`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`LUPIN LTD. AND LUPIN PHARMACEUTICALS INC.,
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`Petitioner
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`v.
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`HORIZON THERAPEUTICS, LLC,
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`Patent Owner
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`Case IPR 2017-01159
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`Patent 9,254,278
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`HORIZON THERAPEUTICS, LLC’S PATENT OWNER RESPONSE
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`I.
`II.
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`V.
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`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`BACKGROUND ............................................................................................. 7
`A.
`Prior Art at Issue .................................................................................... 7
`B. Technical Background on Treatment of UCDs ..................................... 7
`C.
`Overview of the ’278 Patent ................................................................10
`III. LUPIN’S DEFINITION OF ONE OF ORDINARY SKILL IN THE
`ART IS OVERLY BROAD ..........................................................................14
`IV. CLAIM INTERPRETATION .......................................................................17
`A.
`“upper limit of normal” .......................................................................18
`B.
`“the subject” ........................................................................................18
`CLAIMS 1-15 WOULD NOT HAVE BEEN OBVIOUS IN VIEW
`OF THE ASSERTED PRIOR ART ..............................................................20
`A. A POSA Would Not Have Been Motivated to Increase the
`Dosage of Glycerol Phenylbutyrate Based on Normal Plasma
`Ammonia Levels .................................................................................20
`1.
`The ’859 Publication and the Prior Art as a Whole
`Taught That Normal Plasma Ammonia Levels Were
`Acceptable .................................................................................20
`The Potential Variability of Normal Plasma Ammonia
`Levels Would Not Have Motivated a POSA to Increase
`the Dosage of Glycerol Phenylbutyrate ....................................31
`Lupin’s Obviousness Analysis Hinges on Dr. Vaux’s
`Conclusory and Unsupported Testimony .................................35
`One of Ordinary Skill Would Have Had No Motivation to
`Combine the Teachings of the ’859 Publication with Those of
`Blau or Simell ......................................................................................40
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`2.
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`3.
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`B.
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`ii
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`1.
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`2.
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`3.
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`Simell Concerns the Dosing of Different Drugs for a
`Different Condition Than the ’859 Publication ........................42
`Simell and Blau Do Not Address the Use of Normal
`Fasting Plasma Ammonia Levels to Treat UCDs .....................46
`Simell, Blau and Brusilow ’979 Fail to Cure the
`Deficiencies of the ’859 Publication .........................................48
`The Prior Art Did Not Disclose or Suggest the Limitations of
`Claims 1-3, 5, 9 and 13 .......................................................................50
`Lupin Fails to Demonstrate a Reasonable Expectation of
`Success ................................................................................................55
`VI. CONCLUSION ..............................................................................................59
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`C.
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`D.
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`iii
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`TABLE OF AUTHORITIES
`
`Cases
`Allergan, Inc. v. Sandoz, Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) ............................................................................38
`Alza Corp. v. Mylan Labs, Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) ............................................................................39
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ....................................................................... 36, 40
`Broadcom Corp. v. Emulex Corp.,
`732 F.3d 1325 (Fed. Cir. 2013) ............................................................................55
`C.R. Bard, Inc. v. Med. Components, Inc.,
`IPR2015-01660, Paper 9 (P.T.A.B. Feb. 9, 2016) ...............................................38
`Catalina Mktg. Int’l v. Coolsavings.com, Inc.,
`289 F.3d 801 (Fed. Cir. 2002) ..............................................................................19
`Disney Enter., Inc. v. Kappos,
`923 F. Supp. 2d 788 (E.D. Va. 2013) ...................................................................26
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ..............................................................................16
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .................................................................................................41
`Hospitality Core Services LLC v. Nomadix, Inc.,
`IPR2016–00052, Paper 8, 2016 WL 2909164 (P.T.A.B. Apr. 27, 2016) ............17
`In re Cyclobenzaprine Extended-Release Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) ..................................................................... 41, 55
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ..............................................................................38
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) ..............................................................................18
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`iv
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`In re Van Geuns,
`988 F.2d 1181 (Fed. Cir. 1993) ............................................................................17
`In re Wilson,
`311 F.2d 266 (C.C.P.A. 1962) ..............................................................................26
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................................22
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) ............................................................................42
`Oil States Energy Servs., LLC v Greene’s Energy Group, LLC,
`No. 16-712 (cert. granted June 12, 2017) .............................................................59
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) ............................................................................19
`Verlander v. Garner,
`348 F.3d 1335 (Fed. Cir. 2003) ............................................................................38
`Zimmer Biomet Holdings, Inc. v. Four Mile Bay, LLC,
`IPR2016-00011, Paper 8 (P.T.A.B. Apr. 1, 2016) ...............................................38
`Regulations
`37 C.F.R. § 42 ..........................................................................................................59
`37 C.F.R. § 42.65(a) .................................................................................... 36, 40, 47
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`v
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`I.
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`INTRODUCTION
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively, “Lupin” or
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`“Petitioner”) has failed to meet its burden of establishing that claims 1-15 of U.S.
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`Patent No. 9,254,278 (“the ’278 patent”) are not patentable. Thus, Horizon
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`Therapeutics, LLC (“Horizon” or “Patent Owner”) respectfully requests that the
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`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
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`obviousness grounds based on Lupin’s mischaracterizations of the prior art and
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`Lupin’s reliance on an affidavit by a doctor who is not a qualified expert in the
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`field of the claimed inventions. As demonstrated herein, one of ordinary skill in
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`the art would not have been led to the claimed treatment methods based on the
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`prior art that Lupin has identified. Indeed, Lupin’s obviousness position is nothing
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`but a hindsight analysis of the prior art. The Supreme Court and the Federal
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`Circuit have repeatedly stated that this type of hindsight approach to obviousness is
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`improper.
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`The ’278 patent claims concern innovative methods of treating patients
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`suffering from a urea cycle disorder (“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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`1
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`

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`characterized by the accumulation of toxic and potentially fatal levels of ammonia
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`U.S. Patent No. 9,254,278
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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 ’278 patent, the prior art consensus was that treatment was
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`effective when a UCD patient presented with a normal or near normal plasma
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`ammonia level. And, as confirmed by internationally recognized UCD expert, Dr.
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`Gregory Enns (“Dr. Enns”), clinicians treating UCDs prior to the 2011 priority
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`date of the ’278 patent did not target any specific plasma ammonia level within the
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`normal range. But even with careful treatment and monitoring, UCD patient
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`outcomes remained poor. Dangerously high plasma ammonia levels (i.e.,
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`hyperammonemia) would occur without warning, often causing irreversible brain
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`damage, coma or death. Recognizing the need for better ammonia control in UCD
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`patients, the inventors of the ’278 patent analyzed extensive plasma ammonia data
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`taken from UCD patients and developed improved methods of UCD treatment with
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`the nitrogen scavenging drug glyceryl tri-[4-phenylbutyrate] (also known as
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`“glycerol phenylbutyrate” or “HPN-100”). In a departure from prior art practice,
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`the treatment and dosage adjustment methods claimed in the ’278 patent
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`counterintuitively direct physicians that certain patients with normal plasma
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`ammonia levels should be administered an increased dosage of drug. For
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`2
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`example, representative independent claim 4 requires, inter alia, administration of
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`U.S. Patent No. 9,254,278
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`an increased dosage of glycerol phenylbutyrate to a UCD patient whose fasting
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`plasma ammonia level falls within the window of less than the upper limit of
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`normal (“ULN”) but greater than half the ULN.
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`In its Institution Decision, the Board focused on Lupin’s contention that it
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`would have been obvious for a person of ordinary skill in the art (“POSA”) to
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`increase the dosage of a patient’s nitrogen scavenging medication even when that
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`patient’s fasting plasma ammonia level was in the normal range because
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`maintaining the plasma ammonia level within the normal range was the goal for
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`treating UCD and it was known that plasma ammonia levels vary during the day,
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`including after eating. Lupin, however, provided no credible support for this
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`contention.
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`First, none of the art that Lupin identified suggest increasing the dosage of a
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`nitrogen scavenging drug for a patient who has achieved a normal fasting plasma
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`ammonia level. In fact, Petitioner’s primary prior art reference, the ’859
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`Publication, expressly teaches that “normal” plasma ammonia levels, which
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`includes levels below the ULN but above half the ULN, indicate that treatment is
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`effective and that the patient is not in need of an increased dosage of drug. Thus,
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`the ’859 Publication expressly refutes Petitioner’s contention that a POSA would
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`have been motivated to administer an increased dosage of glycerol phenylbutyrate
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`3
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`based on a normal fasting plasma ammonia level, or that a POSA would adjust the
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`U.S. Patent No. 9,254,278
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`dosage of medication to target a plasma ammonia level at or below half the upper
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`limit of normal. And Lupin’s secondary references, Simell, Blau and Brusilow
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`’979 fail to cure the deficiencies of the ’859 Publication.
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`Lupin attempts to fill the gap with the conclusory testimony of Dr. Vaux.
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`But, the Board should not credit Dr. Vaux’s testimony because he does not have
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`the requisite qualifications to offer an opinion on the field in question. UCDs are
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`rare, difficult-to-treat, life-threatening disorders, and only a limited number of
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`specialized medical experts have the qualifications and experience necessary to
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`treat and to manage them. Respectfully, Dr. Vaux, a general pediatrician with
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`training in clinical genetics, does not have the highly specialized training and
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`experience with UCD treatment required to offer an expert opinion on the ’278
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`patent claims. Thus, the Board should give little weight to Dr. Vaux’s testimony in
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`this matter.
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`Dr. Vaux fails to identify any support in the art on critical points such as the
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`motivation of a POSA in the art to perform the claimed methods and ignores the
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`fact that the prior art as a whole, including the prior art he cites, teaches that a
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`normal plasma ammonia level was indicative of effective treatment. Dr. Vaux also
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`fails to provide a credible reason to combine the cited prior art references as he
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`4
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`proposes and does not address why the critical differences between the references
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`would not have discouraged a POSA from combining their teachings.
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`Moreover, Dr. Vaux has provided contrary testimony in another IPR,
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`dismissing the value of portions of the ’859 Publication’s disclosures. For
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`example, Dr. Vaux in that testimony dismissed the ’859 Publication’s view that
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`there was “no saturation in the ability of the body to convert PBA or HPN-100 to
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`urinary PAGN.” (Ex. 2052 (Declaration of Dr. Keith Vaux, M.D., Lupin Ltd. et. al
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`v. Horizon Therapeutics, LLC, IPR2018-00459, Ex. 1002 (“Vaux ’197
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`Declaration”)) at ¶ 79 (The absence of such saturation would remove concern over
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`PAA toxicity due to increased dosing).) Dr. Vaux testified that a POSA “would
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`not have discounted the extensive teachings of the prior art [supporting the concept
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`of saturability] . . . in view of this isolated statement [from the ’859 Publication]”).
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`(Id.) As this Panel is aware, Lupin’s position in the present IPR is that a POSA
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`would not have been concerned about increases in dose because the ’859
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`Publication indicates HPN-100 is well-tolerated. (Pet. at 17, 19-20, 43; Ex. 1002
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`at ¶¶ 47, 63-64, 100.)
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`Given the contradictory positions taken by Dr. Vaux as to the significance of
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`teachings in the ’859 Publication, Lupin’s primary reference, and the fact that
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`Lupin has not demonstrated why a POSA would combine the teachings of Simell
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`5
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`and Blau with that of the ’859 Publication, Lupin’s obviousness analysis is
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`fundamentally flawed.
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`Finally, Lupin fails to present any evidence that a POSA would have had a
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`reasonable expectation of success in treating UCD (i.e., reducing the incidence and
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`frequency of hyperammonemia), the purpose of the claimed methods, based on
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`Lupin’s proposed combination of the prior art. Lupin has additionally failed to
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`demonstrate that a POSA would have had a reasonable expectation of success in
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`achieving plasma levels less than half the ULN, as required by claims 1-3, 5, 9 and
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`13. Lupin’s support for these claims is based principally on Dr. Vaux’s testimony
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`concerning portions of the teachings of the ’859 Publication. (Ex. 1002 at ¶ 63-64,
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`100.) However, Dr. Vaux has now characterized certain of these teachings as
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`providing “very little information that would be beneficial to me in caring for a
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`patient” and has provided conflicting testimony concerning others. (Ex. 2051 at
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`31:10-33:16, 47:11-19, 51:14-52:9; Ex. 2052 at ¶¶ 35-38, 64-66, 79). On this basis
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`alone, Lupin has failed as a matter of law to establish that the subject matter of
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`claims 1-15 are obvious.
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`For the reasons stated herein, Lupin has failed to meet its burden of
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`establishing that claims 1-15 are not patentable. Thus, Horizon respectfully
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`requests that the Board affirm the patentability of these claims.
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`6
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`II. BACKGROUND
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`A.
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`Prior Art at Issue
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`The Board instituted this IPR based on the ’859 Publication (Ex. 1007), Blau
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`(Ex. 1006), Simell (Ex. 1005), and the Brusilow ’979 Patent (Ex. 1024) in the
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`following manner:
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`Ground References
`1
`’859 Publication
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`Claims
`1-3
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`2
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`3
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`Blau, Simell, and the ’859 Publication
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`4-7 and 12-15
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`Blau, Simell, the ’859 Publication, and
`the Brusilow ’979 Patent
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`8-11
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`B. Technical Background on Treatment of UCDs
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`As noted, a patient with a UCD cannot remove excess nitrogen from the
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`plasma due to a defect in the operation of the urea cycle, and this results in
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`elevated plasma ammonia levels. (Ex. 1001 at 1:19-21; Ex. 2006 at ¶¶ 33-34.)
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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 ¶¶ 30-31, 37-39.) 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. 2042 at 1-2; Ex. 2006 at ¶ 35; Ex. 2019 at 1-2.) Unfortunately, survival
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`in patients with a UCD is extremely low because high levels of ammonia
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`(hyperammonemia) are extremely toxic to the brain. (Ex. 2006 at ¶¶ 35-36; Ex.
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`7
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`2008 at 1; 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 ¶¶ 31, 36; Ex. 2043 at 1423; Ex. 2017 at S66.)
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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 ¶¶ 30-32, 38; Ex. 2017 at S66-67, S69; Ex. 2040 at S33; Ex. 2044 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 ¶¶ 35, 36; Ex. 2016 at
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`1605S-1606S; Ex. 2017 at S68 (reporting that only 21% of patients ages 12-74
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`months had an IQ over 70); Ex. 2019 at 2.) A UCD diagnosis therefore presents a
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`patient and one’s family with a lifetime of coordinating a complex therapeutic
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`regimen that involves promoting a child’s development while concurrently trying
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`to avoid the potentially devastating consequences of a hyperammonemic crisis.
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`(Ex. 2006 at ¶¶ 37-38, 43; Ex. 2017 at S67.)
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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 ¶ 39; Ex. 2019 at 12-13.) But protein restriction decreases the nutrients
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`needed for growth and normal development, and 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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`8
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`achieve good metabolic control. (Ex. 2006 at ¶ 39; Ex. 2021 at 32-33.) Nitrogen
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`U.S. Patent No. 9,254,278
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`scavenging drugs, such as glyceryl tri-[4-phenylbutyrate], use a different pathway
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`than the urea cycle to remove excess nitrogen from the body. (Ex. 2006 at ¶¶ 40-
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`41; Ex. 1001 at 1:55-2:64.) Glyceryl tri-[4-phenylbutyrate] is a pre-prodrug of
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`phenylacetic acid (“PAA”) and undergoes beta oxidation by the fatty acid
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`oxidation cycle to produce PAA, which converts in vivo to phenylacetylglutamine
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`(“PAGN”). (Ex. 2006 at ¶ 40; Ex. 1001 at 1:65-2:44.) PAGN is then excreted in
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`the urine, bypassing the urea cycle. (Ex. 2006 at ¶¶ 40-41; Ex. 1001 at 1:55-2:60.)
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`Each molecule of glutamine contains two nitrogen atoms, allowing the body to
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`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 ¶¶ 43-
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`45.) 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. (Ex.
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`2006 at ¶ 45; Ex. 2012 at [0090]; Ex. 2016 at 1608S; Ex. 2021 at 33; Ex. 2015 at
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`75, Box 1.)
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`9
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`Given the unpredictable fluctuations of ammonia values, clinicians did not
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`use 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 ¶ 45.) Clinicians only considered plasma
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`ammonia levels well above the ULN as cause to take further action. (Ex. 2006 at ¶¶
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`45, 102-112; Ex. 2019 at 9, Table 4; Ex. 2009 at S51 (“aim of long-term therapy
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`has been to maintain metabolic control with plasma ammonia concentrations less
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`than twice normal”).)
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`C. Overview of the ’278 Patent
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`The inventors of the ’278 patent recognized the need for improved methods
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`of determining the appropriate dosage of nitrogen scavenging drugs such as
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`glyceryl tri-[4-phenylbutyrate] to use in subjects having UCDs to control plasma
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`ammonia levels and to prevent hyperammonemic episodes. (Ex. 1001 at 2:56-60;
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`Ex. 2006 at ¶ 46.)
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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 in the
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`largest group of UCD patients ever studied. (Ex. 1001 at 4:62-5:50, Example 1;
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`Ex. 2006 at ¶ 47.) They discovered from their research data that the patients’
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`fasting plasma ammonia levels correlated with overall daily ammonia exposure.
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`(Id.) Based on this information, the inventors determined that an ammonia value
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`that does not exceed half the ULN is a clinically useful and practical target that is
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`10
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`statistically predictive of average daily ammonia values over twenty-four hours.
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`(Ex. 1001 at 4:64-5:15, 5:51-6:1; Ex. 2006 at ¶ 47.)
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`Example 1 of the ’278 patent details the inventors’ analysis of the
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`relationship between fasting ammonia levels and the profile of ammonia levels
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`over twenty-four hours. (Ex. 1001 at 14:60-15:15; Ex. 2006 at ¶ 48.) The
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`inventors looked at steady-state and fasting ammonia data from sixty-five patients
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`across two Phase 2 studies and one Phase 3 study, and observed a positive and
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`strong relationship between the fasting ammonia levels and the area under the
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`curve (AUC) over twenty-four hours. (Ex. 1001 at 15:16-64; 16:9-14; Ex. 2006 at
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`¶ 48.) By employing modeling with Generalized Estimating Equations, they were
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`able to predict the average daily or highest achieved ammonia level based on this
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`fasting plasma ammonia value. (Ex. 1001 at 16:15-17:53, Table 2; Ex. 2006 at ¶
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`48.)
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`Based on the results of this modeling, the inventors concluded with 95%
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`confidence that the true probability of having an ammonia value AUC in the
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`desired normal range when a fasting ammonia level is less than or equal to half the
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`upper limit of normal is on average 84% and as high as 93%. (Ex. 1001 at 17:54-
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`60; Ex. 2006 at ¶ 48.) The ability to predict with such statistical confidence the
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`highest potential ammonia a patient may experience during the day and the average
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`twenty-four-hour ammonia level from a single fasting plasma ammonia
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`11
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`measurement was previously unknown and has important practical implications for
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`nitrogen scavenging drug dosing guidelines and chronic patient management. (Ex.
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`1001 at 15:10-15; Ex. 2006 at ¶¶ 49-51.)
`
`The inventors used this data to develop methods for treating UCDs and
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`adjusting the dosage of a nitrogen scavenging drug. (Ex. 1001 at 2:64-3:21; Ex.
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`2006 at ¶ 47.) Independent claims 4, 8 and 12 of the ’278 patent recite novel
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`methods of adjusting the dosage of glyceryl tri-[4-phenylbutyrate] in patients being
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`treated for UCD that require administration of an increased dosage of glyceryl
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`phenylbutyrate to a UCD patient who has a fasting plasma ammonia level that falls
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`in the window between half the ULN and the ULN.
`
`Independent claim 4 recites:
`
`4. A method for adjusting the dosage of glyceryl tri-[4-
`phenylbutyrate] in a subject being treated for a urea cycle
`disorder who has previously been administered an initial dosage
`of glyceryl tri-[4-phenylbutyrate] and who has a fasting plasma
`ammonia level less than the upper limit of normal for plasma
`ammonia level, the method comprising:
`a. measuring a fasting plasma ammonia level for the subject;
`b. comparing the fasting plasma ammonia level to the upper
`limit of normal for plasma ammonia level; and
`c. administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate], wherein the adjusted dosage is greater
`than the initial dosage if the fasting plasma ammonia level
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`is greater than half the upper limit of normal for plasma
`ammonia level, and wherein the method further comprises
`restricting the subject's dietary protein intake.
`
`Independent claims 8 and 12 share the same core limitation as claim 4 of
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`administering an increased dosage of glyceryl tri-[4-phenylbutyrate] if the
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`subject’s fasting plasma ammonia level is less than the ULN but greater than half
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`the ULN, but do not further recite restricting the subject’s dietary protein intake.
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`Instead, claim 8 recites that the method further comprises monitoring the subject’s
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`ammonia levels if the glyceryl tri-[4-phenylbutyrate] is not being adequately
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`digested by the subject's pancreatic lipases. Independent claim 12 recites that the
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`subject has previously been administered an initial dosage of sodium
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`phenylbutyrate and that the initial dosage of glyceryl tri-[4-phenylbutyrate]
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`administered is determined by the amount of the initial dosage of sodium
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`phenylbutyrate.
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`Claims 5, 9 and 13 depend from claims 4, 8 and 12, respectively, and further
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`recite repeating the steps of measuring the fasting plasma ammonia level and
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`administering an adjusted dosage until the patient exhibits a fasting plasma
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`ammonia level at or below half the ULN. Similarly, independent claim 1 is
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`directed to a method of treating a subject with a UCD comprising administering a
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`dosage of glyceryl tri-[4-[phenylbutyrate] sufficient to produce a fasting plasma
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`Case No. IPR2017-01159
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`ammonia level less than half the ULN.
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`These patented methods provide significant advantages over previous
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`treatment methods by eliminating the confusion over conflicting ammonia levels,
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`assuring ammonia control, and providing a statistical basis for the adjustment of
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`glyceryl tri-[4-phenylbutyrate] dosages, wherein a subject with a fasting ammonia
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`less than or equal to half the ULN has an 84% chance of an average daily ammonia
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`value. (Ex. 1001 at 5:10-15, 17:56-19; Ex. 2006 at ¶ 47.)
`
`III. LUPIN’S DEFINITION OF ONE OF ORDINARY SKILL IN THE
`ART IS OVERLY BROAD
`Given the rarity and complexity of UCD and the myriad factors that affect
`
`its treatment the definition of a POSA with respect to the ’278 patent is of
`
`particular importance. 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 years of residency/fellowship training in Medical
`
`Genetics, including Biochemical Genetics, followed by certification in Clinical
`
`Genetics and Clinical or Medical Biochemical Genetics by the American Board of
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`Medical Genetics and Genomics, and (c) at least five years of experience treating
`
`patients with nitrogen retention disorders, including UCDs. (Ex. 2006 at ¶ 29.)
`
`Horizon’s expert Dr. Enns meets this definition. (Ex. 2006 at ¶¶ 5-16.) 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 is an internationally recognized
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`U.S. Patent No. 9,254,278
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`expert in UCD treatment. (Ex. 2006 at ¶¶ 8-9; 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 ¶¶ 6-7; Ex. 2007 at 2.) These certifications demonstrate
`
`that he possesses, inter alia, “the ability to integrate clinical and genetic
`
`information and understand the uses, limitations, interpretation, and significance of
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`specialized laboratory and clinical procedures.” (Ex. 2026; Ex. 2006 at ¶ 7.) Dr.
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`Enns possesses far more than five years of experience treating patients with UCD,
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`maintains an active clinical practice focused on the ongoing management of
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`patients with inborn errors of metabolism, has treated approximately one hundred
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`UCD patients over the course of his career, and currently provides treatment for
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`approximately forty UCD patients, a significant number given the rarity of this
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`disorder. (Ex. 2006 at ¶¶ 6, 9-11; Ex. 2007; Ex. 2044 at S86.) Dr. Enns also has
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`published dozens of articles in peer-reviewed journals regarding UCD treatment,
`
`has authored book chapters and reviews on alternative pathway therapies, and has
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`served on the editorial boards of major journals in the field of medical genetics.
`
`(Ex. 2006 at ¶¶ 12-13; Ex. 2007 at 10-45; Ex. 2017.) Dr. Enns testifies that
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`Horizon’s definition of a POSA is appropriate for the claimed subject matter and
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`that he meets (and exceeds) this definition. (Ex. 2006 at ¶¶ 17, 29.)
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`In contrast, Petitioner proposes that a POSA would have been a physician
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`with an M.D. degree, a residency in pediatrics or internal medicine, and an
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`unspecified amount of “specialized training in the treatment of UCDs and other
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`nitrogen retention disorders” (Pet. at 10, citing Ex. 1002 at ¶ 19.) Petitioner’s
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`definition does not detail the type or amount of specialized training needed in the
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`treatment of patients with nitrogen retention disorders, such as UCDs, to qualify as
`
`a POSA. Accordingly, Petitioner’s definition of a POSA is too broad to ensure
`
`that a person who meets its definition possesses the expertise necessary to navigate
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`the complex treatment of UCD patients, and does not align with the emphasis in
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`the prior art that the complex treatment of UCD requires experienced personnel
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`with specific and extensive expertise in genetic metabolic disorders. (Ex. 2017 at
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`S66, S69; Ex. 2040 at S33; Ex. 2044 at S86-87; Ex. 2006 at ¶¶ 30-31; Envtl.
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`Designs, Inc. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983) (listing the prior
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`art, the sophistication of the technology, and the education of workers in the field
`
`as factors to consider when determining the level of ordinary skill).
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`These teachings make clear that a general pediatrician does not possess the
`
`extensive training and experience with UCDs necessary to manage their treatment
`
`and to ensure the survival of a UCD patient, and that substantial specialized
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`training is required. (Ex. 2006 at ¶¶ 30-31.) As Dr. Enns explains, a pediatrician
`
`would refer a UCD patient to a metabolic specialist, and simply would not be
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`responsible for determining the dosage of nitrogen scavenging medication. (Ex.
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`2006 at ¶ 31.) Dr. Vaux even stated before these IPR proceedings commenced that
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`“for most clinicians and trainees, the patient with a potential inborn error of
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`metabolism remains quite intimidating.” (Ex. 2037 (emphasis added).)
`
`Petitioner’s definition should be rejected by the Board because it is over-
`
`inclusive and does not ensure a physician meeting its criteria has sufficient
`
`expertise to treat UCDs. Moreover, because Dr. Vaux is not board-certified in
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`clinical genetics, or clinical or medical biochemical genetics, he does not meet
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`Horizon’s proposed definition of a POSA. (Ex. 1023; Ex. 2034 at 18:15-24.) Dr.
`
`Vaux’s testimony and opinions should be given little or no weight