UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________
`
`
`
`PAR PHARMACEUTICAL, INC.
`Petitioner
`
`v.
`
`
`
`
`
`HYPERION THERAPEUTICS, INC.
`Patent Owner
`
`___________
`
`
`
`Case IPR2015-01117*
`Patent 8,642,012
`
`___________
`
`
`
`PATENT OWNER HORIZON THERAPEUTICS, INC.’S CORRECTED
`PATENT OWNER RESPONSE PURSUANT TO 37 C.F.R. § 42.120
`
`
`
`
`* Case IPR2015-00283, instituted on a petition filed by Lupin Ltd. and Lupin
`Pharmaceuticals, Inc., has been joined with this proceeding.
`
`

`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`D.
`
`Background ........................................................................................... 1
`
`Relief Requested .................................................................................... 2
`
`Related Proceedings .............................................................................. 2
`
`Summary of Argument .......................................................................... 2
`
`II.
`
`RELEVANT LAW .......................................................................................... 7
`
`III. RELEVANT TECHNICAL BACKGROUND ............................................... 9
`
`A. Nitrogen Retention Disorders ................................................................ 9
`
`B.
`
`C.
`
`D.
`
`E.
`
`Prior to August 2008, There was a Need for Reliable
`Biomarkers to Determine Effective Dosages of
`PAA Prodrugs ...................................................................................... 14
`
`Prior to August 2008, Conversion of PAA to PAGN was
`assumed to be Complete or Nearly Complete in UCD
`Patients ................................................................................................ 17
`
`The Development of the Inventions of the ’012 Patent ...................... 23
`
`The Challenged Claims of the ’012 Patent ......................................... 24
`
`IV. LEVEL OF SKILL IN THE ART .................................................................26
`
`V.
`
`INTERPRETATIONS OF THE ’012 PATENT CLAIMS ...........................27
`
`VI. THE SCOPE AND CONTENT OF THE PRIOR ART ................................28
`
`A.
`
`B.
`
`C.
`
`D.
`
`Brusilow ’91 ........................................................................................ 28
`
`Sherwin ’19 ......................................................................................... 30
`
`Shiple ................................................................................................... 32
`
`Comte .................................................................................................. 33
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`E.
`
`F.
`
`G.
`
`Kasumov .............................................................................................. 34
`
`Fernandes ............................................................................................. 34
`
`’647 Patent ........................................................................................... 34
`
`VII. ARGUMENT .................................................................................................35
`
`A.
`
`Petitioner’s Argument that Claims 1, 3-4, 7- 8, 10 and 12
`are Obvious over Brusilow ’91 in view of Sherwin ’19,
`Comte and Shiple Fails Because it Hinges on Dr.
`Sondheimer’s Misreading of Brusilow ’91 in
`Combination with Sherwin ’19, a Discredited Reference ................... 35
`
`1.
`
`2.
`
`Petitioner’s Assertion that a POSA Would Have Been
`Motivated to Combine Brusilow ’91 with Sherwin 1919 Fails
`because Sherwin ’19 was Later Discredited ............................. 42
`
`Sherwin ’19, Shiple and Comte Fail to Cure the Deficiencies of
`Brusilow ’91 because a POSA would not have Understood
`those References to Teach or Suggest Incomplete Conversion 47
`
`Petitioner’s Argument that Claim 5 is Obvious over
`Brusilow ’91 in view of Sherwin ’19, Shiple and
`Fernandes Fails Because it Hinges on Dr. Sondheimer’s
`Misreading of Brusilow ’91 in Combination with
`Sherwin ’19, a Discredited Reference ................................................. 51
`
`Petitioner’s Argument that Claims 2 and 9 are Obvious
`over Brusilow ’91 in view of Sherwin ’19, Shiple and the
`’647 patent Fails Because it Hinges on Dr. Sondheimer’s
`Misreading of Brusilow ’91 in Combination with
`Sherwin ’19, a Discredited Reference ................................................. 52
`
`Petitioner’s Argument that Claims 6 and 11 are Obvious
`over Brusilow ’91 in view of Sherwin ’19, Shiple and
`Kasumov Fails Because it Hinges on Dr. Sondheimer’s
`Misreading of Brusilow ’91 in Combination with
`Sherwin ’19, a Discredited Reference ................................................. 53
`
`B.
`
`C.
`
`D.
`
`VIII. CONCLUSION ..............................................................................................54
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`TABLE OF AUTHORITIES
`
`Cases
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .................................................................................................... 8
`
`In re Cyclobenzaprine Hydrochloride Extended Release Capsule Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .............................................................................. 8
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ................................................................................................ 8
`
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .............................................................................. 9
`
`Ricoh Co., Ltd. v. Quanta Computer, Inc.,
`550 F.3d 1325 (Fed. Cir. 2008) .............................................................................. 9
`
`Transocean Offshore Drilling v. Maersk Drilling USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) .............................................................................. 8
`
`Unigene Labs Inc. v. Apotex, Inc.,
`655 F.3d 1352 (Fed. Cir. 2011) .............................................................................. 8
`
`W.L. Gore & Assocs., Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) .............................................................................. 9
`
`Wyers v. Master Lock Co.,
`616 F.3d 1231 (Fed. Cir. 2010) .............................................................................. 8
`
`Statutes
`
`35 U.S.C. § 103(a) ..................................................................................................... 7
`
`Other Authorities
`
`MPEP 2141.02 ........................................................................................................... 9
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`I.
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`INTRODUCTION
`A. Background
`The Board has ordered an investigation into the patentability of claims 1-12
`
`(collectively “the challenged claims”) of U.S. Patent No. 8,642,012 (“the ’012
`
`patent”).1 The present inter partes review has been instituted for the challenged
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`claims solely on obviousness grounds.
`
`Petitioner’s obviousness arguments require combining features of several
`
`prior art publications. The prior art references at issue are Brusilow ’91 (Ex.
`
`1012), Comte (Ex. 1025), Shiple (Ex. 1017), Sherwin ’19 (Ex. 1016), the ’674
`
`patent (Ex. 1018), Kausmov (Ex.1015) and Fernandes (Ex. 1011). Petitioner
`
`asserts various combinations of the cited references as rendering the challenged
`
`claims obvious, as seen in the summary table below:
`
`
`
`
`1 Lupin Ltd. and Lupin Pharmaceuticals, Inc. (“Lupin”) have filed a Petition for
`
`inter partes review of the ’215 patent that is substantively identical to Par’s
`
`Petition. (See Petition, Paper No. 1, IPR2016-00283.) Lupin filed an unopposed
`
`motion for joinder to the instant inter partes review but their motion has not yet
`
`been granted. (See Motion for Joinder, Paper No. 4 at 4, IPR2016-00284.)
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`Claims
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`Alleged Prior Art
`
`1, 3, 4, 7, 8, 10
`and 12
`
`Brusilow ’91 in view of Sherwin ʼ19, Comte and
`Shiple
`
`5
`
`2, 9
`
`Brusilow ’91 in view of Sherwin ’19, Shiple and
`Fernandes
`
`Brusilow ’91 in view of Sherwin ’19, Shiple and
`the ’647 patent
`
`6 and 11
`
`Brusilow ’91 in view of Sherwin ’19, Shiple and
`Kasumov
`
`B. Relief Requested
`Patent Owner respectfully requests that the Board determine that the
`
`Petitioner has failed to meet its burden to demonstrate that claims 1-12 of the ’012
`
`patent are unpatentable in view of the asserted reference combinations.
`
`C. Related Proceedings
`Petitioners have filed an additional petition for inter partes review of
`
`Horizon’s U.S. Patent No. 8,404,215, although that patent is not related to the ’012
`
`patent.
`
`Summary of Argument
`
`D.
`Prior to August 2008, the prior art as a whole taught that phenylacetic acid
`
`(“PAA”) is completely or nearly completely converted to urinary phenylacetyl
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`glutamine (“UPAGN”) in urea cycle disorder (“UCD”) patients, and clinicians
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`made dosing decisions for those patients based on the assumption of 100%
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`conversion of PAA to UPAGN. In addition, prior to August 2008, nothing in the
`
`prior art taught or suggested that UPAGN excretion should be used as a biomarker
`
`for adjusting the dosage of PAA prodrugs.
`
`Surprisingly, Dr. Bruce Scharschmidt, the inventor of the ’012 patent,
`
`discovered that the prior art was incorrect and that conversion of PAA to UPAGN
`
`was incomplete in UCD patients and as low as about 60%. This discovery was
`
`critical for patients with rare and debilitating UCDs because it meant that many
`
`patients had not been prescribed adequate dosages of PAA prodrug to control their
`
`blood ammonia levels, with life-threatening implications.
`
`Dr. Scharschmidt translated his discovery into the claimed methods of
`
`treating UCD patients that involve determining or calculating an effective dosage
`
`of PAA prodrug based on the finding that UPAGN conversion is not near-complete
`
`as taught in the art, but instead is only about 60%. The claimed methods allow
`
`physicians to use UPAGN excretion as a biomarker to more accurately dose UCD
`
`patients with PAA prodrugs.
`
`Each of Petitioner’s invalidity positions relies on the combination of two
`
`references, Brusilow ’91 and a 1919 Sherwin publication, taken alone or in further
`
`combination with other references. The Board’s decision to institute this inter
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`partes review relied in part on Petitioner’s expert, Dr. Sondheimer’s description of
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`those two prior art references. However, as discussed below, Dr. Sondheimer’s
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`interpretation of Brusilow ’91 is incorrect and Sherwin ’19 was discredited in a
`
`later 1933 publication (Ambrose, Power & Sherwin, “Further Studies on the
`
`Detoxication of Phenylacetic Acid,” J. Biol. Chem., 101, 669-675 at 675 (1933),
`
`Ex. 2027, “Sherwin ’33”) by the same research group, a reference which Dr.
`
`Sonheimer did not address in his Declaration (Ex. 1002).
`
`Dr. Sondheimer’s interpretation of Brusilow ’91 directly conflicts with the
`
`conclusions of the publication. According to Dr. Sondheimer, Brusilow ’91
`
`discloses incomplete conversion of PAA to UPAGN. However, Brusilow ’91’s
`
`explicit conclusion is that PAA “is completely or nearly so,” converted to PAGN.
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`(Ex. 1012 at 149.) Thus, Brusilow ’91 actually teaches away from the claimed
`
`methods, which utilize a PAA to UPAGN conversion of 60% to determine the dose
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`of PAA that is to be administered.
`
`Additionally, Dr. Sondheimer insists that Brusilow ’91 taught adjusting the
`
`dosage of PAA prodrug based on the UPAGN excreted by his patient. However,
`
`the folly of this approach was revealed at Dr. Sondheimer’s deposition where he
`
`conceded that nothing in the text of Brusilow ’91 actually supported this
`
`interpretation. (Sondheimer Deposition Transcript at 120:7-19; 120:22-25,
`
`“Ex. 2012.”) Moreover, Dr. Sondheimer’s interpretation of Brusilow ’91 is
`
`contrary to Dr. Brusilow’s description and stated purpose of his study.
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`Dr. Sondheimer’s reliance on Sherwin ’19, likewise misleads the Board and
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`ultimately exposes a major fallacy with Petitioner’s invalidity argument. Dr.
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`Sondheimer claims that a POSA (person of ordinary skill in the art) would rely on
`
`Sherwin ʼ19 for its data showing low PAA-to-PAGN conversion (51-52%).
`
`However, Sherwin ’33, a later publication by the same research group, expressly
`
`discredits the data in Sherwin ’19. Even more damming, Sherwin ’33 concludes
`
`that conversion of PAA to PAGN is near 100%. Although Dr. Sondheimer ignores
`
`Sherwin ’33, he concedes that a POSA would have considered later publications
`
`concerning PAA to PAGN conversion to be relevant, including references cited in
`
`the ’674 patent—which cites Sherwin ’33.
`
`Other secondary references Dr. Sondheimer relies on—Shiple and the ’647
`
`patent—similarly contradict Dr. Sondheimer’s assertion that a POSA would have
`
`understood conversion of PAA to PAGN to be incomplete. Shiple plainly teaches
`
`away from the claimed methods because it concludes on its face that PAA-to-
`
`PAGN conversion was nearly complete (95%) in a healthy subject at a
`
`therapeutically relevant dose (10 g). The ’647 patent likewise affirms that that
`
`conversion of PAA to UPAGN is nearly complete (91% and 98%, respectively) in
`
`reliance on Sherwin ’33 and James ’72 (James et al., “The Conjugation of
`
`phenylacetic acid in man, sub-human primates and some non-primate species,”
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`Proc. R. Soc. Lond., 182, 25-35 at 32-33 (1972), “Ex. 2026”), references not
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`discussed by Dr. Sondheimer. Petitioner’s remaining cited references, Comte and
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`Kasumov, fail to provide any relevant disclosure because they do not make any
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`claims as to the overall percentage conversion of PAA to PAGN in healthy
`
`subjects, let alone UCD patients after administration of PAA prodrugs. Fernandes,
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`likewise, fails to support Petitioner’s argument because it provides treatment
`
`guidelines for UCD patients that do not suggest measurement of UPAGN
`
`excretion.
`
`Not only do the prior art references, viewed in isolation, teach away from the
`
`challenged claims, Petitioner has failed to provide any support for its proposed
`
`combinations of Brusilow ’91 with secondary references, Sherwin, Shiple, and
`
`Comte. At the outset, Dr. Sondheimer fails to justify why a POSA faced with
`
`Brusilow ’91’s conclusion that PAA to PAGN conversion was close to 100%,
`
`would have sought out additional references to “determine the true rate of
`
`conversion.” Dr. Sondheimer also does not explain why a POSA would ignore the
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`conversion data in Brusilow ’91 (i.e., 80-90%), which he admits a POSA would
`
`consider reliable, and instead would rely solely on seventy (70) year old
`
`discredited data (51-52%) to determine a mean conversion percentage. In this
`
`regard, Patent Owner suggests that the Board consider the weight to be attached to
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`Dr. Sondheimer’s testimony given his willingness to repeatedly ignore the clear
`
`teachings of the prior art.
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`However, even if a POSA faced with Brusilow ’91 were to search for
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`additional references concerning PAA-to-PAGN conversion, they would not have
`
`relied on Sherwin ’19 because its conclusions concerning PAA-to-PAGN
`
`conversion were expressly discredited by Sherwin ’33. Further, if a POSA were to
`
`combine Brusilow ’91 with Shiple or Comte, they could not have arrived at the
`
`claimed methods because Shiple discloses near 100% conversion at a
`
`therapeutically relevant dosage and Comte provides no conclusions concerning
`
`overall conversion of PAA to PAGN.
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`Thus, the Board should find that Petitioner has failed to meet its burden to
`
`show unpatentability because the prior art which Petitioner cites in Grounds 1-4 of
`
`the Petition actually teaches away from the challenged claims and none of the cited
`
`prior art teaches or suggests calculating an effective dosage of a PAA prodrug for a
`
`UCD patient based on PAGN excretion, let alone a mean PAA to UPAGN
`
`conversion of about 60%. Clearly, the Board should reject Petitioner’s invalidity
`
`arguments because they hinge entirely on Dr. Sondheimer’s misinterpretation of
`
`Brusilow ’91 in combination with a discredited 1919 reference.
`
`II. RELEVANT LAW
`Under pre-AIA 35 U.S.C. § 103(a), a claim is obvious “when the subject
`
`matter sought to be patented and the prior art are such that the subject matter as a
`
`whole would have been obvious at the time the invention was made to a person
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`having ordinary skill in the art to which said subject matter pertains.” Wyers v.
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`Master Lock Co., 616 F.3d 1231, 1237 (Fed. Cir. 2010). “[A] patent composed of
`
`several elements is not proved obvious merely by demonstrating that each of its
`
`elements was, independently known in the prior art.” KSR Int’l Co. v. Teleflex
`
`Inc., 550 U.S. 398, 418 (2007). Where a party seeks to invalidate a patent based
`
`on obviousness, it must demonstrate by a preponderance of evidence that a “skilled
`
`artisan would have had reason to combine the teaching of the prior art reference to
`
`achieve the claimed invention and that the skilled artisan would have had a
`
`reasonable expectation of success from doing so.” In re Cyclobenzaprine
`
`Hydrochloride Extended Release Capsule Patent Litig., 676 F.3d 1063, 1068-69
`
`(Fed. Cir. 2012).
`
`Obviousness is a question of law based on underlying findings of fact.
`
`Unigene Labs Inc. v. Apotex, Inc., 655 F.3d 1352, 1360 (Fed. Cir. 2011). In
`
`determining whether a claim is obvious, the Supreme Court has held that the
`
`following four factors must be examined: (1) the scope and content of the prior art;
`
`(2) the differences between the prior art and the claimed invention; (3) the level of
`
`skill in the pertinent art; and (4) any objective indicia of nonobviousness. Graham
`
`v. John Deere Co., 383 U.S. 1, 17-18 (1966). All four factors must be considered
`
`in an obviousness analysis. Transocean Offshore Drilling v. Maersk Drilling USA,
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`Inc., 699 F.3d 1340, 1349 (Fed. Cir. 2012).
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`“A prior art reference must be considered in its entirety, i.e., as a whole,
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`including portions that would lead away from the claimed invention. MPEP
`
`2141.02; see also Panduit Corp. v. Dennison Mfg. Co., 810 F.2d 1561, 1568 (Fed.
`
`Cir. 1987) (citing W.L. Gore & Assocs., Inc. v. Garlock, Inc., 721 F.2d 1540, 1550
`
`(Fed. Cir. 1983)). “A reference may be said to teach away when a person of
`
`ordinary skill, upon reading the reference would be discouraged form following the
`
`pathway set out in the reference, or would be lead in a direction divergent from the
`
`path that was taken by the applicant.” Ricoh Co., Ltd. v. Quanta Computer, Inc.,
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`550 F.3d 1325, 1332 (Fed. Cir. 2008).
`
`III. RELEVANT TECHNICAL BACKGROUND
`A. Nitrogen Retention Disorders
`Ammonia is a toxic metabolic waste product. Nitrogen retention disorders
`
`are conditions that result in elevated blood ammonia2 levels, referred to as
`
`hyperammonemia, and include inherited metabolic disorders such as urea cycle
`
`
`2 The terms “blood ammonia” and “plasma ammonia” are used interchangeably in
`
`the prior art because, in order to measure blood ammonia, a blood sample is taken
`
`from the patient, the blood plasma is extracted from the sample and then analyzed
`
`for ammonia content. Thus, any reference to “blood ammonia” in this document
`
`or in the prior art refers to, and is the same as, “plasma ammonia.”
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`disorders (i.e., UCDs). Hyperammonemia is a significant health risk because high
`
`ammonia levels are toxic to the brain. (Ex. 1002 at 10.) Conversely, there are no
`
`recognized ill effects of ammonia levels which are lower than normal, or even
`
`absent. Thus, nitrogen retention disorders such as UCDs differ from conditions
`
`such as diabetes because there is no minimum level of blood ammonia that must be
`
`maintained for normal body function; instead, physicians focus on maintaining
`
`blood ammonia below a particular level so as to avoid toxicity. (Ex. 1002 at 12.)
`
`In an individual afflicted by a UCD, the plasma ammonia concentration is
`
`raised as a result of metabolic blocks in the urea cycle. (Ex. 1011 at 217.) The
`
`degree to which ammonia is elevated for an individual with a UCD is dependent on
`
`a number of factors, including the enzyme involved, its residual activity, the
`
`patient’s protein intake and the patient’s rate of endogenous protein catabolism.
`
`(Id.)
`
`A normal diet contains a significant amount of protein, which is a source of
`
`nitrogen, and, as such, dietary intake of protein will cause nitrogen accumulation
`
`and hyperammonemia in patients who have nitrogen retention disorders. (Ex. 1002
`
`at 10-12.) Waste nitrogen also accumulates in such patients during times of illness
`
`severe enough to cause catabolism. (Gerard Berry & Robert Steiner, “Long-term
`
`management of patients with urea cycle disorders,” J. Ped., 138(1):S56-61 (2001),
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`“Ex. 2013”; Summar et al., “Unmasked Adult-Onset Urea Cycle Disorders in the
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`Critical Care Setting,” Crit. Care Clin., at S1-S8 (2005), “Ex. 2014.”) Other
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`events that can cause hyperammonemia include trauma, surgery, infection,
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`chemotherapy and treatment with glucocorticoids. (Id.) In short, patients with
`
`nitrogen retention disorders are constantly faced with the potential to accumulate
`
`excess body nitrogen, which will typically result in hyperammonemia with toxic
`
`effects. (Id.)
`
`Most UCD patients require a low-protein diet because dietary protein is a
`
`primary source of waste nitrogen. (Ex. 1011 at 218.) Thus, dietary protein
`
`restriction is one method through which physicians treat patients with UCDs. (Id.)
`
`However, because the intake of dietary protein provides important benefits to the
`
`body, especially for growing children afflicted with UCDs, it is also necessary to
`
`treat such patients with drugs that assist with nitrogen excretion, referred to as
`
`nitrogen scavenging agents. (Id.)
`
`Nitrogen scavenging drugs include sodium phenylbutyrate (NaPBA,
`
`approved in the United States as BUPHENYL® and in Europe as
`
`AMMONAPS®), sodium benzoate, sodium phenylacetate and sodium benzoate
`
`(approved in the United States as AMMONUL®), and glyceryl tri-[4-
`
`phenylbutyrate] (HPN-100 or glycerol phenylbutyrate or glycerol PBA, approved
`
`in the United States as RAVICTI®). (See, e.g., Ex. 1011 at 147-8; Ex. 1015 at 10-
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`11, 13.) NaPBA and HPN-100 share a similar mechanism of action, as both
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`medications function through the production of phenylacetic acid (PAA). (Ex.
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`1002 at 12-13.) NaPBA and HPN-100 are referred to as prodrugs of PAA (“PAA
`
`prodrugs”). (Id.)
`
`The diagram below is helpful to illustrate the mechanism of action of PAA
`
`prodrugs. Namely, NaPBA dissociates in the body into sodium and phenylbutyric
`
`acid (PBA). (Ex. 1001, ’215 patent, Figure 1). HPN-100 is hydrolyzed by
`
`pancreatic lipases, releasing three molecules of PBA for each molecule of HPN-
`
`100 ingested. (Id.)
`
`In either case, in the body PBA is converted to PAA, which in turn is
`
`converted to phenylacetylglutamine (“PAGN”) by an enzymatic reaction that
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`conjugates PAA to the amino acid glutamine. (Ex. 1002 at 13.) PAGN is then
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`excreted in the urine, bypassing the urea cycle. (Id.) Each molecule of glutamine
`
`contains two nitrogen atoms, so the body is able to eliminate two waste nitrogen
`
`atoms for every molecule of PAGN excreted. (Id.)
`
`NaPBA and HPN-100 exert clinical benefits for individuals afflicted with
`
`nitrogen-retention disorders, including UCDs, because PAGN essentially replaces
`
`urea as a modality for waste nitrogen excretion and, thus, decreases the need to
`
`excrete waste nitrogen via the urea cycle. (Ex. 1002 at 14.)
`
`In addition to dietary protein restriction and nitrogen-scavenging agents,
`
`physicians also treat UCD patients with amino acids such as arginine and citrulline.
`
`(Ex. 1011 at 219.) Supplementation of a patient’s diet with such amino acids
`
`provides the necessary intermediates for use in the urea cycle that are not being
`
`formed due to the underlying enzymatic deficiency. (Id.)
`
`As of August 2008, reduction of protein intake, supplementation with amino
`
`acids and utilizing alternative pathways of nitrogen excretion by taking nitrogen
`
`scavenging drugs, formed part of an overall management strategy aimed at
`
`controlling blood ammonia levels in patients with nitrogen-retention disorders such
`
`as UCDs. (Ex. 1011 at 218.) For each patient, long-term therapy also had to be
`
`adapted to the individual patient’s requirements in terms of protein and his
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`individual ammonia processing capacity. (Id. at 219; Ex. 1006 at 275.)
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`B.
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`Prior to August 2008, There was a Need for Reliable Biomarkers
`to Determine Effective Dosages of PAA Prodrugs
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`As of August 2008, it was recognized in the art that, even with appropriate
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`long-term treatment, it was difficult to maintain blood ammonia within normal
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`limits and/or to prevent hyperammonemic episodes in UCD patients. (Ex. 1011 at
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`200 (“All patients with urea cycle disorders are at risk of acute decompensation
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`with acute hyperammonemia”); Geraghty, M.T. and Brusilow, S.W., “Disorders of
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`the Urea Cycle,” in Liver Disease in Children, 827 at 836 (2001), “Ex. 2015”
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`(“Despite attempts to maintain adequate nutrition and metabolic control, patients
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`with urea cycle disorders are constantly at risk for life-threatening
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`hyperammonemia”); Endo, F. et al., “Clinical Manifestations of Inborn Errors of
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`the Urea Cycle and Related Metabolic Disorders During Childhood,” J. Nutrition,
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`134, 1605S, at 1068S (2004), “Ex. 2016” (“During an acute attack, sudden
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`elevations of ammonium levels and associated symptoms emerge in patients whose
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`blood ammonium levels were controlled at normal or near-normal levels”); Ex.
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`1004 at 1630-1634 (“Despite long-term therapy, all such infants are constantly
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`vulnerable to episodes of hyperammonemia and coma”); Maestri et al., “Long-term
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`survival of patients with argininosuccinate synthetase deficiency,” J. Ped., 929-35
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`at 934 (1995), “Ex. 2017” (“All these patients are vulnerable to episodic
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`hyperammonemia . . .”).)
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`In addition, there was little guidance in the art for physicians concerning
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`how to determine an initial effective dosage or to adjust the dosage of PAA
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`prodrugs. For example, the 2003 prescribing information for Buphenyl (sodium
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`phenylbutyrate), which was approved initially in 1996, contains no guidance
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`concerning how to calculate an effective dosage for an individual patient other than
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`including a recommended a range of dosages (450-600 mg/kg/day) based on body
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`weight of the patient. (Ex. 2025.) In addition, the Buphenyl prescribing
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`information provides no guidance on how to adjust the dosage of sodium
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`phenylbutyrate. (Id.)
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`Although, prior to 2008, treatment of a UCD patient was considered to be
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`satisfactory if the patient’s blood ammonia level was less than 80 µmol/L (see,
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`e.g., Ex. 1011 at 219), random blood ammonia measurements were not considered
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`helpful in making dosing decisions because of the known fluctuation in blood
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`ammonia levels. (Ex. 1001, ’012 patent.) In addition, it was understood that blood
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`ammonia values could be influenced by factors such as the timing of the blood
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`draw in relation to the time of the last meal or drug dose. (Id.) Moreover, the art
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`acknowledged that focusing dosing decisions primarily on blood ammonia levels
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`could result in overtreatment with excessive restriction of amino acids which, in
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`turn, could lead to endogenous protein catabolism and hyperammonemia. (See
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`e.g., Ex. 1006 at 275; Singh et al., “Nutritional Management of Urea Cycle
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`Disorders,” in Presentation and Management of Urea Cycle Disorders Outside of
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`the Newborn Period, Critical Care Clinics, 21:S27-35 at S32 (2005), “Ex. 2020.”)
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`Contrary to the acknowledged difficulties in interpreting blood ammonia
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`levels in making dosage adjustment decision, the prior-art consensus was that
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`“[p]lasma glutamine level is a useful marker for effective therapy” and that
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`“glutamine appears to be a better marker than ammonia for chronic management.”
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`(The Urea Cycle Disorders Conference Group, Consensus Statement from a
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`Conference for the Management of Patients with Urea Cycle Disorders, J. Ped.
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`(Supplement) S1-S8 at S3 (2001) (emphasis added), “Ex. 2023”; see also Lichter-
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`Konecki et al., “Ammonia control in children with urea cycle disorders (UCDs):
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`Phase 2 comparison of sodium phenylbutyrate and glycerol phenylbutyrate,” Mol.
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`Gen. & Metab., 103:323-29 at 328 (2011), “Ex. 2018” (“Many metabolic
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`specialists use glutamine levels to monitor treatment and adjust doses.”).) Because
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`“[g]lutamine represents a storage form of nitrogen [it was thought that] increasing
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`levels may be a harbinger of hyperammonemia.” (Ex. 2015 at 834; see also
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`Maestri et al. (1992), “Plasma glutamine concentration: a guide to the management
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`of urea cycle disorders,” J. Pediatr. 121:259-261, “Ex. 2011” (“These data, in
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`conjunction with the reports cited earlier, suggest that glutamine may represent a
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`storage site for nitrogen accumulation” and “increased plasma glutamine levels are
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`forerunner of increased plasma ammonium levels.”).) Physicians agreed that
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`“plasma glutamine level should be maintained at <1000 µmol/L” and that “[h]igher
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`levels indicate that dietary or drug therapy requires modification.” (See e.g., Ex.
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`2023 at S3); Ex. 1009 at 10; Ex. 2011 at 260; Ex. 1007 at 109.) Accordingly, the
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`only prior-art bright-line biomarker for dosage adjustment of nitrogen scavenging
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`drugs in UCD patients related to plasma glutamine and not blood ammonia levels.
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`However, even using plasma glutamine as a biomarker, UCD patients remained at
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`risk for unforeseen episodes of hyperammonemia or hyperammonemic crises.
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`C.
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`Prior to August 2008, Conversion of PAA to PAGN was assumed
`to be Complete or Nearly Complete in UCD Patients
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`As discussed above, prior to August 2008, and as early as the 1980s, it was
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`understood that PAA prodrugs could be used to treat UCD patients by providing an
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`alternative pathway for nitrogen excretion in the form of PAGN, which is excreted
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`in the urine as urinary PAGN (“UPAGN”). (See, e.g., Ex. 1004.) Thus, UPAGN
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`was understood to be a measure of the amount of nitrogen excreted by patients
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`taking PAA prodrugs. (Ex. 1018 at col. 4:35-50.) In addition, there was a
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`consensus in the prior art that conjugation of PAA to UPAGN was close to 100%
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`in UCD patients and healthy subjects. (See, e.g., id. at col. 2:53-67; Ex. 1012 at
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`149; Ex. 2026 (“James ’72”); “Ex. 2027”; BUPHENYL® Prescribing Information
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`(2003), “Ex. 2025”; Ex. 2013 at S57.)
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`More than sixty years prior to the discovery of the use of PAA prodrugs in
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`treating UCDs, Sherwin’s research group discovered that when PAA was ingested
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`by human beings, it was excreted in the urine as PAGN. (See Ex. 1016, “Sherwin
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`’19”.) Sherwin then undertook further research to study PAA metabolism in
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`healthy subjects. (Id.) Sherwin ’19 focused on determining how much glutamine a
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`healthy subject (on a glutamine-free diet) could furnish to conjugate with PAA,
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`which was administered in increasing dosages over a period of twenty-four days.
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`(Id. at 113.) Based on the amount of PAGN recovered in the urine, the researchers
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`concluded that the amount of glutamine furnished by the body was approximately
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`one-half the necessary amount for detoxication of PAA; however, they noted that
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`“[i]t is probably that more of the phenylacetylglutamine would have appeared in
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`the urine after each dose of the acid, had the acid been ingested at regular intervals
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`covering a period of 10 or 12 hours.” (Id. at 118.)
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`In 1922, Sherwin published a related study which also reported, inter alia,
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`the amo