogen excretion . . . referred to sometimes as their
`residual urea synthesis capacity.
`
`Id. at 8:16–30.
`
`D. Illustrative Claims
`
`Petitioner challenges claims 1–12 of the ’012 patent. Claims 1 and 8
`
`are independent claims. Claims 1 and 8, reproduced below (with indenting
`
`added), are illustrative.
`
`1. 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 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
`
`(c) administering the effective initial dosage of PAA
`prodrug to the patient.
`
`
`
`
`
`7
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`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`A method of administering a phenylacetic acid (PAA)
`8.
`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.
`
`Id. at 42:16–15, 41–52.
`
`II. ANALYSIS
`
`A. Real Party-In-Interest
`
`Petitioner identifies Par Pharmaceutical, Inc. (“Par Inc.”) as the real
`
`party-in-interest. Pet. 7. We note that Petitioner represents that Par Inc. is a
`
`wholly owned subsidiary of Par Pharmaceutical Companies, Inc., but does
`
`not identify Par Pharmaceutical Companies, Inc. as a real party-in-interest.
`
`Pet. 7 n.4.
`
`Patent Owner argues that Par Pharmaceutical Companies, Inc. (“Par
`
`Co.”) was not properly identified as a real party-in-interest. Prelim. Resp. 5.
`
`Patent Owner argues that because of this deficiency, the Petition violates the
`
`statutory and regulatory requirements for receiving a filing date, citing 35
`
`U.S.C. § 312(a) and 37 C.F.R. § 42.8(b)(1). Patent Owner argues further
`
`8
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`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`that because the Petition was filed exactly one year after Par Inc. was served
`
`with the complaint in litigation in the Eastern District of Texas, Petitioner
`
`cannot correct the failure to name all the real parties-in-interest by filing a
`
`new petition. Prelim. Resp. 5.
`
`According to Patent Owner, Par Co. is a real party-in-interest to the
`
`proceeding because it is involved in developing, manufacturing, and
`
`distributing generic pharmaceutical products. Prelim. Resp. 8 (citing Ex.
`
`2003 ¶ 4; Ex. 2004, 42; Ex. 2005). Patent Owner also provides evidence
`
`that Par Co., in a different proceeding, pleaded guilty pursuant to an
`
`agreement with the United States Attorney for the District of New Jersey,
`
`and agreed to perform certain actions on behalf of Petitioner. Prelim. Resp.
`
`10 (citing Ex. 2007, 1).
`
`In addition, Patent Owner cites to a Securities and Exchange
`
`Commission (SEC) filing that defines the term “we” as including Petitioner
`
`and Par Co. Prelim. Resp. 11–13 (citing Ex. 2004, 8). Patent Owner also
`
`cites to the statement in the SEC filing that “[o]n April 29, 2015, we filed
`
`Inter Partes Review petitions seeking institution of a trial on invalidity at the
`
`U.S. Patent and Trademark Office for both of the patents asserted in the
`
`Texas litigation [the ’012 patent and the ’215 patent].” Id. at 11 (citing Ex.
`
`2004, 36). Patent Owner argues that the use of “we” in this statement was a
`
`deliberate indication that the current Petition was filed at the behest of Par
`
`Co. Prelim. Resp. 12.
`
`9
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`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`Finally, Patent Owner asserts that Thomas J. Haughey is the General
`
`Counsel and CAO of both Par Co. and Par Inc. and is also the President of
`
`Par Inc., indicating the unified nature of the relationship between Par Co.
`
`and the Petitioner. Prelim. Resp. 15 (citing Ex. 2008, 70; Ex. 2009).
`
`Nevertheless, on this record, we are not persuaded that the Petition
`
`failed to name all real parties-in-interest. Specifically, the use of the term
`
`“we” in an SEC filing, even if used deliberately when referring to what
`
`could be the current Petition, does not establish adequately that Par Co. has
`
`control over this proceeding. Nor does the evidence show that Par Co.
`
`exerts control over this proceeding merely because Par Co. and Petitioner
`
`are in a similar business and the same person has roles in both Par Co. and
`
`Par Inc. Similarly, evidence of control in a different, unrelated litigation is
`
`not evidence of Par Co.’s role in this proceeding. Patent Owner has failed to
`
`provide us with evidence of actual control by an unnamed entity sufficient to
`
`indicate that Petitioner failed to name all real parties-in-interest. See Taylor
`
`v. Sturgell, 553 U.S. 880, 893–95 (2008).
`
`B. Claim Construction
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their 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. 48,756, 48,766 (Aug. 14,
`
`2012); In re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1275–79 (Fed. Cir.
`
`2015). Under that standard, claim terms are given their ordinary and
`
`10
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`

`IPR2015-01117
`Patent 8,642,012 B2
`
`customary meaning, as would be understood by one of ordinary skill in the
`
`art in the context of the entire disclosure. In re Translogic Tech., Inc., 504
`
`F.3d 1249, 1257 (Fed. Cir. 2007).
`
`1. “mean conversion . . . of about 60%”
`
`
`
`Petitioner argues that the term “mean conversion of PAA prodrug to
`
`urinary PAGN of about 60%” should be construed “as encompassing a range
`
`of mean conversion between 53–67%.” Pet. 10–12.
`
`However, we determine it is not necessary to construe the term for
`
`purposes of this decision, and will interpret the term, should it become
`
`necessary, based on the full record developed at trial.
`
`C. Claims 1, 3, 4, 7, 8, 10, 12—Asserted Obviousness over
`Brusilow ’91, Sherwin, Comte, and Shiple
`
`1. Brusilow ’91 (Ex. 1012)
`
`Brusilow ’91 reports the results of an evaluation of PAG nitrogen
`
`(PAGN) as an alternate vehicle for waste nitrogen excretion in patients with
`
`inborn errors of urea synthesis (i.e., urea cycle disorders, or UCDs).
`
`Briefly, the daily protein intake of a 7½-year-old boy with a UCD was
`
`used to calculate his required waste nitrogen excretion, and the required
`
`nitrogen excretion was used to calculate a target amount of urinary PAGN to
`
`be excreted. The target amount of PAGN to be excreted was used, in turn,
`
`to calculate initial doses of PAA and PBA, based on complete (i.e., 100%)
`
`conversion of the drugs to PAGN. Urinary excretion of PAGN was
`
`measured over three, three-day periods in which the patient was treated once
`
`11
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`

`IPR2015-01117
`Patent 8,642,012 B2
`
`with sodium phenylacetate (NaPAA) and twice with sodium phenylbutyrate
`
`(NaPBA). Ex. 1012, 147.
`
`The resultant measurements showed that the conversion of NaPBA
`
`was not complete—rather, “90% of the predicted amount of PAG[N]
`
`synthesized [was] excreted” following the first dose of NaPBA. Id. at 148.
`
`The second dose of NaPBA was increased to account for the lower than
`
`expected conversion of NaPBA to PAGN, and only 80% of the predicted
`
`amount of PAGN was excreted. Id., Table 1.
`
`2. Sherwin (Ex. 1016)
`
`
`
`Sherwin discusses the results of a study of the conversion of PAA into
`
`urinary PAGN in humans. Varying doses of PAA were administered to a
`
`normal man (i.e., a healthy subject). Ex. 1016, 114. The subject ingested
`
`doses of PAA ranging from 2.5–15.0 grams, and each dose was taken all at
`
`once over three to five minutes. Id. The subject’s urine was collected
`
`during twenty-four hour periods beginning at the time of ingestion of the
`
`dose. Id. Urinary PAGN was measured and a percent conversion from PAA
`
`to PAGN was calculated. Id. at 114, 116 , Table I. The conversion rate
`
`ranged from about 50–67% for all doses, and from about 51–52% for doses
`
`of 10 grams or more. Id. Moreover, Sherwin suggests that “[t]t 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. at 118.
`
`12
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`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`3. Comte (Ex. 1025)
`
`Comte discloses that metabolism of PBA in humans produces PAGN,
`
`as well as another metabolite, phenylbutyrlglutamine. Ex. 1025, 581.
`
`Comte observed about 54% conversion of PBA to urinary PAGN in seven
`
`normal subjects. Id. at 585–586.
`
`4. Shiple (Ex. 1017)
`
`
`
`Shiple discloses that PAA suppresses urea production in normal
`
`subjects, and glutamine is synthesized at the expense of urea nitrogen in the
`
`presence of PAA. Ex. 1025, 619, 623.
`
`Claim 1
`
`5. Analysis
`
`Petitioner contends that Brusilow ’91 discloses all the steps of the
`
`claimed method of treating a patient suffering from a UCD by administering
`
`a PAA prodrug, except that Brusilow ’91’s effective dose of the PAA
`
`prodrug was calculated based on a mean conversion of PAA prodrug to
`
`urinary PAGN of about 90%, rather than about 60%, as recited in claim 1.
`
`Pet. 20.
`
`Nevertheless, Petitioner, supported by the testimony of its witness,
`
`Dr. Sondheimer, contends that a person of ordinary skill in the art,
`
`recognizing that “Brusilow ’91 involved only a single subject and observed a
`
`range of conversion rates (80–90%)” in that single subject, would have
`
`looked to other references, such as Sherwin and Shiple, to find more
`
`information on conversion rates, “because each discusses the conversion of
`13
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`IPR2015-01117
`Patent 8,642,012 B2
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`PAA to PAGN” (Pet. 17 (citing Ex. 1002 ¶¶ 42–45)). Petitioner contends
`
`that these additional references, in turn, would have led one of ordinary skill
`
`in the art to expect a lower conversion rate of PAA prodrugs to urinary
`
`PAGN—i.e., about 60%. Id. at 19.
`
`In this regard, Dr. Sondheimer testifies, “[a]s seen in Table I of
`
`Sherwin, the conversion of PAA into normal PAGN in normal subjects
`
`ranged from about 50–67 for all doses” and “at clinically relevant doses (10
`
`grams or higher), Sherwin teaches a 51–52% conversion of PAA into urinary
`
`PAGN in normal subjects.” Ex. 1002 ¶ 52 (citing Ex. 1016, 114, 116,
`
`Table I). According to Dr. Sondheimer, “[a] person of ordinary skill
`
`reviewing Sherwin would understand that the 51–52% figures are low”
`
`because “Sherwin further states that ‘[i]t 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. (citing Ex. 1016, 118).
`
`Dr. Sondheimer further testifies that one of ordinary skill in the art
`
`would also understand that “Sherwin’s figures are lower than one would
`
`expect to see in a UCD patient” because “UCD patients are not dosed with a
`
`single large dose . . . and by dosing smaller doses over the course of a day,
`
`the percent conversion of PAA to PAGN would be higher.” Ex. 1002 ¶ 53.
`
`In addition, Dr. Sondheimer testifies that Shiple “demonstrates that urea
`
`synthesis in normal people is suppressed when treated with PAA” (id. ¶ 54
`
`(citing Ex. 1017, 620, Table II, 623)), and “a person of ordinary skill in the
`
`14
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`

`IPR2015-01117
`Patent 8,642,012 B2
`
`art would have understood from reading Shiple and Brusilow ’91 that a
`
`normal subject treated with PAA excretes urea at about the same rate as a
`
`UCD patient” (id. ¶ 55). According to Dr. Sondheimer,
`
`A person of ordinary skill in the art would have understood that
`the conversion rates observed in Sherwin for the normal subject
`would also be applicable to the UCD patient. Therefore, a
`person of ordinary skill in the art reading Sherwin in view of
`Shiple would have understood that the percentage conversion of
`administered PAA to PAGN observed in the healthy volunteer
`of Sherwin would also have been observed in a UCD patient.
`
`Ex. 1002 ¶ 55.
`
` Consequently, Petitioner, supported by the testimony of
`
`Dr. Sondheimer, contends that one of ordinary skill in the art “would have
`
`used Sherwin’s conversion rate to obtain the effective dosage of NaPBA to
`
`be administered [to a UCD patient] according to the method described in
`
`Brusilow ’91.” Pet. 22–23 (citing Ex. 1002 ¶ 56).
`
`Claim 8
`
`With respect to independent claim 8, Petitioner’s contentions and
`
`cited evidence, discussed on pages 23 through 27 of the Petition, are
`
`essentially the same as for claim 1.
`
`Dependent Claims 3, 4, 7, 10, and 12
`
`Claims 3 and 12 depend from claims 1 and 12, respectively, and
`
`require that administration of the effective initial dosage of PAA prodrug
`
`produces a normal plasma ammonia level in the patient. Petitioner cites
`
`Brusilow ’91’s teaching that treatment with NaPBA produces a mean plasma
`
`15
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`IPR2015-01117
`Patent 8,642,012 B2
`
`ammonium level within the normal range as meeting this limitation (Pet. 27
`
`(citing Ex. 1012, 148–149)).
`
`Claim 4 depends from claim 1 and recites that calculation of the target
`
`PAGN output takes into account the patient’s dietary protein intake.
`
`Petitioner asserts that Brusilow ’91 takes dietary protein intake into account
`
`in calculating the dosage for the PAA prodrug (Pet. 28 (citing Ex. 1012,
`
`147)).
`
`Claims 7 and 10 depend from claims 1 and 8, respectively, and require
`
`that the pharmaceutically acceptable salt of PBA is sodium PBA. Petitioner
`
`cites Brusilow ’91’s disclosure of treating the patient with NaPBA as
`
`meeting this limitation (Pet. 28 (citing Ex. 1012, 147–148, Table 1)).
`
`6. Conclusion
`
`Patent Owner has not addressed Petitioner’s contentions, and is under
`
`no obligation to do so. In the absence of any countervailing argument,
`
`however, at this stage of the proceedings, Petitioner’s contentions appear to
`
`be supported adequately, and we are persuaded that, on this record,
`
`Petitioner has demonstrated a reasonable likelihood of showing that claims
`
`1, 3, 4, 7, 8, 10, and 12 would have been obvious over Brusilow ’91,
`
`Sherwin, Comte, and Shiple.
`
`D. Claim 5—Asserted Obviousness over Brusilow ’91, Sherwin,
`Shiple, and Fernandes
`
`Claim 5 depends from claim 1 and requires that the target PAGN
`
`output take into account the patient’s dietary protein intake.
`
`16
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`Fernandes discusses diagnosis and treatment of inborn metabolic
`
`diseases, including UCDs. Ex. 1011, 219–20. Fernandes discloses a
`
`guideline for the management of patients with UCDs, which includes the
`
`administration of nitrogen scavenging drugs such as phenylbutyrate.
`
`Id. at 219, Fig. 17.2. Fernandes teaches that nitrogen scavenging drugs
`
`reduce the load on the urea cycle in patients with UCDs. Id. at 219.
`
`Fernandes further discusses general aspects of therapy and, specifically, that
`
`the balance of diet and medicine is important (id. at 219), and that protein
`
`intake of patients varies considerably and that residual enzyme activity of
`
`the UCD patient must be taken into account during treatment (id. at 219–20).
`
`Petitioner contends that the subject matter of claim 5 would have been
`
`obvious because a person of ordinary skill in the art “reading Brusilow ’91
`
`and Fernandes would have considered the residual enzyme activity of the
`
`patient, and therefore his or her residual urea synthesis capacity.” Pet. 30
`
`(citing Ex. 1002 ¶ 76).
`
`Petitioner’s contentions appear to be supported adequately on this
`
`record, and we are persuaded that Petitioner has demonstrated a reasonable
`
`likelihood of showing that claim 5 would have been obvious over
`
`Brusilow ’91, Sherwin, Shiple, and Fernandes.
`
`17
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`E. Claims 2 and 9—Asserted Obviousness over Brusilow ’91,
`Sherwin, Shiple, and the ’647 Patent
`
`
`
`Claims 2 and 9 depend from claims 1 and 8, respectively, and recite
`
`that target urinary PAGN output is determined as a ratio of the concentration
`
`of urinary PAGN to urinary creatinine.
`
`Petitioner notes that “Brusilow ’91 teaches measuring creatinine levels
`
`in the UCD patients treated with phenylacetate or NaPBA (Ex. 1012 at 148)
`
`but does not expressly mention determining target urinary PAGN output as a
`
`ratio of urinary PAGN to urinary creatinine.” Pet. 33.
`
`
`
`However, Petitioner cites the ’647 patent as disclosing measuring
`
`urinary creatinine, urinary PAGN, and total urinary nitrogen in a UCD
`
`patient after PAA administration, and as disclosing using the ratio of urinary
`
`PAGN to creatinine as a convenient measure for an increase in urinary
`
`excretion of nitrogen that does not require collection of total daily urine.
`
`Pet. 33 (citing Ex. 1018, 3:53–4.6, 4:35–50).
`
`
`
`Petitioner contends that one of ordinary skill in the art would have
`
`recognized that target urinary PAGN could conveniently be determined as a
`
`ratio of urinary PAGN to urinary creatinine. Pet. 33.
`
`Petitioner’s contentions appear to be supported adequately on this
`
`record, and we are persuaded that Petitioner has demonstrated a reasonable
`
`likelihood of showing that claims 2 and 9 would have been obvious over
`
`Brusilow ’91, Sherwin, Shiple, and the ’647 patent.
`
`
`
`18
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`F. Claims 6 and 11—Asserted Obviousness over Brusilow ’91,
`Sherwin, Shiple, and Kasumov
`
`Claims 6 and 11 depend from claims 1 and 8, respectively, and recite
`
`that the PAA prodrug is HPN-100.
`
`Petitioner acknowledges that none of Brusilow ’91, Sherwin, or
`
`Shiple discloses HPN-100 as the nitrogen scavenging drug.
`
`However, Petitioner argues that it would have been obvious to
`
`substitute HPN-100 for NaPBA in Brusilow ’91’s method because Kasumov
`
`discloses that NaPBA may be toxic at high doses (Pet. 34 (citing Ex. 1015,
`
`10, 13)), and because the ’979 patent also discloses HPN-100, and teaches
`
`that such drugs are useful to treat patients with diseases of nitrogen
`
`accumulation.
`
`Petitioner’s contentions appear to be supported adequately on this
`
`record, and we are persuaded that Petitioner has demonstrated a reasonable
`
`likelihood of showing that claims 6 and 11 would have been obvious over
`
`Brusilow ’91, Sherwin, Shiple, Kasumov, and the ’979 patent.
`
`G. Remaining Challenges
`
`Petitioner also challenges claims 1–12 as obvious over Brusilow ’91
`
`alone, or in combination with one or more of Simell, Fernandes, the ’647
`
`patent, and Kasumov. Pet. 36–60. In light of our determination, discussed
`
`above, that there is a reasonable likelihood that Petitioner would prevail in
`
`showing that claims 1–12 are unpatentable as obvious over Brusilow ’91,
`
`Sherwin, Comte, and Shiple, together with Fernandes, the ’647 patent, or
`
`19
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`Kasumov, we exercise our discretion under 37 C.F.R. § 42.108(a) and
`
`decline to institute trial as to claims 1–12 based on the remaining asserted
`
`grounds. Specifically, in that regard, Petitioner does not direct us to
`
`information sufficient to persuade us that going forward to trial on multiple
`
`grounds, directed to the same patent claims, is an efficient allocation of
`
`Board or party resources. See 35 U.S.C. § 316(b) (regulations for AIA post-
`
`grant proceedings take into account “the efficient administration of the
`
`Office” and “the ability of the Office to timely complete [instituted]
`
`proceedings”); 37 C.F.R. § 42.1(b) (patent rules promulgated for AIA post-
`
`grant proceedings, including those pertaining to institution, are “construed to
`
`secure the just, speedy, and inexpensive resolution of every proceeding”); 37
`
`C.F.R. § 42.108 (a) (the Board has discretion to authorize an inter partes
`
`review “on all or some” grounds stated in Petition) (emphasis added)).
`
`III. CONCLUSION
`
`Having considered the information presented in the Petition and the
`
`Preliminary Response, we institute an inter partes review, as we determine
`
`that Petitioner has established a reasonable likelihood that it would prevail in
`
`its challenges to claims 1–12 of the ’012 patent.
`
`At this stage in the proceeding, the Board has not made a final
`
`determination as to the construction of any claim term or the patentability of
`
`any challenged claim. Our final determination will be based on the record as
`
`fully developed at trial.
`
`20
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`
`It is
`
`IV. ORDER
`
`ORDERED that pursuant to 35 U.S.C. § 314(a), an inter partes
`
`review is instituted as to claims 1–12 of U.S. Patent No. 8,642,012 B2 on the
`
`following grounds of unpatentability:
`
`Claims 1, 3, 4, 7, 8, 10, and 12 under 35 U.S.C. § 103 as unpatentable
`
`over Brusilow ’91, Sherwin, Comte, and Shiple;
`
`claim 5 under 35 U.S.C. § 103 as unpatentable over Brusilow ’91,
`
`Sherwin, Shiple, and Fernandes;
`
`claims 2 and 9 under 35 U.S.C. § 103 as unpatentable over Brusilow
`
`’91, Sherwin, Shiple, and the ’647 patent; and
`
`claims 6 and 11 under 35 U.S.C. § 103 as unpatentable over Brusilow
`
`’91, Sherwin, Shiple, and Kasumov.
`
`It is
`
`FURTHER ORDERED that pursuant to 35 U.S.C. § 314(c) and 37
`
`C.F.R. § 42.4, notice is hereby given of the institution of a trial commencing
`
`on the entry date of this decision; and
`
`FURTHER ORDERED that no other grounds of unpatentability are
`
`authorized for this inter partes review other than those identified above.
`
`21
`
`
`
`

`

`IPR2015-01117
`Patent 8,642,012 B2
`
`For PETITIONER:
`
`Michael J. Freno: michael.freno@klgates.com
`David H. Silverstein: david.silverstein@parpharm.com
`Sanjay K. Murthy: sanjay.murthy@klgates.com
`
`
`
`For PATENT OWNER:
`
`Lauren Stevens
`Dennis Bennett
`GLOBAL PATENT GROUP, LLC
`lstevens@globalpatentgroup.com
`dennisbennett@globalpatentgroup.com
`
`Matthew Phillips (Reg. No. 43,403)
`RENAISSANCE IP LAW GROUP LLP
`9600 S.W. Oak Street, Suite 560
`Portland, Oregon 97223
`matthew.phillips@renaissanceiplaw.com
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`22
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`
`
`

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