Paper 53
`
`
`
`
`
`
`Trials@uspto.gov
` Entered: November 3, 2016
`
`
`
`571-272-7822
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PAR PHARMACEUTICAL, INC.,
`LUPIN LTD., and LUPIN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC,1
`Patent Owner.
`
`
`Case IPR2015-011172
`Patent 8,642,012 B2
`
`
`
`Before TONI R. SCHEINER, DEBORAH KATZ, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 and 37 C.F.R. § 42.73
`
`
`
`1 Patent owner represents “that it has changed name and converted form and
`is now Horizon Therapeutics, LLC.” Paper 51.
`2 Case IPR2016-00283, instituted on a petition filed by Lupin Ltd. and
`Lupin Pharmaceuticals, Inc., has been joined with Case IPR2015-01117.
`See Paper 32.
`
`
`
`
`
`
`
`
`Trials@uspto.gov
` Entered: November 3, 2016
`
`
`
`571-272-7822
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PAR PHARMACEUTICAL, INC.,
`LUPIN LTD., and LUPIN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC,1
`Patent Owner.
`
`
`Case IPR2015-011172
`Patent 8,642,012 B2
`
`
`
`Before TONI R. SCHEINER, DEBORAH KATZ, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 and 37 C.F.R. § 42.73
`
`
`
`1 Patent owner represents “that it has changed name and converted form and
`is now Horizon Therapeutics, LLC.” Paper 51.
`2 Case IPR2016-00283, instituted on a petition filed by Lupin Ltd. and
`Lupin Pharmaceuticals, Inc., has been joined with Case IPR2015-01117.
`See Paper 32.
`
`
`
`IPR2015-01117
`Patent 8,642,012 B2
`
`
`I. INTRODUCTION
`Par Pharmaceutical, Inc. (“Par” or “Petitioner Par”) 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. (“Horizon” or “Patent Owner”) filed a
`Preliminary Response (Paper 8) on August 5, 2015. On November 4, 2015,
`we instituted trial as to all of the challenged claims, on the following
`grounds.3
`
`References
`
`Basis
`
`Claims Challenged
`
`§ 103
`
`1, 3, 4, 7, 8, 10, 12
`
`Brusilow ’91,4 Sherwin ’19,5
`Comte,6 and Shiple7
`
`3 Par supported its challenge with a Declaration, executed April 29, 2015,
`by Neal Sondheimer, M.D., Ph.D. (“Sondheimer Declaration”) (Ex. 1002).
`4 Saul W. Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle
`for Waste Nitrogen Excretion, 29 PEDIATRIC RESEARCH 147–150 (1991)
`(“Brusilow ’91”) (Ex. 1012).
`5 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 ’19”) (Ex. 1016).
`6 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).
`7 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).
`2
`
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`IPR2015-01117
`Patent 8,642,012 B2
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`
`References
`
`Basis
`
`Claims Challenged
`
`Brusilow ’91 , Sherwin ’19,
`Shiple, and Fernandes8
`Brusilow ’91, Sherwin ’19,
`Shiple, and the ’647 patent9
`Brusilow ’91, Sherwin ’19,
`Shiple, Kasumov,10 and the
`’979 patent11
`
`§ 103
`
`§ 103
`
`5
`
`2, 9
`
`§ 103
`
`6, 11
`
`
`
`After institution, Lupin Ltd. and Lupin Pharmaceuticals, Inc.
`(“Lupin”) filed a Petition based on the same grounds as the Par Petition,
`with arguments and evidence substantially identical to those put forth by
`Par. See IPR2016-00283, Paper 1. Lupin’s Petition was accompanied by a
`Motion for Joinder. See IPR2016-00283, Paper 4. We instituted trial on the
`same challenges of Lupin’s Petition that we instituted trial on in the current
`inter partes review and joined the two proceedings in this single review. No
`
`
`8 INBORN METABOLIC DISEASES: DIAGNOSIS AND TREATMENT 219–220
`(John Fernandes et al. eds., Springer Verlag 3d ed. 2000) (“Fernandes”)
`(Ex. 1011).
`9 U.S. Patent No. 4,284,647, issued August 18, 1981 to Brusilow et al. (“the
`’647 patent”) (Ex. 1018).
`10 Takhar Kasumov et al., New Secondary Metabolites of Phenylbutyrate in
`Humans and Rats, 32 DRUG METABOLISM AND DISPOSITION 10–19 (2004)
`(“Kasumov”) (Ex. 1015).
`11 U.S. Patent No. 5,968,979, issued October 19, 1999 to Brusilow (“the
`’979 patent”) (Ex. 1026).
`
`3
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`IPR2015-01117
`Patent 8,642,012 B2
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`further submissions have been entered on Lupin’s part. Paper 32; see
`IPR2016-00283, Paper 12.
`Horizon filed a Patent Owner Response (Paper 25, “PO Resp.”), and
`Par filed a Reply (Paper 30, “Reply”). With our authorization, Horizon filed
`a Corrected Patent Owner Response (Paper 41, “Corr. PO Resp.”)—
`superseding Paper 25—in order to correct citations to Exhibit 2012. See
`Paper 40. Petitioner Par, with our authorization, filed a Supplemental Reply
`to the Corrected Patent Owner Response (Paper 45, “Supp. Reply”).
`Horizon did not move to amend any claim of the ’012 Patent.
`Horizon and Par each filed a Motion to Exclude (Papers 36, 38), and
`each filed an Opposition to the Motion of the other party (Papers 42, 44). In
`addition, Horizon filed a Reply to Par’s Opposition (Papers 46).
`We heard oral argument on July 26, 2016. A transcript of the
`argument has been entered into the record as Paper 52.
`We have jurisdiction under 35 U.S.C. § 6. Petitioner bears the burden
`of proving unpatentability of the challenged claims, and that burden never
`shifts to Patent Owner. Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375, 1378 (Fed. Cir. 2015). To prevail, Petitioner must establish
`facts supporting its challenge by a preponderance of the evidence. See 35
`U.S.C. § 316(e); 37 C.F.R. § 42.1(d). This Final Written Decision is issued
`pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73.
`For the reasons that follow, we determine that Par has not proved by a
`preponderance of the evidence that claims 1–12 are unpatentable.
`
`4
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`IPR2015-01117
`Patent 8,642,012 B2
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`
`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 Par 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.
`
`In addition, Patent Owner filed suit against Lupin, alleging
`infringement of the ’012 patent, in Horizon Therapeutics, Inc. v. Lupin Ltd.,
`Case No. 1:15-cv-07624-RBK-JS (D.N.J. filed Oct. 19, 2015). See
`IPR2016-00283, Paper 1, 8.
`B. 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.
`
`
`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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`
`“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.
`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
`
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`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.
`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 percentage 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.
`
`C. Illustrative Claims
`Par challenges claims 1–12 of the ’012 patent. Claims 1 and 8 are
`independent claims. Claims 1 and 8, reproduced below (with formatting
`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
`7
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`IPR2015-01117
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`
`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.
`
`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 (see Certificate of Correction for claim 8).
`
`II. ANALYSIS
`A. Level of Skill in the Art
`Par, supported by Dr. Sondheimer’s testimony, contends that a person
`of ordinary skill in the art “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.”
`Pet. 8–9 (citing Ex. 1002 ¶ 24).
`
`8
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`IPR2015-01117
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`
`Horizon, on the other hand, contends that a person of ordinary skill in
`the art would have the following qualifications:
`(a) An M.D. or equivalent degree; (b) At least three years of
`residency/fellowship training in Medical Genetics, including
`Biochemical Genetics, followed by certification in Clinical
`Genetics and Clinical Biochemical Genetics by the American
`Board of Medical Genetics and Genomics; and (c) At least five
`years of experience treating patients with nitrogen retention
`disorders, including UCDs.
`Corr. PO Resp. 26.
`
`Horizon contends that Par’s definition “does not require . . . any
`experience treating patients with urea cycle disorders or other nitrogen
`retention disorders,” but “simply requires ‘specialized training in the
`diagnosis or treatment of inherited metabolic disorders, such as UCD and
`other nitrogen retention disorders.’” Id. Horizon contends because “the
`challenged claims specifically relate to methods of treating UCD patients,”
`one of ordinary skill in the art should have experience treating UCD patients.
`Id.
`Horizon’s point is well taken—that is, we agree that one of ordinary
`
`skill in the art should have experience treating, as well as diagnosing, UCD
`patients. In any case, our ultimate disposition of this case would not change
`under either Par’s or Horizon’s definition.
`B. Petitioner’s Witness, Dr. Sondheimer
`As discussed above, Par relies on the testimony of Neal Sondheimer,
`M.D., Ph.D. (Ex. 1002). Dr. Sondheimer testifies that he currently holds
`
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`several positions at the Children’s Hospital of Philadelphia and the
`University of Pennsylvania, including Attending Physician in the Division of
`Biochemical Genetics, Training Director for the Clinical Biochemical
`Genetics Group, Program Director for Medical Genetics, and Assistant
`Professor of Pediatrics. Ex. 1002 ¶ 10. Dr. Sondheimer testifies that he has
`been involved in several research studies involving the treatment of urea
`cycle defects and has co-authored several publications about the use of
`ammonia-scavenging medications. Id. ¶ 12.
`Horizon does not take issue with Dr. Sondheimer’s qualifications, and
`we find Dr. Sondheimer qualified to provide opinions on the subject matter
`at issue.
`
`C. 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);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016)
`(upholding the use of the broadest reasonable interpretation standard).
`Under that standard, claim terms are given their ordinary and 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).
`
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`
`“mean conversion . . . of about 60%”
`The term “mean conversion of PAA prodrug to urinary PAGN of
`
`about 60%” appears in both independent claims 1 and 8.
`In the Petition, Par argued that the term should be construed “as
`encompassing a range of mean conversion between 53–67%.” Pet. 10–12.
`Horizon did not address this issue in its Preliminary Response, and we
`determined it was not necessary to construe the term for purposes of
`institution. See Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361
`(Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to the extent
`necessary to resolve the controversy.’”) (Quoting Vivid Techs., Inc. v. Am.
`Sci. Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
`In its Corrected Patent Owner Response, Horizon contends that “the
`claim term ‘about 60%’ has its plain and ordinary meaning and would be
`understood by a [person of ordinary skill in the art] to encompass 67%”
`(Corr. PO Resp. 27), but nothing in the claims, specification or prosecution
`history of the ’012 patent supports Par’s “assertion that ‘about 60%’ should
`be construed to encompass 53%” (id.). Nevertheless, we again determine
`that it is not necessary to expressly construe the term for purposes of this
`decision. To the extent Par relies on the term as “encompassing a range of
`mean conversion between 53–67%,” however, we reject its proposed
`construction.
`The specification of the ’012 patent states “in contrast to the
`assumptions inherent in current treatment guidelines that all administered
`
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`sodium PBA is converted to urinary PAGN, considerable inter-individual
`variability was observed in the percentage of administered PAA converted to
`PAGN, which averaged ~60% and similar [sic] both sodium PBA and HPN-
`100” in UCD patients. Ex. 1001, 32:3–9. The ’012 patent further states that
`“HPN-100 is typically converted into urinary PAGN with an efficiency of
`about 60% to 75%,” but clarifies that “typically about 60% conversion was
`found in UCD patients;” while “conversion in cirrhotic patients was about
`75%.” Id. at 40:33–36.
`Nothing in the specification, then, explicitly supports Par’s contention
`that the term “about 60%” encompasses a range of about 53–67%. That, in
`and of itself, does not settle the matter. We still must consider Par’s
`contention that its construction is supported by the prosecution history of the
`’012 patent. DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 469 F.3d
`1005, 1014 (Fed. Cir. 2006) (“In determining the meaning of the disputed
`claim limitation, we look principally to the intrinsic evidence of record,
`examining the claim language itself, the written description, and the
`prosecution history, if in evidence.”); Microsoft Corp. v. Proxyconn, Inc.,
`789 F.3d 1292, 1298 (Fed. Cir. 2015) (stating that the PTO should consider
`prosecution history in inter partes review).
`In support of its contention, Par directs us to “the November 20, 2012
`Declaration of Bruce Scharschmidt [M.D.], [the] named inventor, submitted
`during prosecution of the ’012 patent” (Pet. 11 (citing Ex. 1021 (prosecution
`history of the ’012 patent), 682–683)); the Examiner’s Amendment and
`
`12
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`Reasons for Allowance (id. at 11–12 (citing Ex. 1021, 718–719)); and
`finally, Dr. Sondheimer’s testimony regarding how a person of ordinary skill
`in the art would have construed the term “about 60%” given the
`Scharschmidt Declaration and Examiner’s Amendment and Reasons for
`Allowance (id. at 6, 10 (citing Ex. 1002 ¶ 27)).
`In his Declaration, Dr. Scharschmidt noted that “[t]he pending claims
`. . . have been amended to specify [treatment of] urea cycle disorder (rather
`than nitrogen retention disorders generally” and provided “detailed data for
`PAA prodrug conversion to urinary PAGN in approximately 65 UCD
`patients . . . during steady state dosing” with sodium PBA or HPN-100. Ex.
`1021, 683. Dr. Scharschmidt reported that “the mean percent conversion of
`PAA prodrug to urinary PAGN in UCD patients was 67%, with a . . . 99%
`confidence range of 63–71%” (id.), which “falls squarely within the range
`[of 60% to 75%] recited in the present claims, and . . . well below 80%”
`(id.).
`Following the submission of Dr. Scharschmidt’s Declaration, the
`
`Examiner entered an Examiner’s Amendment as follows, in relevant part:
`“wherein the effective dosage of PAA prodrug is calculated based on a mean
`conversion of PAA prodrug to urinary PAGN of about 60% to 75%” (Ex.
`1021, 718). In the Reasons for Allowance, the Examiner stated, in relevant
`part: “[Dr. Scharschmidt’s] Declaration filed 11/21/2012 contains data
`drawn to an about 60% conversion rate of PAA to urinary PAGN as
`
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`disclosed in the specification, which supports applicants disclosed drug
`conversion in the as filed specification.” Id. at 719.
`
`Finally, Dr. Sondheimer “reviewed the correspondence between the
`patent office and the applicant” and testifies that “[t]he examiner would not
`grant a patent to the claimed methods until after applicant submitted test data
`showing a mean percent conversion of 67%, and the examiner narrowed the
`claims to a mean percent conversion of about 60%.” Ex. 1002 ¶ 27. Based
`on this, Dr. Sondheimer concludes that “about 60% includes 67%,” and
`further testifies that in his opinion, “a person of ordinary skill in the art
`would interpret the patent term ‘mean conversion . . . of about 60%’ as
`meaning at least 53–67%.” Id.
`Nevertheless, we are not persuaded that the Examiner’s statement in
`the Reasons for Allowance that Dr. Scharschmidt’s Declaration “contains
`data drawn to and about 60% conversion rate” unambiguously conveys to
`one of ordinary skill in the art that “about 60%” should be construed “as
`encompassing a range of mean conversion between 53–67%” (Pet. 10–12),
`inasmuch as the specification of the ’012 patent discloses expressly that the
`conversion rate in UCD patients averages “about 60%,” but a large portion
`of the range 53–67% does not even fall within the 99% confidence range of
`63–71% reported in Dr. Scharschmidt’s Declaration.
`In any case, for the reasons discussed below, even if we credit Dr.
`Sondheimer’s testimony in this regard and accept Par’s proposed
`construction of the term “mean conversion . . . of about 60%” as
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`encompassing a range of mean conversion between 53–67%, it would not
`change our ultimate disposition of the case.
`
`D. Claims 1, 3, 4, 7, 8, 10, 12—Asserted Obviousness over
`Brusilow ’91, Sherwin ’19, Comte, and Shiple
`
`Par, relying on the testimony of Dr. Sondheimer, contends that
`
`Brusilow ’91, Sherwin ’19, Comte, and Shiple represent the state of the art
`with respect to treatment of urea cycle disorders with phenylbutyric acid,
`and that their combined teachings would have rendered the subject matter of
`claims 1, 3, 4, 7, 8, 10, and 12 obvious to one of ordinary skill in the art.
`Pet. 15–28.
`Horizon argues, among other things, that the references relied on by
`Par represent an incomplete, and therefore misleading picture of the state of
`the art, and presents additional evidence in support of its arguments. Corr.
`PO Resp. 5–7, 41–47.
`We begin our analysis of the state of the art with a discussion of the
`prior art cited by Par.
`
`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
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`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
`with sodium phenylacetate (NaPAA) and twice with sodium phenylbutyrate
`(NaPBA). Ex. 1012, 147. Table 1 of Brusilow ’91 is reproduced below:
`
`
`
`between
`stoichiometry
`the
`compares
`1
`Table
`phenylacetate or phenylbutyrate administration and urinary
`excretion of PAG. The amount of PAG excreted was a function
`of phenylacetate or phenylbutyrate dose; between 80 and 90%
`of the predicted amount of PAG synthesized is excreted. That
`these may be minimum excretion values is suggested by the
`coefficient of variation of the creatinine excretion over the 9 d,
`which was 14%. . . . Phenylacetate, phenylbutyrate, or total
`glucuronide excretion in the urine did not exceed 1% of the
`administered drug in any period.
`Ex. 1012, 148.
`
`According to Brusilow ’91, “Table 1 demonstrates both that
`phenylbutyrate appears to be completely oxidized to phenylacetate and that
`phenylacetate is completely, or nearly so, conjugated with glutamine.” Id. at
`
`16
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`149. “That complete conjugation of the drugs occurs may be further
`adduced by the insignificant amount of unchanged drugs or their esters in
`urine and by the lack of accumulation in overnight fasting plasma.” Id.
`2. Sherwin ’19 (Ex. 1016)13
`Sherwin ’19 discusses the results of a study of the conversion of
`
`phenylacetic acid (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 ’19
`suggests 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. at 118.
`
`3. Comte (Ex. 1025)
`Comte discloses that metabolism of phenylbutyrate in humans
`produces PAGN, as well as another metabolite, phenylbutyrlglutamine
`
`
`13 Horizon refers to Exhibit 1016 as “Sherwin ’19” in the Corrected Patent
`Owner Response, and we do likewise throughout this opinion to avoid
`confusion with Exhibit 2027, “Sherwin ’33.”
`17
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`(PBGN). Ex. 1025, 581. Comte observed that “[t]he total recovery of the
`ingested dose of phenylbutyrate as identified urinary compounds
`(PA+PB+PAGN+PBGN) was 53.4 ± 4.5% after 8 h.” in seven normal
`subjects. Id. at 589. Comte postulates that “part of the ingested PB is
`converted to metabolite(s) which have not yet been identified.” Id. at 590.
`
`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. 1017, 619, 623. Shiple further discloses that about
`95% of a 10 g dose of phenylacetic acid was excreted as phenylacetyl
`glutamine in a 24-hour urine sample, while only about 78% was recovered
`after smaller doses. Id. at 623.
`
`5. Analysis
`
`Claim 1
`In its Petition, Par 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 the dose of the PAA prodrug
`administered during period III (see Ex. 1012, Table 1) was calculated based
`on a mean conversion of PAA prodrug to urinary PAGN of about 90%
`during period II, rather than about 60%, as recited in claim 1. Pet. 20.
`Nevertheless, Par, relying on 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
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`range of conversion rates (80–90%)” in that single subject, would have
`looked to other references, such as Sherwin ’19 and Shiple, for more
`information on conversion rates, “because each discusses the conversion of
`PAA to PAGN” (Pet. 17 (citing Ex. 1002 ¶¶ 42–45)). Par 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%, or as construed by Par, between 53–67%. Id. at 19.
`In this regard, Dr. Sondheimer testifies, “[a]s seen in Table I of
`Sherwin [’19], the conversion of PAA into urinary PAGN in normal subjects
`ranged from about 50–67% for all doses” and “at clinically relevant doses
`(10 grams or higher), Sherwin [’19] 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 [’19] would understand that the 51–52% figures are
`low” because “Sherwin [’19] 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 [’19’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
`
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`¶ 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 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 [’19] for the normal
`subject would also be applicable
`to
`the UCD patient.
`Therefore, a person of ordinary skill in the art reading Sherwin
`[’19] in view of Shiple would have understood that the
`percentage conversion of administered PAA to PAGN observed
`in the healthy volunteer of Sherwin [’19] would also have been
`observed in a UCD patient.
`Ex. 1002 ¶ 55.
` Consequently, Par, supported by the testimony of Dr. Sondheimer,
`contends that one of ordinary skill in the art “would have used Sherwin
`[’19’s] conversion rates 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).
`In its Corrected Patent Owner Response, Horizon contends that “prior
`to August 2008, and as early as the 1980s,” urinary PAGN “was understood
`to be a measure of the amount of nitrogen excreted by patients taking PAA
`prodrugs” (Corr. PO Resp. 17 (citing Ex. 1018, 4:35–50)), and contrary to
`Petitioner’s contentions, “there was a consensus in the prior art that
`conjugation of PAA to [urinary PAGN] was close to 100% in UCD patients
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`and healthy subjects” (id. (citing Ex. 1018, 2:53–67, 4:35–50; Ex. 1012, 149;
`Ex. 2025; Ex. 2026; Ex. 2027)).
`According to Horizon, Dr. Sondheimer’s assertion that “Dr. Brusilow
`‘averaged the observed PAGN excretion in the first two phases to determine
`an effective dosage based on a mean conversion of PAA prodrug to urinary
`PAGN of about 86% . . . conflicts with and has no support in the text of
`Brusilow ’91.” Id. at 36–37 (citing Ex. 1002, 32).
`In particular, Horizon contends that “the purpose of th[e] experiment
`in Brusilow ’91 was not to make dosing recommendations for the patient
`based on the results of the experiment.” Corr. PO Resp. 38. Rather,
`the purpose of the experiment [described in Brusilow ’91] was
`to study the “stoichiometry between oral sodium phenylacetate
`or
`sodium phenylbutyrate administration and PAG[N]
`excretion.” It follows that Brusilow predetermined the dosages
`of sodium phenylacetate or sodium phenylbutyrate (10 g, 12 g
`and 14 g, respectively) to administer to the patient, expressly
`predicted a 100% conversion of PAA to PAGN (190 mmol, 193
`mmol, and 225 mmol, respectively) and then measured the
`resulting UPAGN excretion for each period I, II and III.
`Id. (citing Ex. 1012, 147–148, Table 1) (internal citation omitted).
`According to Horizon, Dr. Sondheimer
`acknowledged at his deposition that Table 1 of Brusilow ’91
`predicts a 100% conversion of PAAto PAGN (190, 193, and
`225 mmol of PAGN) for each of the 10 g, 12 g, 14 g doses of
`PAA prodrug to be administered to the patient during Periods
`I–III of the study.
`Corr. PO Resp., 39 (citing Ex. 1012, 148, Table 1; Ex. 2012, 116:20–117:7,
`117:18–118:1, 118:13–17, 118:18–119:2 (“Q. . . . 225 millimoles assume[s]
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`100 percent conversion of the 14-gram dose of PBA to PAGN, correct? A.
`Yes.”)). Consequently, Horizon contends there is no support for Dr.
`Sondheimer’s “asse
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