UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner
`________________
`
`Case IPR 2016-00829
`Patent 9,095,559
`________________
`
`
`
`PATENT OWNER HORIZON THERAPEUTICS, INC.’S
`PRELIMINARY REPSONSE
`
`

`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND ............................................................................................. 1
`
`III.
`
`SUMMARY OF ARGUMENT ....................................................................... 2
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART AND CLAIM
`CONSTRUCTION .......................................................................................... 4
`
`A.
`
`B.
`
`Level of Ordinary Skill in the Art ......................................................... 4
`
`Claim Construction................................................................................ 5
`
`V.
`
`THE PETITION FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIM IS
`UNPATENTABLE .......................................................................................... 7
`
`A.
`
`The ’559 Patent Claims Recite an Upper Limit for Drug
`Adjustment ............................................................................................ 7
`
`B.
`
`Ground 1 of the Petition Should Be Denied........................................ 11
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`The ’859 Publication Teaches Away from Adjusting the
`Dosage of Nitrogen Scavenging Medication Based on
`Plasma Ammonia Levels .......................................................... 12
`
`The ’859 Publication Teaches Away from Relying on a
`Single Fasting Plasma Ammonia Level in Making a
`Dosing Decision ........................................................................ 14
`
`The ’859 Publication Teaches Away from Increasing the
`Dosage of Nitrogen Scavenging Medication based on a
`Fasting Plasma Ammonia Level Less than the ULN but
`Greater than Half the ULN ....................................................... 15
`
`The ’859 Publication Does Not Teach Comparison of
`Fasting Plasma Ammonia Levels to the ULN .......................... 19
`
`Simell and Blau Fail to Cure the Deficiencies of the ’859
`Publication ................................................................................ 20
`
`C.
`
`IPR2016-00829
`
`Ground 2 of the Petition Should be Denied ........................................ 24
`
`i
`
`
`
`

`
`1.
`
`2.
`
`3.
`
`The Petition Does Not Provide a Basis on which the
`Board Could Find Claim 3 Obvious ......................................... 24
`
`Brusilow ’84 Fails to Cure the Deficiencies of the ’859
`Publication ................................................................................ 27
`
`The Petition Does Not Provide a Basis on which the
`Board Could Find Claim 6 Obvious ......................................... 31
`
`VI. THE PETITION SHOULD BE REJECTED UNDER 35 U.S.C. §
`325(D) ............................................................................................................ 33
`
`VII. THE PETITION SHOULD BE DENIED FOR VIOLATING 37
`C.F.R. §§ 42.104(B)(4) AND 42.22(A)(2) .................................................... 34
`
`VIII. CONCLUSION .............................................................................................. 41
`
`
`
`IPR2016-00829
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`
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`ii
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`

`
`TABLE OF AUTHORITIES
`
`Cases
`Apotex Inc. v. Wyeth LLC,
`IPR2015-00873, Paper 8 (PTAB Sept. 16, 2015) ................................................40
`
`C.R. Bard, Inc. v. Medical Components, Inc.,
`IPR2016-01660, Paper 9 (PTAB February 9, 2016) ............................................35
`
`Cisco Systems Inc. v. C-CATION Techs., Inc.,
`IPR2014-00454, Paper 12 (PTAB Aug. 29, 2014) ..............................................35
`
`Excelsior Med. Corp. v. Lake,
`IPR2013-00494, Paper 10 (PTAB Feb. 6, 2014) .................................................34
`
`Hospitality Core Services LLC v. Nomadix, Inc.,
` 2016 WL 2909164 (PTAB Apr. 27, 2016) ............................................................ 5
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................39
`
`In re Bigio,
`381 F.3d 1320 (Fed Cir. 2004) ............................................................................... 5
`
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) ................................................................................ 6
`
`In re Translogic Tech., Inc.,
`504 F.3d 1249 (Fed. Cir. 2007) .............................................................................. 5
`
`In re Van Geuns,
`988 F.2d 1181 (Fed. Cir. 1993) .............................................................................. 6
`
`Integrated Global Concepts v. J2 Global, Inc.,
`IPR2014-01028, Paper 13 (PTAB Dec. 22, 2014) ...............................................34
`
`Merial Ltd. v. Virbac,
`IPR2014-01279, Paper 13 (PTAB Jan. 22, 2015) ................................................34
`
`Tissue Transplant Tech. Ltd. et al. v. Mimedx Group, Inc.,
`IPR2015-00320, Paper 13 (PTAB June 29, 2015) ...............................................40
`
`IPR2016-00829
`
`
`
`
`iii
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`

`
`Zimmer Biomet Holdings, Inc. v. Four Mile Bay, LLC,
`IPR2016-00011, Paper 8 (PTAB Apr. 1, 2016) ...................................................35
`
`Statutes
`
`35 U.S.C. § 103(a) ............................................................................................ 12, 24
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314(a) ..................................................................................................... 7
`
`35 U.S.C. § 325(d) ...................................................................................................33
`
`Other Authorities
`
`Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756 (Aug. 14, 2012) .............35
`
`Rules
`
`37 C.F.R. § 42.104(b)(4) ................................................................................... 34, 39
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`
`37 C.F.R. § 42.22(a)(2) ............................................................................... 34, 39, 40
`
`
`
`
`
`IPR2016-00829
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`iv
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`

`
`I.
`
`INTRODUCTION
`
`Horizon Therapeutics, Inc. (“Horizon” or “Patent Owner”) submits this
`
`Preliminary Response pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, in
`
`response to the Petition for inter partes review (“IPR”) of U.S. Patent No.
`
`9,095,559 (“the ’559 patent”) (Paper 2, herein “the Petition” or “Pet.”) filed by
`
`Lupin Ltd. and Lupin Pharmaceuticals, Inc. (collectively, “Lupin” or “Petitioner”).
`
`Because the Petition is both substantively and legally defective, it should be
`
`denied.
`
`II. BACKGROUND
`Horizon markets an FDA approved drug product under the tradename
`
`RAVICTI® (glycerol phenylbutyrate oral liquid). RAVICTI® is approved for use
`
`as a nitrogen-binding agent for chronic management of adult and pediatric patients
`
`at least two years of age with urea cycle disorders (“UCDs”). Horizon is the
`
`holder of approved new drug application (“NDA”) No. 20-3284 for the
`
`RAVICTI® product, which was first approved on February 1, 2013.
`
`Horizon is the owner of U.S. Patent No. 9,095,559 (“the ’559 patent”). The
`
`’559 patent is listed in the FDA “Orange Book” (formally known as Approved
`
`Drug Products with Therapeutic Equivalence Evaluations) in connection with
`
`NDA No. 20-3284 because it claims the approved drug product and an approved
`
`use of the drug product that is the subject of that NDA.
`
`IPR2016-00829
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`1
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`
`Lupin Ltd. filed Abbreviated New Drug Application (ANDA) No. 207694
`
`with the FDA seeking approval to market a generic version of RAVICTI® (“Lupin
`
`ANDA Product”) before the expiration of the ’559 patent. Lupin’s ANDA
`
`includes a “Paragraph IV” certification asserting that the ’559 patent is invalid or
`
`would not be infringed by the manufacture, use or sale of the Lupin ANDA
`
`Product.
`
`Horizon has brought suit against Lupin for infringement of the ’559 patent in
`
`the United States District Court for the District of New Jersey.1 See Horizon
`
`Therapeutics, Inc. v. Lupin Ltd. et al., Civil Action No. 15-cv-07624-RBK-JS
`
`(D.N.J.), D.I. No. 001 (Ex. 2001).
`
`III. SUMMARY OF ARGUMENT
`The ’559 patent claims concern methods of treating urea cycle disorder
`
`(“UCD”) patients with glycerol phenylbutyrate.2 The challenged claims all require
`
`measurement of the patient’s fasting plasma ammonia level and comparison of that
`
`
`1 The New Jersey litigation originally included claims for infringement of U.S.
`
`Patent Nos. 8,404,215 (“the ’215 patent”) and 8,642,012 (“the ’012 patent”);
`
`however, Horizon amended its Complaint to remove the ’215 patent and the ’012
`
`patent from the litigation. (D.I. 001, Ex. 2001; D.I. 036, Ex. 2002.)
`
`2 Glycerol phenylbutyrate is the active ingredient in RAVICTI® and is referred to
`
`in the ’559 patent claims as “glyceryl tri-[4-phenylbutyrate].
`
`IPR2016-00829
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`2
`
`

`
`level to the ULN in making a dosing decision. For example, independent claim 2
`
`requires,
`
`inter alia, administration of an
`
`increased dosage of glycerol
`
`phenylbutyrate to a urea cycle disorder (“UCD”) patient whose fasting blood
`
`ammonia level is less than the upper limit of normal (“ULN”) but greater than
`
`half the ULN.
`
`The Board should deny institution of IPR of the ’559 patent because the
`
`Petition hinges on hindsight-driven assertions, which are contradicted by the prior
`
`art.
`
`Petitioner’s primary prior art reference, the ’859 Publication, teaches away
`
`from, and contradicts, Petitioner’s assertions concerning the motivations of a
`
`POSA to perform the claimed methods. The ’859 Publication teaches away from
`
`such methods because it teaches that plasma ammonia levels are unreliable and
`
`disfavored in making dosing decisions for UCD patients. In addition, the ’859
`
`Publication teaches that a single fasting plasma ammonia measurement is not a
`
`reliable biomarker for dosage adjustment of nitrogen scavenging drugs. Critically,
`
`the ’859 Publication also teaches that “normal” plasma ammonia levels, which
`
`includes levels below the ULN but above half the ULN, indicates that treatment is
`
`effective and the UCD patient is not in need of an increased dosage of drug. Thus,
`
`the ’859 Publication specifically refutes Petitioner’s assertion that a POSA would
`
`have been motivated to administer an increased or an initial dosage of glycerol
`
`IPR2016-00829
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`
`phenylbutyrate when the fasting plasma ammonia level is “normal,” which
`
`includes levels below the ULN but above half the ULN.
`
`Secondary references Blau, Simell, and Brusilow ’84 fail to cure the
`
`deficiencies of the ’859 Publication because they fail to teach or suggest adjusting
`
`the dosage of glycerol phenylbutyrate based on a fasting plasma ammonia level, let
`
`alone a fasting blood ammonia level that is greater than half the ULN but less than
`
`the ULN. Furthermore, Brusilow ’84, like the ’859 Publication, teaches that
`
`“normal or nearly normal” plasma ammonia levels are satisfactory, thus, also
`
`teaching away from the claimed inventions and refuting any purported motivation
`
`to combine. (Ex. 1004 at 1631.)
`
`IV. LEVEL OF ORDINARY SKILL IN THE ART AND CLAIM
`CONSTRUCTION
`A. Level of Ordinary Skill in the Art
`A person of ordinary skill in the art (POSA) of the ’559 patent 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 (urea cycle disorders).
`
`IPR2016-00829
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`4
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`
`The difference between the Patent Owner’s and Petitioner’s definition of a
`
`POSA is that the Petitioner’s definition does not require a POSA to have any
`
`experience treating patients with nitrogen retention disorders such as UCDs.
`
`Rather, the Petitioner’s definition simply requires “specialized training in the
`
`diagnosis or treatment of inherited metabolic disorders, such as UCD and other
`
`nitrogen retention disorders.” (Pet. at 8.) Because the challenged claims
`
`specifically relate to methods of administering and adjusting the dosage of nitrogen
`
`scavenging medications to treat nitrogen retention disorders, which include UCDs,
`
`Petitioner’s definition, which does not require that a POSA have experience
`
`treating patients having such disorders, should be rejected by the Board.
`
`B. Claim Construction
`Under the broadest-reasonable-interpretation standard, claim terms are given
`
`their ordinary and customary meaning, as would be understood by one of ordinary
`
`skill in the art at the time of the invention. Hospitality Core Services LLC v.
`
`Nomadix, Inc., 2016 WL 2909164 at *2 (PTAB Apr. 27, 2016) citing In re
`
`Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). “Absent claim
`
`language carrying a narrow meaning, the PTO should only limit the claim based on
`
`the specification . . . when [it] expressly disclaim[s] the broader definition.” In re
`
`Bigio, 381 F.3d 1320, 1325 (Fed Cir. 2004). Thus, it is improper to read a
`
`particular embodiment appearing in the written description into the claim, if the
`
`IPR2016-00829
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`5
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`

`
`claim language is broader than the embodiment. In re Van Geuns, 988 F.2d 1181,
`
`1184 (Fed. Cir. 1993).
`
`The Patent Owner proposes an interpretation of the term “upper limit of
`
`normal” that mirrors the definition of the term set forth by the inventors in the
`
`specification of the ’559 patent. The ’559 patent specification provides the
`
`following definition for ULN, which is an acronym for “upper limit of normal”:
`
`“The ULN for blood ammonia typically represents the highest level in the range of
`
`normal values...” (Ex. 1001 at 12:11-12.) Elsewhere, the ’559 patent specification
`
`repeatedly recognizes that normal blood ammonia values are in a range, and that
`
`the upper limit of normal is the highest level within that range. (See, e.g., Ex. 1001
`
`at 4:31-32 (“Control of blood ammonia level generally refers to ammonia values
`
`within the normal range…”); 3:11-12, 3:37-38, 3:67-4:1 (“In certain embodiments,
`
`the ULN is around 35 μmol/L…”); 12:46-49 (“In certain of these embodiments,
`
`the ULN for blood ammonia may be in the range of…”).) The Patent Owner’s
`
`interpretation of the term “upper limit of normal” as representing “the highest
`
`value in the range of normal values” is thus described in the specification “with
`
`reasonable clarity, deliberateness, and precision.” In re Paulsen, 30 F.3d 1475,
`
`1480 (Fed. Cir. 1994). Accordingly, the Board should adopt the Patent Owner’s
`
`proposed construction of “upper limit of normal.”
`
`IPR2016-00829
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`6
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`

`
`The Patent Owner proposes that the remaining claim terms in the ’559 patent
`
`claims should be assigned their ordinary meaning. In particular, the Patent Owner
`
`disagrees with Petitioner that the claim term “greater than the initial dosage”
`
`should be limited to specific examples of increased dosages provided in the
`
`specification because there is no indication in the claims or the specification of the
`
`’559 patent that the inventors intended to assign a special or limited definition to
`
`the claim term “greater than.”
`
`V. THE PETITION FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIM IS
`UNPATENTABLE
`
`Under 35 U.S.C. § 314(a), an IPR may not be instituted “unless the Director
`
`determines . . . that there is a reasonable likelihood that the Petitioner would
`
`prevail with respect to at least 1 of the claims challenged in the petition.” The
`
`Board should deny the Petition and refuse to institute trial because Petitioner has
`
`not met its burden to demonstrate a reasonable likelihood that it will prevail as to at
`
`least one challenged claim.
`
`A. The ’559 Patent Claims Recite an Upper Limit for Drug
`Adjustment
`
`The ’559 patent is a continuation of U.S. Patent No. 8,404,215 (“the ’215
`
`patent”). Par Pharmaceutical Inc. filed IPR2015-01127 with respect to the ’215
`
`IPR2016-00829
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`7
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`
`patent. That IPR was instituted and is currently pending.3 Lupin filed IPR2016-
`
`00284 against the ’215 patent, together with a motion for joinder with IPR2015-
`
`01127, which was granted.
`
`Although Horizon strongly disagrees that the ’215 patent claims are invalid,
`
`the Board’s discussion of its grounds for instituting an IPR for that patent serve to
`
`illustrate why the Board should deny institution of an IPR for the ’559 patent
`
`claims.
`
`In instituting the IPR on the’215 patent, PTAB held that “under the broadest
`
`reasonable interpretation, Patent Owner’s claims specify only a lower limit for
`
`drug adjustment (“half the upper limit of normal”) not an upper limit.” (IPR2015-
`
`01127, Paper No. 13 at 12.) In contrast, the ’559 patent claims include an upper
`
`limit for dosage adjustment—the upper limit of normal.
`
`Representative independent claim 3 of the ’215 patent recites:
`
`3. A method of treating a subject with a nitrogen
`retention disorder who has previously been administered
`
`
`3 Par Pharmaceutical Inc. also filed IPR2015-001117 with respect to the ’012
`
`patent, which was instituted and is currently pending. Lupin filed IPR2016-
`
`00283 against the ’012 patent, together with a motion for joinder with IPR2015-
`
`01117, which was granted.
`
`IPR2016-00829
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`8
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`

`
`initial dosage of a nitrogen scavenging drug
`an
`comprising:
`(a) measuring a fasting blood ammonia level for the
`subject;
`(b) comparing the fasting blood ammonia level to the
`upper limit of normal for blood ammonia level; and
`(c) administering an adjusted dosage of the nitrogen
`scavenging drug that is greater than the initial dosage if
`the fasting blood ammonia level is greater than half
`the upper limit of normal for blood ammonia level.
`
`Representative independent claim 2 of the ’559 patent recites:
`
`2. A method of treating a subject with a urea cycle
`disorder who has previously been administered an initial
`dosage of glyceryl tri-[4-phenylbutyrate] and who has a
`fasting plasma ammonia level less than the upper
`limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the
`subject;
`(b) comparing the fasting plasma ammonia level to the
`upper limit of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate, that is greater than the initial dosage if
`the fasting plasma ammonia level is greater than half
`the upper limit of normal for plasma ammonia level.
`
`IPR2016-00829
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`9
`
`

`
`Thus, as further illustrated below, the claims of the ’559 patent address
`
`dosage adjustment and administration for patients who have a fasting plasma
`
`ammonia level that falls in the window (highlighted in gray in the figure below)
`
`between half the ULN and the ULN. In contrast, the ’215 patent claims have been
`
`construed by the Board to address dosage adjustment for patients who have plasma
`
`ammonia greater than the ULN.
`
`
`As explained in detail below, dosage adjustment and administration for
`
`patients who have a fasting plasma ammonia level that falls in the window between
`
`half the ULN and the ULN is not disclosed or suggested by the prior art.
`
`Accordingly, the very reason PTAB instituted IPR for the ’215 patent claims is
`
`absent for the claims of the ’559 patent.
`
`IPR2016-00829
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`10
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`
`B. Ground 1 of the Petition Should Be Denied
`Independent claims 1 and 2 (set forth below) concern methods of treating
`
`UCD patients and require administration of an increased dosage of glycerol
`
`phenylbutyrate to a UCD patient who has a fasting plasma ammonia level that falls
`
`in the window between half the ULN and the ULN.
`
`1. A method for adjusting the dosage of glyceryl tri-[4-
`phenylbutyrate] in a subject being treated for a urea cycle
`disorder who has previously been administered an initial
`dosage of glyceryl tri-[4-phenylbutyrate] and who has a
`fasting plasma ammonia level less than the upper
`limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the
`subject;
`(b) comparing the fasting plasma ammonia level to the
`upper limit of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate, wherein the adjusted dosage is greater
`than the initial dosage if the fasting plasma ammonia
`level is greater than half the upper limit of normal for
`plasma ammonia level.
`
`2. A method of treating a subject with a urea cycle
`disorder who has previously been administered an initial
`dosage of glyceryl tri-[4-phenylbutyrate] and who has a
`fasting plasma ammonia level less than the upper
`
`IPR2016-00829
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`11
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`

`
`limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the
`subject;
`(b) comparing the fasting plasma ammonia level to the
`upper limit of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate, that is greater than the initial dosage if
`the fasting plasma ammonia level is greater than half
`the upper limit of normal for plasma ammonia level.
`
`The Petition asserts that independent claims 1 and 2 and dependent claims 4,
`
`5, 7-10, 12 and 13 are obvious under 35 U.S.C. § 103(a) over the ’859 Publication
`
`in view of Blau and Simell. However, the Petition should be denied because
`
`Petitioner’s primary prior art reference, the ’859 Publication, teaches away from
`
`the inventions recited in the challenged claims and refutes the Petition’s assertions
`
`concerning the alleged motivation of a person of ordinary skill in the art to perform
`
`the claimed inventions. Furthermore, the deficiencies of the ’859 Publication are
`
`not rectified by the secondary references, Blau and Simell.
`
`1.
`
`The ’859 Publication Teaches Away from Adjusting the
`Dosage of Nitrogen Scavenging Medication Based on
`Plasma Ammonia Levels
`
`The ’859 Publication teaches adjustment of nitrogen scavenging drug dosage
`
`based on a new biomarker, urinary phenylacetylglutamine (“UPAGN”) excretion.
`
`IPR2016-00829
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`12
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`
`(Ex. 1007 at [0020] (“The invention provides a novel approach for determining and
`
`adjusting the schedule and dose of orally administered nitrogen scavenging drugs,
`
`including . . . (HPN-100), based upon the urinary excretion of the drug metabolite
`
`phenylacetylglutamine (PAGN) and/or total urinary nitrogen”); see also id. at
`
`[0039] and [0064].) Not only does the ’859 Publication promote using urinary
`
`PAGN excretion as a new biomarker for dosage adjustment of nitrogen scavenging
`
`drugs, it recommends “adjusting of the initial dosage . . . based on the amount of
`
`urinary PAGN . . . preferably without relying upon levels of ammonia.” (Ex. 1007
`
`at [0099] (emphasis added).)
`
`The ’859 Publication teaches away from reliance on plasma ammonia levels
`
`in assessing drug dosage because “plasma ammonia levels are affected by many
`
`factors and might be elevated regardless of how well a drug treatment works; it
`
`reflects dietary and other factors as well as the adequacy of a drug dosage being
`
`used.” (Id. at [0073]). Additionally, the ’859 Publication acknowledges that:
`
`[P]lasma ammonia varies a good deal even when
`relatively well-controlled, based on meal timing, drug
`timing and various other factors. Thus, to meaningfully
`reflect drug effect, the plasma ammonia levels need to be
`monitored over time by repeated blood samplings, which
`is not practical . . . and which does not provide direct
`information about whether an ammonia scavenging drug
`is working.
`
`IPR2016-00829
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`13
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`
`(Id.)
`
`In view of the known problems in interpreting plasma ammonia levels, the
`
`’859 Publication advises that “the appropriate method for determining a suitable
`
`dose of HPN-100 [glycerol phenylbutyrate] will take account of the excreted
`
`PAGN, rather than being based only on less reliable criteria for evaluating the
`
`orally delivered PBA prodrug.” (Id. at [0135] (emphasis added).) The ’859
`
`Publication indicates that a subject’s plasma ammonia level may optionally be
`
`determined “for tracking effectiveness of an overall treatment program, but reflects
`
`a variety of factors such as dietary protein and physiological stress, as well as the
`
`effect of a drug used to promote nitrogen excretion.” (Id. at [0039] (emphasis
`
`added).) Thus, the ’859 Publication expressly teaches away from reliance on
`
`plasma ammonia measurements in making dosing decisions in view of the
`
`unreliability of such measurements and instead provides that plasma ammonia
`
`levels should only be optionally monitored to track the overall effectiveness of the
`
`treatment regimen and not as a biomarker for dosage adjustment.
`
`2.
`
`The ’859 Publication Teaches Away from Relying on a
`Single Fasting Plasma Ammonia Level in Making a Dosing
`Decision
`
`Moreover, the ’859 Publication teaches away from reliance on a single
`
`plasma ammonia measurement (under fed or fasted conditions) in assessing the
`
`dosage of nitrogen scavenging drugs. As mentioned above, the ’859 Publication
`
`IPR2016-00829
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`14
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`

`
`acknowledges that “[p]lasma ammonia varies a good deal even when relatively
`
`well-controlled based on meal timing, drug timing and various other factors.” (Id.
`
`at [0073].) Thus, the ’859 Publication teaches that “to meaningfully reflect drug
`
`effect, the plasma ammonia levels need to be monitored over time by repeated
`
`blood samplings . . . which does not provide direct information about whether an
`
`ammonia scavenging drug is working.” (Id. (emphasis added); see also id. at
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`[0003].) As such, the ’859 Publication teaches that a single plasma ammonia
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`measurement (taken while fasting or otherwise) would not “meaningfully reflect
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`drug effect,” and that even multiple measurements throughout the day would not
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`be considered to provide “direct information about whether an ammonia
`
`scavenging drug is working.” (Id. at [0073].) Thus, the ’859 Publication refutes
`
`Petitioner’s assertion that a POSA would have considered a single fasting plasma
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`ammonia measurement to be a reliable indicator of the adequacy of drug dosage in
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`a UCD patient and teaches away from the claimed methods.
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`3.
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`The ’859 Publication Teaches Away from Increasing the
`Dosage of Nitrogen Scavenging Medication based on a
`Fasting Plasma Ammonia Level Less than the ULN but
`Greater than Half the ULN
`
`Although the Petitioner agrees that the ’859 Publication teaches that plasma
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`levels of ammonia are “acceptable when they are at or below a level considered
`
`normal for the subject,” the Petitioner concurrently asserts that “for a patient with
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`fasting plasma ammonia levels approaching the ULN, a POSA would have been
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`motivated to increase the dose of drug to lower the patient’s baseline ammonia and
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`to help ensure that the patient routinely stayed within normal plasma ammonia
`
`limits.” (Pet. at 29.) This argument is inconsistent on its face and directly
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`conflicts with the ’859 Publication, which teaches away from increasing the dosage
`
`of nitrogen scavenging medication when a patient’s plasma ammonia level is
`
`below the ULN but above half the ULN.
`
`Specifically, the ’859 Publication explains that “a plasma ammonia level that
`
`was normal . . . would indicate that treatment was effective” and plasma ammonia
`
`levels are “acceptable when they are at or below a level considered normal for the
`
`subject,” (Ex. 1007 at [0085] and [0094]; see also [0074].) “[A] level considered
`
`normal for the subject” includes plasma ammonia levels “below about 40 µmol/L.”
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`(Id. at [0094].) Since, according to the ’859 Publication, “about” means +/-10%,
`
`“below about 40 µmol/L” encompasses a range of 36-44 µmol/L. (Id. (“‘about’
`
`means the value is approximate, and typically is within +/-10% of the stated
`
`numeric value.”).) The ’859 Publication reports the ULN as 26-35 µmol/L. (Id. at
`
`[0094].) Thus, according to the ’859 Publication, “normal” plasma ammonia
`
`levels (i.e., below 44 µmol/L) includes plasma ammonia levels above the ULN
`
`(26-35 µmol/L). (Id.) It follows that plasma ammonia levels greater than half the
`
`ULN but below the ULN are also “normal” according to the ’859 Publication.
`
`Thus, the ’859 Publication teaches that UCD treatment is effective and a patient’s
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`plasma ammonia levels are adequately controlled if the patient exhibits a plasma
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`ammonia level below 44 µmol/L, which includes levels above half the ULN and
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`even above the ULN.
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`The ’859 Publication further provides that “[i]f the ammonia control is
`
`inadequate, the dosage of the nitrogen scavenging drug may need to be increased if
`
`that can be done, or the patient’s dietary protein intake can be decreased if that is
`
`feasible.” (Id. at [0083] (emphasis added).) It logically follows that the ’859
`
`Publication teaches away from increasing the dosage of nitrogen scavenging
`
`medication if a patient’s plasma ammonia levels are “normal” or “acceptable,” i.e.,
`
`below 44 µmol/L, which includes levels greater than half the ULN and less than
`
`the ULN. Thus, the ’859 Publication refutes Petitioner’s assertion that a POSA
`
`would have been motivated to increase the dosage of glycerol phenylbutyrate when
`
`faced with a patient having a fasting plasma ammonia level greater than half the
`
`ULN but below the ULN as required by the claimed methods.
`
`The Petitioner’s argument that a POSA’s desire to “maintain the patient at
`
`normal ammonia levels” and awareness of the “variation in ammonia levels due to
`
`time of day and/or ingestion of food would potentially take the patient outside of
`
`normal levels” would somehow motivate a POSA “to increase the dose of drug to
`
`lower the patient’s baseline ammonia and to help ensure that the patient routinely
`
`stayed within normal plasma ammonia limits,” is meritless. (Pet. at 29.) At the
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`outset, neither the Petition nor Dr. Vaux explain what “baseline ammonia” refers to
`
`or cite to any prior art reference in support of such a term. In addition, the
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`Petitioner fails to explain how a POSA’s alleged knowledge of variability of
`
`plasma ammonia in UCD patients and the desirability of maintaining a “normal”
`
`ammonia level would motivate a POSA to perform the specifically claimed
`
`methods which focus on increasing the dosage based on a fasting plasma ammonia
`
`level greater than half the ULN but less than the ULN. Notwithstanding these
`
`deficiencies, Petitioner’s argument fails because it is specifically refuted by the
`
`’859 Publication.
`
`Like the Petition, the ’859 Publication specifically acknowledges the
`
`variation in plasma ammonia levels owing to meals or time of day: “[p]lasma
`
`ammonia varies a good deal even when relatively well-controlled, based on meal
`
`timing, drug timing and various other factors.” (Ex. 1007 at [0073].) Regardless,
`
`the ’859 Publication teaches that “normal” plasma ammonia levels (i.e., levels that
`
`fall below 44 µmol/L), which include levels greater than half the ULN but less than
`
`the ULN, suggest treatment is effective and that the patient is not in need of an
`
`increased dosage. Accordingly, the ’859 Publication refutes the notion that in view
`
`of the known variation in ammonia levels due to meals or time of day, a POSA
`
`would have been motivated to increase the dosage of nitrogen scavenging agent in
`
`patients having a fasting plasma ammonia level below the ULN.
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`4.
`
`The ’859 Publication Does Not Teach Comparison of
`Fasting Plasma Ammonia Levels to the ULN
`
`The ’859 Publication also fails to teach comparison of a patient’s fasting
`
`plasma ammonia levels to the ULN in determining whether to administer or
`
`increase the dosage of nitrogen