`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner
`__________
`
`Case IPR2017-01767
`Patent 9,254,278
`__________
`
`HORIZON THERAPEUTICS, LLC’S RESPONSE TO PETITION FOR
`INTER PARTES REVIEW
`
`
`
`
`I.
`II.
`
`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`BACKGROUND AND STATE OF THE ART .............................................. 6
`A.
`Prior Art at Issue .................................................................................... 6
`B.
`Technical Background on Treatment of UCDs ..................................... 6
`III. THE ’278 PATENT CLAIMS .......................................................................10
`IV. PAR’S DEFINITION OF ONE OF ORDINARY SKILL IN THE
`ART IS OVERLY BROAD ..........................................................................12
`CLAIM INTERPRETATION .......................................................................15
`V.
`VI. CLAIMS 1-15 WOULD NOT HAVE BEEN OBVIOUS IN VIEW
`OF THE ASSERTED PRIOR ART ..............................................................17
`A.
`The Board’s Finding of Unpatentability of the ’215 Patent is
`Inapplicable .........................................................................................17
`Ground 3 Fails .....................................................................................18
`1.
`The Prior Art Did Not Recognize That UCD Patients
`Having a Plasma Ammonia Level Within the Normal
`Range Required an Increased Dosage of Nitrogen
`Scavenging Medication .............................................................19
`(a)
`The Cited Prior Art Provides No Motivation to
`Increase the Dosage for a Patient With a Normal
`Plasma Ammonia Level ................................................. 20
`The Prior Art as a Whole Refutes Par’s Assertion
`that a POSA Would Have Been Motivated to
`Perform the Claimed Methods ....................................... 29
`The Variability in Plasma Ammonia Levels Discouraged
`Reliance on Normal Plasma Ammonia Levels in Making
`Dosage Adjustments .................................................................35
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`i
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`B.
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`(b)
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`2.
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`3.
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`4.
`
`5.
`
`C.
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`The Prior Art Does Not Suggest Reliance on Fasting
`Plasma Ammonia Measurements For Dosage Adjustment ......40
`Par Fails to Demonstrate a Reasonable Expectation of
`Success ......................................................................................43
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given No Weight ...................................47
`Grounds 2 and 4 Fail ...........................................................................50
`1.
`The Prior Art Does Not Suggest Targeting a Fasting
`Plasma Ammonia Level at or Below Half the ULN .................50
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given No Weight ...................................52
`Par Fails to Demonstrate a Reasonable Expectation of
`Success ......................................................................................57
`D. Ground 1 Fails .....................................................................................60
`VII. CONCLUSION ..............................................................................................63
`
`
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`2.
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`3.
`
`ii
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`TABLE OF AUTHORITIES
`
`Cases
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) ..................................................................... 56, 57
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ....................................................................... 34, 47
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) ............................................................................22
`DePuy Spine Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ............................................................................44
`Disney Enter., Inc. v. Kappos,
`923 F. Supp. 2d 788 (E.D. Va. 2013) ...................................................................31
`DSS Tech. Mgmt., Inc. v. Apple Inc.,
`885 F.3d. 1367 (Fed. Cir. 2018) .................................................................... 56, 57
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ..............................................................................15
`Hospitality Core Services LLC v. Nomadix, Inc.,
`IPR2016-00052, Paper 8 (PTAB Apr. 27, 2016) .................................................15
`In re Cyclobenzaprine Extended-Release Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) ............................................................................44
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ..............................................................................47
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) ............................................................................26
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) ..............................................................................16
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) ......................................................................... 22, 23
`
`iii
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`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ..................................................................... 45, 58
`K/S HIMPP v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) ............................................................................56
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................56
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................................20
`Perfect Web Techs., Inc. v. InfoUSA, Inc.,
`587 F.3d 1324 (Fed. Cir. 2009) ............................................................................57
`Tissue Transplant Tech. Ltd. et al. v. Mimedx Group, Inc.,
`IPR2015-00320, Paper 13 (PTAB June 29, 2015) ...............................................47
`W.L. Gore & Assocs. Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ............................................................................54
`Statutes
`35 U.S.C. § 102(b) ..................................................................................................... 6
`35 U.S.C. § 103(a) ..................................................................................................... 6
`35 U.S.C. § 316(e) ...................................................................................................26
`Regulations
`37 C.F.R. § 42.65(a) .......................................................................................... 34, 47
`
`
`
`iv
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`
`
`INTRODUCTION
`Par Pharmaceutical, Inc. (“Par” or “Petitioner”) has failed to meet its burden
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`I.
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`of establishing that claims 1-15 of U.S. Patent No. 9,254,278 (“the ’278 patent”)
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`are not patentable. Thus, Horizon Therapeutics, LLC (“Horizon” or “Patent
`
`Owner”) respectfully requests that the Patent Trial and Appeal Board (“Board”)
`
`affirm the patentability of these claims.
`
`The Board instituted inter partes review (“IPR”) proceedings on four
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`grounds based on Par’s mischaracterizations of the prior art. See Decision -
`
`Institution of Inter Partes Review (Paper No. 10, herein “Institution Decision”).
`
`As demonstrated herein, one of ordinary skill in the art would not have been led to
`
`the claimed treatment methods based on the prior art that Par has identified.
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`Indeed, Par’s obviousness position is nothing but a hindsight analysis of the prior
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`art. The Supreme Court and the Federal Circuit have repeatedly stated that this
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`type of hindsight approach to obviousness is improper.
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`The ’278 patent claims are directed to innovative methods of treating a
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`patient suffering from a urea cycle disorder (“UCD”) and of adjusting the dosage
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`of glyceryl tri-[4-phenylbutyrate] (also known as “glycerol phenylbutyrate,”
`
`“HPN-100” or “GPB”) in subjects being treated for UCD. UCDs are genetic
`
`metabolic disorders that are extremely rare (only 113 new U.S. patients per year),
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`1
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`
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`difficult to diagnose and to treat, and, most alarmingly, have an extremely low
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`survival rate (an estimated 65% mortality rate in newborns presenting with UCD).
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`UCDs are characterized by the accumulation of toxic and potentially fatal levels of
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`ammonia in the plasma and brain arising from the body’s inability to remove
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`excess ammonia. UCD treatment involves a complex regimen of dietary protein
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`restriction, nitrogen scavenging medication and/or amino acid supplementation.
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`Prior to the ’278 patent, the prior art consensus was that UCD treatment was
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`effective when a patient presented with a plasma ammonia level falling within the
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`normal or near normal range. And, as confirmed by internationally recognized
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`UCD expert, Dr. Gregory Enns (“Dr. Enns”), clinicians treating UCDs prior to the
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`2011 priority date of the ’278 patent did not seek to reduce ammonia levels to any
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`particular level within the normal range. But assessment of treatment effect based
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`on ammonia levels was confounded by the fact that individual plasma ammonia
`
`levels were subject to unpredictable daily variation. And even with careful
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`treatment and monitoring, UCD patient outcomes remained poor and previously
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`stabilized patients could experience dangerously high plasma ammonia levels (i.e.,
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`hyperammonemia) without warning, often causing irreversible brain damage, coma
`
`or death. Recognizing the need for improved UCD treatment methods and dosing
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`guidance, the inventors of the ’278 patent analyzed extensive plasma ammonia
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`2
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`
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`data and discovered that certain UCD patients with normal fasting plasma
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`ammonia levels were at risk and should be administered an increased dosage of
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`medication.
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`To address this previously unrecognized problem, the inventors developed
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`treatment methods that counterintuitively direct physicians to increase the dosage
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`of glycerol phenylbutyrate for certain UCD patients previously considered to have
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`satisfactory normal ammonia levels. For example, representative independent
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`claim 4 requires, inter alia, administration of an increased dosage of glycerol
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`phenylbutyrate to a UCD patient whose fasting plasma ammonia level is less than
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`the upper limit of normal (“ULN”) but greater than half the ULN. (Ex. 1001 at
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`24:31-45.) These methods provide significant advantages over the prior art by
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`eliminating confusion over interpretation of ammonia levels, providing much
`
`needed dosing guidance and assuring improved ammonia control.
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`Par’s assertion that the claimed methods would have been obvious is
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`unfounded and hindsight-fueled. Par fails to demonstrate even a prima facie case
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`of obviousness because Par has not identified any recognition in the prior art that a
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`normal plasma ammonia level (i.e., below the ULN but above half the ULN) was
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`of any concern or warranted dosage adjustment. The first indication that a normal
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`plasma ammonia level should and could be relied on to adjust dosage because of
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`
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`3
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`the risk associated with a plasma ammonia level below the ULN and above half the
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`ULN was in U.S. Patent No. 9,095,559 (“the ’559 patent”), of which the ’278
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`patent is a continuation. And the prior art, including Par’s primary references—
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`Fernandes and the ’859 Publication—refutes Par’s obviousness theory by
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`consistently expressing satisfaction with plasma ammonia levels anywhere within
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`or even near normal levels (e.g., <80 µmol/L).
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`Fernandes teaches that a plasma ammonia level less than 80 µmol/L, which
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`includes levels above the ULN, are satisfactory and the goal of treatment. And
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`Fernandes only suggests that very high plasma ammonia levels well above the
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`normal range (e.g., >120 µmol/L) mandate a dosage increase. (Ex. 1015 at 220-
`
`221.) The ’859 Publication also teaches that ammonia levels within the normal
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`range are indicative of an effective dosage and confines dosage increases to
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`patients with inadequate (i.e., above normal) ammonia levels. Secondary
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`references Lee and Lichter-Konecki likewise provide no support for Par because
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`they suggest that ammonia levels anywhere within or near the normal range
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`indicate satisfactory ammonia control. And none of these references, nor the
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`additionally cited Simell or Blau, suggests dosage adjustment based on normal
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`fasting plasma ammonia levels.
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`
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`4
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`
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`Aside from the prior art’s failure to recognize any risk or disadvantage
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`associated with plasma ammonia levels falling within the normal range (i.e., below
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`the ULN but above half the ULN), the prior art as a whole taught away from the
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`claimed methods. Fernandes, the ’859 Publication, Lee, Lichter-Konecki and
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`others expressly discouraged reliance on normal plasma ammonia levels in making
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`dosing adjustments in stabilized patients due to the recognized potential for
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`unpredictable fluctuations in daily plasma ammonia levels.
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`Finding no prior art support for its theory, Par depends entirely on the
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`testimony of its expert, Dr. Sondheimer, to supply a reason to pursue the claimed
`
`methods. But Dr. Sondheimer’s testimony should be given no weight as it is
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`unsupported and impermissibly interprets the prior art through the lens of the ’278
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`patent claims. Dr. Sondheimer also ignores decades of prior art concerning the use
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`of nitrogen scavenging drugs that discourages performance of the claimed methods
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`and refutes his over-simplistic theory that a person of ordinary skill in the art
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`(“POSA”) would be singularly focused on repeatedly administering more drug to a
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`patient who already has satisfactory normal ammonia levels when there was no
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`known benefit in doing so. Thus, on this basis alone, Par has failed as a matter of
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`law to establish that the challenged claims are obvious.
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`
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`5
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`
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`For the reasons herein, Par fails to establish that claims 1-15 of the ’278
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`patent are not patentable. Thus, Horizon respectfully requests that the Board
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`affirm the patentability of these claims.
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`II. BACKGROUND AND STATE OF THE ART
`Prior Art at Issue
`A.
`The Board instituted this IPR as to claims 1-15 of the ’278 patent based on
`
`the following four grounds:
`
`References
`Ground Basis
`’859 Publication
`1
`35 U.S.C. § 102(b)
`2
`35 U.S.C. § 103(a) Fernandes in view of the ’859
`Publication and Lee or Lichter-Konecki,
`optionally in further view of Blau or
`Simell
`35 U.S.C. § 103(a) Fernandes in view of the ’859
`Publication, and optionally in view of
`Blau, Simell, and/or Lee
`35 U.S.C. § 103(a) Fernandes in view of the ’859
`Publication and Lee or Lichter-Konecki,
`and optionally further in view of Blau or
`Simell
`
`3
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`4
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`Claims
`1-3
`1-3
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`4, 6-8,
`10-12,
`14-15
`5, 9, 13
`
`
`(Institution Decision at 20).
`Technical Background on Treatment of UCDs
`B.
`In conducting an obviousness analysis, one must consider the state of the art
`
`at the time of the claimed inventions. As noted, UCD patients cannot remove
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`
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`6
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`
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`excess nitrogen due to a defect in the operation of the urea cycle, resulting in
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`elevated plasma ammonia levels. (Ex. 1001 at 1:19-24; Ex. 2006 at ¶¶ 36-37.)
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`This genetic metabolic disorder is extremely rare and difficult to diagnose and to
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`treat. (Ex. 2006 at ¶¶ 31-34, 38-41.) It is estimated that only one out of 35,000
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`live births have this disorder, resulting in only 113 new patients in the U.S. per
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`year. (Ex. 2035 at 1-2; Ex. 2006 at ¶ 38; Ex. 2019 at 1-2.) Unfortunately, survival
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`in UCD patients is extremely low because high levels of ammonia
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`(hyperammonemia) are toxic to the brain. (Ex. 2006 at ¶¶ 38-40; Ex. 2008 at 1;
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`Ex. 2020 at 21.) Between 1982 and 2003, patients presenting with
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`hyperammonemia within the first 30 days of life had only a 35% survival rate
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`(65% mortality rate). (Ex. 2006 at ¶¶ 34, 39; Ex. 2036 at 1423; Ex. 2017 at S66-
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`68.)
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`Because of the rarity and complexity of UCD, it requires the supervision of
`
`specialists in metabolic genetic disorders rather than general practitioners. (Ex.
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`2006 at ¶¶ 30-34, 41; Ex. 2017 at S66-67, S69; Ex. 2034 at S33; Ex. 2037 at S87.)
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`But even with frequent monitoring and specialized treatment, even well-controlled
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`UCD patients remain at risk for life-threatening episodic hyperammonemia, which
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`can lead to brain damage, coma and death. (Ex. 2006 at ¶¶ 38-39, 41; Ex. 2016 at
`
`1605S-1606S; Ex. 2017 at S68 (reporting that only 21% of patients ages 12-74
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`7
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`
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`months had an IQ over 70); Ex. 2019 at 1-2; Ex. 1011 at 3; Ex. 2039 at 133.) A
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`UCD diagnosis therefore presents a patient and the patient’s family with a lifetime
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`of coordinating a complex therapeutic regimen aimed at promoting growth and
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`development while concurrently trying to avoid the potentially devastating
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`consequences of a hyperammonemic crisis. (Ex. 2006 at ¶¶ 40-41, 46; Ex. 2017 at
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`S67; Ex. 2019 at 12-13.)
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`Dietary treatment is the “cornerstone of therapy” for UCD patients because
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`minimizing protein intake will decrease the nitrogen load on the urea cycle. (Ex.
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`2006 at ¶ 42; Ex. 2019 at 12-13.) But protein restriction decreases the nutrients
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`needed for growth and normal development. Therefore, essential amino acid
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`supplementation and/or the use of nitrogen scavenging drugs is often necessary to
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`achieve good metabolic control. (Ex. 2006 at ¶ 42; Ex. 2021 at 32-33.) Nitrogen
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`scavenging drugs, such as glycerol phenylbutyrate, use a different pathway than
`
`the urea cycle to remove excess nitrogen from the body. (Ex. 2006 at ¶¶ 43-45;
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`Ex. 1001 at 1:55-2:60.) Glycerol phenylbutyrate is a pre-prodrug of phenylacetic
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`acid (“PAA”) and undergoes the fatty acid oxidation cycle to produce PAA, which
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`converts in vivo to phenylacetylglutamine (“PAGN”). (Ex. 2006 at ¶¶ 43-44; Ex.
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`1001 at 1:65-2:44.) PAGN is then excreted in the urine, bypassing the urea cycle.
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`
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`8
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`
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`(Id.) Each molecule of glutamine contains two nitrogen atoms, allowing the body
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`to eliminate two waste nitrogen atoms for every molecule of PAGN excreted. (Id.)
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`Although the prior art teaches that clinicians must monitor a patient’s
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`clinical status and plasma ammonia level to track the effectiveness of UCD
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`treatment, inherent difficulties exist with the interpretation of plasma ammonia
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`levels that have undermined its usefulness as a diagnostic tool. (Ex. 2006 at ¶¶ 47-
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`48.) With any given individual, ammonia values undergo a several-fold fluctuation
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`throughout the day. Such factors as diet, infection, routine surgery, pregnancy,
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`medication, and exercise can cause an increase in plasma ammonia levels. (Id.;
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`Ex. 2013 at 101; Ex. 2012 at [0090]; Ex. 2016 at 1608S; Ex. 2021 at 33; Ex. 2015
`
`at 75, Box 1.)
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`Given the unpredictable fluctuations of ammonia values, clinicians did not
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`rely on normal plasma ammonia levels prior to the ’278 patent as a basis to adjust a
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`patient’s treatment. (Ex. 2006 at ¶ 48.) Clinicians only considered plasma
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`ammonia levels well above the ULN as cause to act. (Id. at ¶¶ 48, 96-105; Ex.
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`2019 at 9, Table 4; Ex. 2009 at S51 (“aim of long-term therapy has been to
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`maintain metabolic control with plasma ammonia concentrations less than twice
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`normal”).)
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`9
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`III. THE ’278 PATENT CLAIMS
`The ’278 patent addresses the limitations in the art noted above. For
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`example, the ’278 patent explains that the dosing of nitrogen scavenging drugs is
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`usually based upon the clinical assessment and measurement of ammonia, but such
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`assessment and treatment are confounded by the fact that individual ammonia
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`values vary over the course of a day and are impacted by the timing of the blood
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`draw. (Ex. 1001 at 4:34-41; Ex. 2006 at ¶ 49.) The inventors of the ’278 patent
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`identified a need for improved methods of determining the appropriate dosage of
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`nitrogen scavenging drugs such as glycerol phenylbutyrate to use in subjects
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`having UCDs. (Ex. 1001 at 2:56-60; Ex. 2006 at ¶ 49.)
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`In response to this need, the inventors investigated the previously unknown
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`relationship between a fasting ammonia level and daily ammonia exposure. (Ex
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`1001 at 4:62-5:15, 14:60-19:4 (Example 1); Ex. 2006 at ¶¶ 50-51.) From their
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`results, the inventors recognized for the first time that patients who were
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`previously deemed to be well-controlled with a fasting ammonia level within the
`
`normal range carried an increased risk of having elevated ammonia levels
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`compared to patients with ammonia levels at or below half the ULN. (Id.) The
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`inventors also discovered that a fasting ammonia value that does not exceed half of
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`the ULN is a clinically useful target that is predictive of average daily ammonia
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`10
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`values over twenty-four hours. (Ex. 1001 at 4:64-5:15, 5:51-6:1; Ex. 2006 at ¶ 50.)
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`The inventors translated these discoveries into bright-line methods for adjusting
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`the dosage of a nitrogen scavenging drug, glycerol phenylbutyrate. (Ex. 1001 at
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`2:64-3:10; Ex. 2006 at ¶ 50.) These methods provide significant advantages over
`
`the prior art by eliminating the confusion over conflicting ammonia levels,
`
`assuring ammonia control, and providing a statistical basis for the adjustment of
`
`glycerol phenylbutyrate dosages. (Ex. 1001 at 5:10-15, 15:10-14; Ex. 2006 at
`
`¶ 50.)
`
`Example 1 of the ’278 patent details the inventors’ investigation of the
`
`relationship between fasting ammonia levels and the profile of ammonia levels
`
`over twenty-four hours using plasma ammonia data from sixty-five UCD patients.
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`(Ex. 1001 at 14:60-15:15; Ex. 2006 at ¶ 51.) From their statistical analysis, the
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`inventors concluded with 95% confidence that the true probability of having an
`
`ammonia value (measured as “area under the curve” or “AUC”) in the desired
`
`normal range when a fasting ammonia level is less than or equal to half the ULN is
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`on average 84% and as high as 93%. (Ex. 1001 at 17:56-19:4; Ex. 2006 at ¶¶ 51-
`
`52.) Conversely, the inventors determined that a patient with a fasting ammonia
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`level above half the ULN but below the ULN had only a 58% likelihood of having
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`
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`11
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`
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`an average daily ammonia level in the normal range. (Ex. 1001 at 17:1-54 (Table
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`2); Ex. 2006 at ¶ 52.)
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`Thus, the ’278 patent inventors were the first to recognize that a normal
`
`fasting plasma ammonia level (i.e., below the ULN but above half the ULN)
`
`carries an increased risk of having elevated ammonia levels. (Id.) The inventors
`
`translated this discovery into treatment methods that eliminated prior art confusion
`
`over plasma ammonia levels. (Ex. 1001 at 5:10-15.) As Dr. Enns explains, the
`
`information reported in the ’278 patent represented “an advance in the treatment of
`
`urea cycle disorders and a new way of thinking about treating patients with this
`
`disorder.” (Ex. 2006 at ¶ 128.) Without this, a POSA would not have had any
`
`expectation that an increased dosage of nitrogen scavenging drug when the
`
`patient’s fasting plasma level was already within normal limits would confer a
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`treatment benefit, i.e., ensure that the patient stayed within the normal limits over
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`the course of the day and reduce the likelihood of hyperammonemic crises. (Id.)
`
`Rather, the POSA was content with plasma ammonia values within the normal
`
`range. (Id. at ¶¶ 96-105.)
`
`IV. PAR’S DEFINITION OF ONE OF ORDINARY SKILL IN THE ART
`IS OVERLY BROAD
`Based on the subject matter of the ’278 patent claims, a POSA would have
`
`had the following qualifications: (a) an M.D. or equivalent degree, (b) at least three
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`
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`12
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`
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`years of residency/fellowship training in Medical Genetics, including Biochemical
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`Genetics, followed by certification in Clinical Genetics and Clinical or Medical
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`Biochemical Genetics by the American Board of Medical Genetics and Genomics,
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`and (c) at least five years of experience treating patients with nitrogen retention
`
`disorders, including UCDs (urea cycle disorders). (Ex. 2006 at ¶ 30.)
`
`Horizon’s expert Dr. Enns meets this definition. (Id. at ¶¶ 6-17.) He is a
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`Professor of Pediatrics-Medical Genetics at the Lucile Salter Packard Children’s
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`Hospital of Stanford University and an internationally recognized expert in UCD
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`treatment. (Id. at ¶¶ 9-12; Ex. 2007 at 1.) He completed a three-year residency in
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`medical genetics at the University of California, San Francisco, and is board
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`certified in Clinical Genetics and Clinical Biochemical Genetics. (Ex. 2006 at ¶¶
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`6-8; Ex. 2007 at 2.) These certifications demonstrate that he possesses, broad
`
`knowledge in, inter alia, “the etiology, pathogenesis, clinical manifestations, and
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`management of human inherited biochemical disorders,” including UCDs. (Ex.
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`2026; Ex. 2006 at ¶¶ 8, 32.) Dr. Enns testifies that Horizon’s POSA definition is
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`appropriate for the claimed subject matter and that he meets (and exceeds) this
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`definition. (Ex. 2006 at ¶¶ 18, 30.)
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`Par proposes that a POSA would have been a “physician or scientist with a
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`Ph.D. or M.D. degree and specialized training in the diagnosis or treatment of
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`13
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`inherited metabolic disorders, such as UCD and other nitrogen retention
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`disorders.” (Pet. at 18-19; Ex. 1002 at ¶ 40). Par also provides that “such a person
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`may also have post-graduate training to fulfill the requirements of the American
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`Board of Medical Genetics and Genomics in Clinical Genetics, Clinical
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`Biochemical Genetics, or Medical Biochemical Genetics.” (Pet. at 18-19
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`(emphasis added).) Par’s definition should not be adopted because it does not
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`require any experience treating UCDs or specify the amount of specialized training
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`needed in the treatment or diagnosis of patients with nitrogen retention disorders,
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`such as UCDs. Indeed, the Board in IPR2016-00829, concerning the ’559 patent
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`(the parent of the ’278 patent), specifically found that it “agree[d] with Patent
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`Owner that one of ordinary skill in the art would have experience treating patients
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`with nitrogen retention disorders, including UCDs.” (IPR2016-00829, Final
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`Written Decision, Paper No. 42 at 15.)1
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`1 The ’559 patent is also the subject of IPR2016-00829, filed by Lupin on April 1,
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`2016. On September 26, 2017, the Board issued a Final Written Decision holding
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`that all of the claims of the ’559 patent are unpatentable. Horizon strongly
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`disagrees with the Board and filed an appeal of its Decision to the Federal Circuit
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`on November 22, 2017.
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`14
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`Accordingly, Par’s definition is too broad to ensure that a POSA possesses
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`the expertise necessary to navigate the complex treatment of UCD patients. And
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`Par’s definition does not align with the prior art’s emphasis that the complexity of
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`UCD treatment requires experienced personnel with specific and extensive
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`expertise in genetic metabolic disorders. (Ex. 2017 at S66, S69; Ex. 2034 at S33;
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`Ex. 2037 at S86-87; Ex. 2006 at ¶¶ 31-34; Envtl. Designs, Inc. v. Union Oil Co.,
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`713 F.2d 693, 696 (Fed. Cir. 1983) (listing the prior art, the sophistication of the
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`technology, and the education of workers in the field as factors to consider when
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`determining the level of ordinary skill).) Thus, as an initial matter, because Par’s
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`expert Dr. Sondheimer employed a diluted conception of a POSA without any
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`required experience treating UCD patients as found necessary in IPR2016-00829,
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`he did not testify as to the motivations or understandings of the proper POSA.
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`Par’s obviousness analysis, which relies on Dr. Sondheimer’s unsupported
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`testimony to assert the unpatentability of claims 1-15, should therefore be rejected.
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`V. CLAIM INTERPRETATION
`Under the broadest reasonable interpretation standard, claim terms are given
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`their ordinary and customary meaning, as would be understood by a POSA at the
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`time of the invention, in light of the specification. Hospitality Core Servs. LLC v.
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`Nomadix, Inc., IPR2016-00052, Paper 8 at 7 (Apr. 27, 2016).
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`15
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`Horizon proposes an interpretation of the term “upper limit of normal”
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`(“ULN”) that mirrors the definition set forth in the ’278 patent specification. The
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`’278 patent provides the following definition for ULN: “The ULN for blood
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`ammonia typically represents the highest level in the range of normal values . . .”
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`(Ex. 1001 at 12:7-8.) The ’278 patent repeatedly recognizes that normal blood
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`ammonia values are in a range, with the ULN as the highest level within that range.
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`(See, e.g., Ex. 1001 at 4:29-30 (“Control of blood ammonia level generally refers
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`to ammonia values within the normal range . . .”); 3:9-10, 3:35-36, 3:65-66; 12:46-
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`49 (“In certain of these embodiments, the ULN for blood ammonia may be in the
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`range of . . .”).) Horizon’s interpretation of the term “upper limit of normal” as
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`representing “the highest value in the range of normal values” is thus described in
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`the specification “with reasonable clarity, deliberateness, and precision.” In re
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`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994); (Ex. 2006 at ¶¶ 60-63.)
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`Accordingly, the Board should adopt Horizon’s proposed construction of “upper
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`limit of normal.”
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`Horizon proposes that the remaining claim terms in the ’278 patent claims
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`should be assigned their ordinary meaning.
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`16
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`VI. CLAIMS 1-15 WOULD NOT HAVE BEEN OBVIOUS IN VIEW OF
`THE ASSERTED PRIOR ART
`A. The Board’s Finding of Unpatentability of the ’215 Patent is
`Inapplicable
`The Petition asserts that the “challenged claims are nearly identical” to the
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`claims of U.S Patent No. 8,404,215 (“the ’215 patent”), held unpatentable in
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`IPR2015-01127, and thus, should also be found unpatentable. (Pet. at 2-3.) But
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`the Board’s finding of unpatentability for the ’215 patent has no bearing here
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`because the ’278 patent’s methods of treatment differ from those of the ’215
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`patent.
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`Significantly, the Board construed the ’215 patent claims to include dosage
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`adjustment for patients who have any plasma ammonia level greater than half the
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`ULN. (IPR2015-01127, Paper No. 49 at 14-15.) Par asserted (and the Board was
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`persuaded) that the prior art taught increasing the dosage of nitrogen scavenging
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`medication where plasma ammonia levels were greater than the ULN, but did not
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`suggest that the prior art suggested increasing the dosage for ammonia levels
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`below the ULN. (IPR2015-01127, Paper No. 2 at 19-22, citing Ex. 1002 at ¶¶ 53,
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`57; Paper No. 49 at 17.) In contrast, as depicted below, the ’278 patent claims
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`address increasing the dosage for fasting ammonia levels within the normal range
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`i.e., between half the ULN and the ULN. Thus, the reason the Board found the
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`claims of the ’215 patent unpatentable is not present for the ’278 patent. And, as
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`17
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`explained herein, the prior art raised in the ’215 patent IPR, including Fernandes,
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`does not render the ’278 patent claims obvious.
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`B. Ground 3 Fails
`Par asserts that independent claims 4, 8 and 12 and dependent claims 6, 7,
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`10, 11, 14 and 15 are obvious over Fer