`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner
`__________
`
`Case IPR2017-01769
`Patent 9,326,966
`__________
`
`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 ..................................... 7
`III. THE ’966 PATENT CLAIMS .......................................................................10
`IV. PAR’S DEFINITION OF ONE OF ORDINARY SKILL IN THE
`ART IS OVERLY BROAD ..........................................................................13
`CLAIM INTERPRETATION .......................................................................16
`V.
`VI. CLAIMS 1-11 AND 13 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 1 Fails .....................................................................................19
`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 ..................................................21
`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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`Case No. IPR2017-01769
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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.
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`5.
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`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 ......................................................................................44
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given No Weight ...................................47
`Grounds 2 and 3 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 ...................................53
`Par Fails to Demonstrate a Reasonable Expectation of
`Success ......................................................................................58
`VII. CONCLUSION ..............................................................................................60
`
`
`
`2.
`
`3.
`
`ii
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`Case No. IPR2017-01769
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`TABLE OF AUTHORITIES
`
`Cases
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) ..................................................................... 57, 58
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ....................................................................... 35, 48
`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) ............................................................................45
`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) ...........................................................................58
`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) .................................................16
`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) ..............................................................................48
`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) ..............................................................................17
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) ......................................................................... 22, 23
`
`iii
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`Case No. IPR2017-01769
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`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ............................................................................46
`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) ............................................................................58
`Tissue Transplant Tech. Ltd. et al. v. Mimedx Group, Inc.,
`IPR2015-00320, Paper 13 (PTAB June 29, 2015) ...............................................48
`W.L. Gore & Assocs. Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ............................................................................55
`Statutes
`35 U.S.C. § 103 .......................................................................................................... 6
`35 U.S.C. § 253(a) ..................................................................................................... 1
`35 U.S.C. § 316(e) ...................................................................................................26
`Regulations
`37 C.F.R. § 42.65(a) .......................................................................................... 35, 47
`
`
`
`iv
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`
`
`INTRODUCTION
`Par Pharmaceutical, Inc. (“Par” or “Petitioner”) has failed to meet its burden
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`Case No. IPR2017-01769
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`I.
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`of establishing that claims 1-11 and 13 of U.S. Patent No. 9,326,966 (“the ’966
`
`patent”) are not patentable. 1 Thus, Horizon Therapeutics, LLC (“Horizon” or
`
`“Patent Owner”) respectfully requests that the Patent Trial and Appeal Board
`
`(“Board”) affirm the patentability of these claims.
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`The Board instituted inter partes review (“IPR”) proceedings on three
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`obviousness grounds based on Par’s mischaracterizations of the prior art. See
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`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. Indeed, Par’s obviousness position is nothing but a hindsight analysis
`
`of the prior art. The Supreme Court and the Federal Circuit have repeatedly stated
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`that this type of hindsight approach to obviousness is improper.
`
`
`1 On June 28, 2017, Horizon filed a statutory disclaimer under 35 U.S.C. § 253(a)
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`disclaiming claims 12, 14, and 15 of the ’966 patent. (Ex. 2001.) Accordingly,
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`only claims 1-11 and 13 of the ’966 patent remain at issue in this proceeding. See
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`Institution Decision at 1-2, n.1.
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`1
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`
`
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`The ’966 patent claims are directed to innovative methods of treating a
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`patient suffering from a urea cycle disorder (“UCD”) by adjusting the dosage of
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`glyceryl tri-[4-phenylbutyrate] (also known as “glycerol phenylbutyrate,” “HPN-
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`100” or “GPB”) in subjects being treated for UCD. UCDs are genetic metabolic
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`disorders that are extremely rare (only 113 new U.S. patients per year), difficult to
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`diagnose and to treat, and, most alarmingly, have an extremely low survival rate
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`(an estimated 65% mortality rate in newborns presenting with UCD). UCDs are
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`characterized by the accumulation of toxic and potentially fatal levels of ammonia
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`in the plasma and brain arising from the body’s inability to remove excess
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`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 ’966 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 ’966 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
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`levels were subject to unpredictable daily variation. And even with careful
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`2
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`
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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,
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`coma, or death. Recognizing the need for improved UCD treatment methods and
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`dosing guidance, the inventors of the ’966 patent analyzed extensive plasma
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`ammonia data and discovered that certain UCD patients with normal fasting
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`plasma ammonia levels were at risk and should be administered an increased
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`dosage of 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 1 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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`24:11-25.) These methods provide significant advantages over the prior art by
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`eliminating confusion over interpretation of ammonia levels, providing much
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`needed dosing guidance and assuring improved ammonia control.
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`3
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`
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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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`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 ’966
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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-
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`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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`4
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`
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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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`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
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`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 ’966
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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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`5
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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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`For the reasons herein, Par fails to establish that claims 1-11 and 13 of the
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`’966 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 ’966 patent under 35
`
`U.S.C. § 103 based on the following four grounds:
`
`Ground References
`1
`Fernandes in view of the ’859 Publication, optionally in
`further view of Blau, Simell and/or Lee
`Fernandes in view of the ’859 Publication and Lee or
`Lichter-Konecki, optionally in further view of Blau or
`Simell
`The ’859 Publication in view of Lee or Lichter-
`Konecki, and optionally further in view of Blau
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`2
`
`3
`
`Claims
`1-3, 5-6, 8-9,
`11
`4, 7, 10
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`13
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`(Institution Decision at 23.)
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`6
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`
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`Technical Background on Treatment of UCDs
`B.
`In conducting an obviousness analysis, one must consider the state of the art
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`at the time of the claimed inventions. As noted, a patient with a UCD cannot
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`remove excess nitrogen due to a defect in the operation of the urea cycle, resulting
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`in elevated plasma ammonia levels. (Ex. 1001 at 1:21-26; 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
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`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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`7
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`
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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
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`1605S-1606S; Ex. 2017 at S68 (reporting that only 21% of patients ages 12-74
`
`months had an IQ over 70); Ex. 2019 at 2 (reporting in 2012 that despite the
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`existence of effective therapy outcomes remain poor); Ex. 1011 at 3; Ex. 2039 at
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`133.) A UCD diagnosis therefore presents a patient and the patient’s family with a
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`lifetime of coordinating a complex therapeutic regimen aimed at promoting growth
`
`and 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 1:57-2:63.) Glycerol phenylbutyrate is a pre-prodrug of phenylacetic
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`8
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`
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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 1:67-2:46.) PAGN is then excreted in the urine, bypassing the urea cycle.
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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
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`at 75, Box 1.)
`
`Given the unpredictable fluctuations of ammonia values, clinicians did not
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`rely on normal plasma ammonia levels prior to the ’966 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. (Ex. 2006 at ¶¶ 48, 95-104;
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`Ex. 2019 at 9, Table 4; Ex. 2009 at S51 (“aim of long-term therapy has been to
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`9
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`maintain metabolic control with plasma ammonia concentrations less than twice
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`normal”).)
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`III. THE ’966 PATENT CLAIMS
`The ’966 patent addresses the limitations in the art noted above. For
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`example, the ’966 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 4:36-43; Ex. 2006 at ¶ 49.) The inventors of the ’966 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 2:58-62; 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 4:64-5:17, 14:60-18:67 (Example 1); Ex. 2006 at ¶ 50.) From their results,
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`the inventors recognized for the first time that patients who were previously
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`deemed to be well-controlled with a fasting ammonia level within the normal range
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`carried an increased risk of having elevated ammonia levels compared to patients
`
`with ammonia levels at or below half the ULN. (Id.) The inventors also
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`10
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`
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`discovered that a fasting ammonia value that does not exceed half of the upper
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`limit of normal (“ULN”) is a clinically useful target that is predictive of average
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`daily ammonia values over twenty-four hours. (Ex. 1001 at 4:64-5:17, 5:54-6:4;
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`Ex. 2006 at ¶ 50.) The inventors translated these discoveries into bright-line
`
`methods for adjusting the dosage of a nitrogen scavenging drug, glycerol
`
`phenylbutyrate. (Ex. 1001 at 2:65-3:12; 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 5:12-17,
`
`15:11-15; Ex. 2006 at ¶ 50.)
`
`Example 1 of the ’966 patent details the inventors’ investigation of the
`
`relationship between fasting ammonia levels and the profile of ammonia levels
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`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 of this
`
`data, the 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 on average 84% and as high as 93%. (Ex. 1001 at 17:54-18:67; Ex. 2006 at
`
`¶¶ 51-52.) Conversely, the inventors determined that a patient with a fasting
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`11
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`
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`ammonia level above half the ULN but below the ULN had only a 58% likelihood
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`of having an average daily ammonia level in the normal range. (Ex. 1001 at 17:1-
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`53 (Table 2); Ex. 2006 at ¶ 52.)
`
`Thus, the inventors of the ’966 patent 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.) And the
`
`inventors translated this discovery into treatment methods that eliminated prior art
`
`confusion over plasma ammonia levels. (Ex. 1001 at 5:12-17.) As Dr. Enns
`
`explains, the information reported in the ’966 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 ¶ 127.) 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
`
`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. (Ex.
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`2006 at ¶ 127.) Rather, the POSA was content with plasma ammonia values within
`
`the normal range. (Ex. 2006 at ¶¶ 95-104.)
`
`12
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`
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`IV. PAR’S DEFINITION OF ONE OF ORDINARY SKILL IN THE ART
`IS OVERLY BROAD
`Based on the subject matter of the ’966 patent claims, a POSA would have
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`had the following qualifications: (a) an M.D. or equivalent degree, (b) at least three
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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
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`disorders, including UCDs (urea cycle disorders). (Ex. 2006 at ¶ 30.)
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`Horizon’s expert Dr. Enns meets this definition. (Ex. 2006 at ¶¶ 6-17.) He
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`is a Professor of Pediatrics-Medical Genetics at the Lucile Salter Packard
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`Children’s Hospital of Stanford University and an internationally recognized
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`expert in UCD treatment. (Ex. 2006 at ¶¶ 9-12; Ex. 2007 at 1.) He completed a
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`three-year residency in medical genetics at the University of California, San
`
`Francisco, and is board certified in Clinical Genetics and Clinical Biochemical
`
`Genetics. (Ex. 2006 at ¶¶ 6-8; Ex. 2007 at 2.) These certifications demonstrate
`
`that he possesses broad knowledge in, inter alia, “the etiology, pathogenesis,
`
`clinical manifestations, and management of human inherited biochemical
`
`disorders,” including UCDs. (Ex. 2026; Ex. 2006 at ¶¶ 8, 32.) Dr. Enns testifies
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`13
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`that Horizon’s definition of a POSA is appropriate for the claimed subject matter
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`and that he meets (and exceeds) this 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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`inherited metabolic disorders, such as UCD and other nitrogen retention
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`disorders.” (Pet. at 20; Ex. 1002 at ¶ 47). 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 20 (emphasis
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`added).) Par’s POSA definition should not be adopted because it does not require
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`any experience treating UCDs or specify the amount of specialized training needed
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`in the treatment or diagnosis of patients with nitrogen retention disorders, such as
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`UCDs. Indeed, the Board in IPR2016-00829, concerning the ’559 patent (of which
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`the ’966 patent is a continuation), 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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`14
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`with nitrogen retention disorders, including UCDs.” (IPR2016-00829, Final
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`Written Decision, Paper No. 42 at 15.)2
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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 by the Board in
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`2 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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`15
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`IPR2016-00829, he did not testify as to the motivations or understandings of the
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`proper POSA. Par’s obviousness analysis, which relies on Dr. Sondheimer’s
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`unsupported testimony to assert the unpatentability of claims 1-11 and 13, should
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`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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`Horizon proposes an interpretation of the term “upper limit of normal”
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`(“ULN”) that mirrors the definition set forth in the ’966 patent specification. The
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`’966 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 12:11-12.) Elsewhere, the ’966 patent repeatedly recognizes that
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`normal blood ammonia values are in a range, and that the ULN is the highest level
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`within that range. (See, e.g., Ex. 1001 at 4:31-32 (“Control of blood ammonia
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`level generally refers to ammonia values within the normal range . . . ”); 3:11-12,
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`3:37-38, 3:67-4:1 (“In certain embodiments, the ULN is around 35 μmol/L . . . ”);
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`12:46-49 (“In certain of these embodiments, the ULN for blood ammonia may be
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`16
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`in the range of . . . ”).) Horizon’s interpretation of the term “upper limit of normal”
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`as representing “the highest value in the range of normal values” is thus described
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`in 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 ¶¶ 59-62.)
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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 ’966 patent claims
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`should be assigned their ordinary meaning.
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`VI. CLAIMS 1-11 AND 13 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, the ’966 patent should also be found unpatentable. (Pet.
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`at 2-3.) But the Board’s finding of unpatentability for the ’215 patent has no
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`bearing here because the ’966 patent’s methods of treatment differ from those of
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`the ’215 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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`17
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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 ’966 patent claims
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`address increasing the dosage of drug for fasting ammonia levels within the normal
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`range i.e., between half the ULN and the ULN. Thus, the reason the Board found
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`the claims of the ’215 patent unpatentable is not present for the’966 patent. And,
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`as explained herein, the prior art raised in the ’215 patent IPR, including
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`Fernandes, does not render
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