`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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`PATENT OWNER HORIZON THERAPEUTICS, LLC’S
`PRELIMINARY RESPONSE
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`TABLE OF CONTENTS
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`
`I.
`
`II.
`
`III.
`
`IV.
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`INTRODUCTION .............................................................................................................. 1
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`BACKGROUND ................................................................................................................ 4
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`A.
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`Related Patents and IPR Proceedings ..................................................................... 4
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`B.
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`Technical Background on Treatment of UCDs ...................................................... 7
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`C.
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`Overview of the ’278 Patent ................................................................................... 9
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`LEVEL OF ORDINARY SKILL IN THE ART .............................................................. 12
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`CLAIM INTERPRETATION ........................................................................................... 15
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`A.
`
`B.
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`“upper limit of normal” ......................................................................................... 15
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`“the subject” .......................................................................................................... 16
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`V.
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`THE PETITION FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT THE CHALLENGED CLAIMS ARE OBVIOUS ...................... 17
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`A.
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`A POSA Would Not Have Been Motivated to Increase the Dosage of
`Glycerol Phenylbutyrate Based on Normal Plasma Ammonia Levels ................. 17
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`1.
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`2.
`
`3.
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`The ’859 Publication and the Prior Art as a Whole Taught That
`Normal Plasma Ammonia Levels Were Acceptable ................................ 17
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`The Potential Variability of Normal Plasma Ammonia Levels
`Would Not Have Motivated a POSA to Increase the Dosage of
`Glycerol Phenylbutyrate ........................................................................... 24
`
`Lupin’s Obviousness Analysis Hinges on Dr. Vaux’s Conclusory
`and Unsupported Testimony ..................................................................... 27
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`B.
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`Lupin Has Failed to Demonstrate that a POSA Would Have Combined the
`Prior Art ................................................................................................................ 31
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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 ........................................................ 31
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`Simell and Blau Do Not Address the Use of Normal Fasting Plasma
`Ammonia Levels to Treat UCDs .............................................................. 35
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`Simell, Blau and Brusilow ’979 Fail to Cure the Deficiencies of the
`’859 Publication ........................................................................................ 37
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`C.
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`The Petition Fails to Demonstrate a Reasonable Expectation of Success ............ 38
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`ii
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`Lupin Has Not Demonstrated that Claims 1-3, 5, 9 or 13 are Obvious Over
`the Prior Art .......................................................................................................... 40
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`D.
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`VI.
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`CONCLUSION ................................................................................................................. 43
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`iii
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`TABLE OF AUTHORITIES
`
`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
`
`
`Cases
`
`Allergan, Inc. v. Sandoz, Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) ................................................................................................ 30
`
`Alza Corp. v. Mylan Labs, Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) ................................................................................................ 30
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ............................................................................................ 27, 31
`
`Broadcom Corp. v. Emulex Corp.,
`732 F.3d 1325 (Fed. Cir. 2013) ................................................................................................ 38
`
`C.R. Bard, Inc. v. Med. Components, Inc.,
`IPR2015-01660 (P.T.A.B. Feb. 9, 2016) .................................................................................. 29
`
`Catalina Mktg. Int’l v. Coolsavings.com, Inc.,
`289 F.3d 801 (Fed. Cir. 2002) .................................................................................................. 16
`
`Disney Enter., Inc. v. Kappos,
`923 F. Supp. 2d 788 (E.D. Va. 2013) ....................................................................................... 22
`
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) .................................................................................................. 14
`
`Hospitality Core Services LLC v. Nomadix, Inc.,
`IPR2016–00052, 2016 WL 2909164 (P.T.A.B. Apr. 27, 2016) ............................................... 15
`
`In re Cyclobenzaprine Extended-Release Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) ................................................................................................ 38
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) .................................................................................................. 30
`
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) .................................................................................................. 16
`
`In re Van Geuns,
`988 F.2d 1181 (Fed. Cir. 1993) ................................................................................................ 15
`
`In re Wilson,
`311 F.2d 266 (C.C.P.A. 1962) .................................................................................................. 22
`
`Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359 (Fed. Cir. 2016) .................................................................................................. 3
`
`
`
`iv
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`

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`Kinetic Techs., Inc. v. Skyworks Solutions, Inc.,
`IPR2014-00529 (P.T.A.B. Sept. 23, 2014) ............................................................................... 34
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
`
`
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ................................................................................................ 19
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`Oil States Energy Servs., LLC v Greene’s Energy Group, LLC,
`No. 16-712 (cert. granted June 12, 2017) ................................................................................. 43
`
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) ................................................................................................ 16
`
`Verlander v. Garner,
`348 F.3d 1335 (Fed. Cir. 2003) ................................................................................................ 29
`
`Zimmer Biomet Holdings, Inc. v. Four Mile Bay, LLC,
`IPR2016-00011 (P.T.A.B. Apr. 1, 2016) .................................................................................. 29
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`Statutes
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`35 U.S.C. § 103 ............................................................................................................................. 17
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`35 U.S.C. § 312(a)(3) ...................................................................................................................... 3
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`35 U.S.C. § 313 ............................................................................................................................... 1
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`35 U.S.C. § 314(a) ........................................................................................................................ 17
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`Regulations
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`37 C.F.R. § 42 ........................................................................................................................... 6, 43
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`37 C.F.R. § 42.104(b)(4) ................................................................................................................. 3
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`37 C.F.R. § 42.107 .......................................................................................................................... 1
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`37 C.F.R. § 42.108(c).......................................................................................................... 6, 28, 32
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`37 C.F.R. § 42.22(a)(2) ................................................................................................................... 3
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`37 C.F.R. § 42.5(b) ......................................................................................................................... 6
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`37 C.F.R. § 42.65(a).......................................................................................................... 27, 31, 36
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`v
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`I.
`
`INTRODUCTION
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
`
`
`Horizon Therapeutics, LLC (“Horizon” or “Patent Owner”) submits this Preliminary
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`Response pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, in response to the Petition for
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`inter partes review (“IPR”) of U.S. Patent No. 9,254,278 (“the ’278 patent”) (Paper 003, herein
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`“the Petition” or “Pet.”) filed by Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively,
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`“Lupin” or “Petitioner”). Lupin has failed to meet its burden of demonstrating a reasonable
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`likelihood of unpatentability of claims 1-15 of the ’278 patent (“the challenged claims”). Thus,
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`Horizon respectfully requests that the Petition be rejected.
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`The ’278 patent claims concern innovative methods of treating patients suffering from a
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`urea cycle disorder (“UCD”). UCDs are genetic metabolic disorders that are extremely rare
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`(only 113 new U.S. patients per year), difficult to diagnose and to treat, and, most alarmingly,
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`have an extremely low survival rate (an estimated 65% mortality rate in newborns presenting
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`with UCD). UCDs are characterized by the accumulation of toxic and potentially fatal levels of
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`ammonia in the plasma and brain arising from the body’s inability to remove excess ammonia.
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`UCD treatment involves a complex regimen of dietary protein restriction, nitrogen scavenging
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`medication and/or amino acid supplementation.
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`Prior to the ’278 patent, the prior art consensus was that treatment was effective when a
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`UCD patient presented with a normal or near normal plasma ammonia level. And, as confirmed
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`by internationally recognized UCD expert, Dr. Gregory Enns (“Dr. Enns”), clinicians treating
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`UCDs prior to the 2011 priority date of the ’278 patent did not target any specific plasma
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`ammonia level within the normal range. But even with careful treatment and monitoring, UCD
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`patient outcomes remained poor. Dangerously high plasma ammonia levels (i.e.,
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`hyperammonemia) would occur without warning, often causing irreversible brain damage, coma
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`
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`1
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`

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`or death. Recognizing the need for better ammonia control in UCD patients, the inventors of the
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`’278 patent analyzed extensive plasma ammonia data taken from UCD patients and developed
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`improved methods of UCD treatment with the nitrogen scavenging drug glyceryl tri-[4-
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`phenylbutyrate] (also known as “glycerol phenylbutyrate” or “HPN-100”). In a departure from
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`prior art practice, the treatment and dosage adjustment methods claimed in the ’278 patent
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`counterintuitively direct physicians that certain patients with normal plasma ammonia levels
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`should be administered an increased dosage of drug. For example, representative independent
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`claim 4 requires, inter alia, administration of an increased dosage of glycerol phenylbutyrate to a
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`UCD patient whose fasting plasma ammonia level falls within the window of less than the upper
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`limit of normal (“ULN”) but greater than half the ULN.
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`Contrary to Lupin’s allegations, nothing in the prior art taught or suggested increasing the
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`dosage of a 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 Publication, expressly
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`teaches that “normal” plasma ammonia levels, which includes levels below the ULN but above
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`half the ULN, indicate that treatment is effective and that the patient is not in need of an
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`increased dosage of drug. Thus, the ’859 Publication expressly refutes Petitioner’s contention
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`that a POSA (person of ordinary skill in the art) would have been motivated to administer an
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`increased dosage of glycerol phenylbutyrate based on a normal fasting plasma ammonia level, or
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`that a POSA would adjust the dosage of medication to target a plasma ammonia level at or below
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`half the upper 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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`Finding no support for its position in the prior art, Lupin attempts to fill the gap with the
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`conclusory testimony of Dr. Vaux. But, the Board should not credit Dr. Vaux’s testimony
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`2
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`

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`because he does not have the requisite qualifications to offer an opinion on the field in question.
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`UCDs are 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 treat and to
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`manage them. Respectfully, Dr. Vaux, a general pediatrician with training in clinical genetics,
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`does not have the highly specialized training and experience with UCD treatment required to
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`offer an expert opinion on the ’278 patent claims. Thus, the Board should give little weight to
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`Dr. Vaux’s testimony in this matter.
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`Dr. Vaux’s lack of expertise in UCD treatment is apparent from the lack of support in the
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`prior art for his positions. Dr. Vaux fails to identify any support in the art on critical points such
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`as the motivation of a POSA in the art to perform the claimed methods and ignores the fact that
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`the prior art as a whole, including the prior art he cites, teaches that a normal plasma ammonia
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`level was indicative of effective treatment. For this reason alone, the Board should deny Lupin’s
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`Petition pursuant to 37 C.F.R. § 42.104(b)(4) and/or 37 C.F.R. § 42.22(a)(2). See also Intelligent
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`Bio-Systems, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1369 (Fed. Cir. 2016) (Petitioner
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`must “identify ‘with particularity’ the ‘evidence that supports the grounds for the challenge to
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`each claim,” per 35 U.S.C. § 312(a)(3).)
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`Dr. Vaux also fails to provide a credible reason to combine the cited prior art references
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`as he proposes and does not address why the critical differences between the references would
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`not have discouraged a POSA from combining their teachings. Accordingly, Lupin’s Petition
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`does not demonstrate why a POSA would combine the teachings of Simell and Blau with that of
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`the ’859 Publication, and thus, is fundamentally flawed.
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`Finally, Lupin fails to present any evidence that a POSA would have had a reasonable
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`expectation of success in treating UCD (i.e., reducing the incidence and frequency of
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`
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`3
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`

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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`hyperammonemia), the purpose of the claimed methods, based on Lupin’s proposed combination
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`of the prior art. Thus, 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 to demonstrate a
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`reasonable likelihood that it will prevail, and the Petition should therefore be rejected.
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`II.
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`BACKGROUND
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`A.
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`Related Patents and IPR Proceedings
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`Horizon markets an FDA-approved drug product under the trademark RAVICTI®
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`(glycerol phenylbutyrate oral liquid). RAVICTI® is approved for use as a nitrogen-binding
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`agent for chronic management of adult and pediatric patients at least two months of age and
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`older with UCDs who cannot be managed by dietary protein restriction and/or amino acid
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`supplementation alone. Horizon is the holder of approved new drug application (“NDA”) No.
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`20-3284 for the RAVICTI® product, which was first approved on February 1, 2013.
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`U.S. Patent Nos. 8,404,215 (“the ’215 patent”), 9,095,559 (“the ’559 patent”), 9,254,278
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`(“the ’278 patent”), 9,326,966 (“the ’966 patent”) and 8,642,012 (the “’012 patent”) are owned
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`by Horizon and are listed in the FDA “Orange Book” (formally known as Approved Drug
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`Products with Therapeutic Equivalence Evaluations) in connection with NDA No. 20-3284
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`because they claim an approved use of the drug product that is the subject of that NDA.
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`The ’278 patent was filed on August 3, 2015, and is a continuation of U.S. Application
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`No. 13/775,000, filed February 22, 2013, now the ’559 patent. The ’559 patent is a continuation
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`of U.S. Application No. 13/417,137, filed March 9, 2012, now the ’215 patent. The ’278 patent
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`claims the benefit of U.S. Provisional Application No. 61/564,668, filed November 29, 2011, and
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`U.S. Provisional Application No. 61/542,100, filed September 30, 2011.
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`4
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`The ’278 patent, a continuation of the ’559 patent, shares an identical patent specification
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`and prior art priority date. The ’559 patent is the subject of IPR2016-00829, which is currently
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`pending with Oral Argument scheduled for July 28, 2017. Independent claims 4, 8 and 12 of the
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`’278 patent contain the same core claim limitation as independent claims 1 and 2 of the ’559
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`patent, i.e., for a subject who has a fasting plasma ammonia level less than the ULN,
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`“administering an adjusted dosage of glyceryl tri-[4-phenylbutyrate], wherein the adjusted
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`dosage is greater than the initial dosage if the fasting plasma ammonia level is greater than half
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`the upper limit or normal for plasma ammonia level.” (Compare Ex. 1001 at 24:31-47, 24:56-
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`25:7, 25:16-26:12 with Ex. 2005 at 24:21-35, 24:36-48.) Further, like claim 5 of the ’559 patent,
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`claims 1-3, 5, 9 and 13 of the ’278 patent claim methods of treating UCD that target a fasting
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`plasma ammonia level at or below half the ULN. (Compare Ex. 1001 at 24:20-30, 24:48-51,
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`25:8-11, 26:13-17 with Ex. 2005 at 24:64-67.)
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`In the ’559 patent IPR, Lupin raises the same core prior art (the ’859 Publication, Simell
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`and Blau) and substantially the same invalidity arguments as those raised here. Dr. Enns,
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`Horizon’s expert in this case, submitted a declaration in support of Horizon’s ’559 Patent Owner
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`Response and was later deposed by Lupin. (Ex. 2001, Declaration of Dr. Gregory M. Enns,
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`M.D., Lupin Ltd. et al. v. Horizon Therapeutics, Inc., IPR2016-00829 (“Enns ’559 Decl.”); see
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`also Deposition Transcript of Gregory Enns, M.D., IPR2016-00829, Ex. 1026.) Because Dr.
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`Enns’s trial testimony in the ’559 patent case is substantially the same as his preliminary
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`testimony here, Horizon includes a copy of Dr. Enns’s declaration submitted in the ’559 patent
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`IPR as an exhibit in this matter. (Ex. 2001; compare § IX.A of Ex. 2006 at ¶¶ 67-89 with § IX.A
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`of Ex. 2001 at ¶¶ 59-84 (discussing the prior art’s lack of teaching or suggestion of increasing a
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`dosage of glyceryl tri-[4-phenylbutyrate] in a patient with normal plasma ammonia levels);
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`5
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`§ IX.B.1-2 of Ex. 2006 at ¶¶ 90-115 with § IX.B.2-3 of Ex. 2001 at ¶¶ 85-87, 100-121
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`(discussing the lack of motivation to increase the dosage for a subject with normal plasma
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`ammonia levels); § IX.B.3 of Ex. 2006 at ¶¶ 116-127 with § IX.B.1 of Ex. 2001 at ¶¶ 88-99
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`(discussing the lack of motivation to combine the ’859 Publication with Blau and/or Simell);
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`§ IX.C of Ex. 2006 at ¶¶ 128-130 with § IX.C of Ex. 2001 at ¶¶ 122-124 (discussing the lack of a
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`reasonable expectation of success); and § IX.D of Ex. 2006 at ¶¶ 131-140 with § IX.D of Ex.
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`2001 at ¶¶ 125-127 (discussing the prior art’s lack of teaching of targeting a plasma ammonia
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`level at or below half the ULN).) Dr. Enns also submitted a declaration on behalf of Horizon in
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`the IPR proceeding filed by Lupin concerning the related ’966 patent, IPR2017-01160. Lupin
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`filed its Petition on the ’966 patent concurrently with the Petition in the instant matter, and relies
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`on the same core prior art references and largely the same arguments.
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`Horizon submits that the Board should not properly view the parties’ expert testimony on
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`contested issues of fact in the light most favorable to Lupin under 37 C.F.R. § 42.108(c) because
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`Lupin has already had the opportunity to cross-examine Dr. Enns concerning the substance of his
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`testimony in this IPR. And the Board will have fully vetted Dr. Enns’s testimony in the ’559
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`patent IPR by the time an institution decision is due here. See 37 C.F.R. § 42.5(b) (Board may
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`waive or suspend a requirement of 37 C.F.R. § 42).)
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`The related ’215 patent was the subject of IPR2015-01127 filed by Par Pharmaceutical,
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`Inc. (“Par”) and joined by Lupin (IPR2016-00284), which was instituted and concluded on
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`September 29, 2016, with a Final Written Decision in favor of Petitioners. The ’215 patent
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`claims were construed by the Board to include dosage adjustment for patients who have any
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`plasma ammonia level greater than the ULN, and Petitioners ultimately prevailed in that IPR
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`because the Board was persuaded that the prior art taught increasing the dosage of drug when
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`6
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`patients had plasma ammonia levels above the ULN (e.g., >80 µmol/L). (IPR2015-01127, Paper
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`No. 49 at 17.) As set forth in Horizon’s Patent Owner Response in IPR2016-00829, (IPR2016-
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`00829, Paper No. 26), the ’559 patent claims differ significantly from those of the ’215 patent
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`because they address increasing the dosage of drug for fasting plasma ammonia levels within a
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`targeted range between half the ULN and the ULN. Claims 1-15 of the ’278 patent are
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`distinguishable over the claims of the ’215 patent and the prior art for the same reasons as the
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`’559 patent.
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`B. Technical Background on Treatment of UCDs
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`In conducting an obviousness analysis, one must consider the state of the art at the time
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`of the claimed inventions. As noted, a patient with a UCD cannot remove excess nitrogen from
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`the plasma due to a defect in the operation of the urea cycle, and this results in elevated plasma
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`ammonia levels. (Ex. 1001 at 1:19-21; Ex. 2006 at ¶¶ 33-34.) This genetic metabolic disorder is
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`extremely rare and difficult to diagnose and to treat. (Ex. 2006 at ¶¶ 30-31, 37-39.) It is
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`estimated that one out of only 35,000 live births have this disorder, resulting in only 113 new
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`patients in the U.S. per year. (Ex. 2042 at 1-2; Ex. 2006 at ¶ 35; Ex. 2019 at 1-2.)
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`Unfortunately, survival 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. 2008 at 1; Ex.
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`2020 at 21.) Between 1982 and 2003, patients presenting with hyperammonemia within the first
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`30 days of life had only a 35% survival rate (65% mortality rate). (Ex. 2006 at ¶¶ 31, 36; Ex.
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`2043 at 1423; Ex. 2017 at S66.)
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`Because of the rarity and complexity of UCD, it requires the supervision of specialists in
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`metabolic genetic disorders rather than general practitioners. (Ex. 2006 at ¶¶ 30-32, 38; Ex.
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`2017 at S66-67, S69; Ex. 2040 at S33; Ex. 2044 at S87.) But even with frequent monitoring and
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`7
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`specialized treatment, even well-controlled UCD patients remain at risk for life-threatening
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`episodic hyperammonemia, which can lead to brain damage, coma and death. (Ex. 2006 at ¶¶
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`35, 36; Ex. 2016 at 1605S-1606S; Ex. 2017 at S68 (reporting that only 21% of patients ages 12-
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`74 months had an IQ over 70); Ex. 2019 at 2.) A UCD diagnosis therefore presents a patient and
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`one’s family with a lifetime of coordinating a complex therapeutic regimen that involves
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`promoting a child’s development while concurrently trying to avoid the potentially devastating
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`consequences of a hyperammonemic crisis. (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 minimizing
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`protein intake will decrease the nitrogen load on the urea cycle. (Ex. 2006 at ¶ 39; Ex. 2019 at
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`12-13.) But protein restriction decreases the nutrients needed for growth and normal
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`development, and therefore essential amino acid supplementation and/or the use of nitrogen
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`scavenging drugs is often necessary to achieve good metabolic control. (Ex. 2006 at ¶ 39; Ex.
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`2021 at 32-33.) Nitrogen scavenging drugs, such as glyceryl tri-[4-phenylbutyrate], use a
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`different pathway than the urea cycle to remove excess nitrogen from the body. (Ex. 2006 at ¶¶
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`40-41; Ex. 1001 at 1:55-2:64.) Glyceryl tri-[4-phenylbutyrate] is a pre-prodrug of phenylacetic
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`acid (“PAA”) and undergoes beta oxidation by the fatty acid oxidation cycle to produce PAA,
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`which converts in vivo to phenylacetylglutamine (“PAGN”). (Ex. 2006 at ¶ 40; Ex. 1001 at
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`1:65-2:44.) PAGN is then excreted in the urine, bypassing the urea cycle. (Ex. 2006 at ¶¶ 40-
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`41; Ex. 1001 at 1:55-2:60.) Each molecule of glutamine contains two nitrogen atoms, allowing
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`the body 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 clinical status and
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`plasma ammonia level to track the effectiveness of UCD treatment, inherent difficulties exist
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`with the interpretation of plasma ammonia levels that have undermined its usefulness as a
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`8
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`diagnostic tool. (Ex. 2006 at ¶¶ 43-45.) With any given individual, ammonia values undergo a
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`several-fold fluctuation throughout the day. Such factors as diet, infection, routine surgery,
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`pregnancy, 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 75, Box 1.)
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`Given the unpredictable fluctuations of ammonia values, clinicians did not use normal
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`plasma ammonia levels prior to the ’278 patent as a basis to adjust a patient’s treatment. (Ex.
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`2006 at ¶ 45.) Clinicians only considered plasma ammonia levels well above the ULN as cause
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`to take further action. (Ex. 2006 at ¶¶ 45, 102-112; Ex. 2019 at 9, Table 4; Ex. 2009 at S51 (“aim
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`of long-term therapy has been to maintain metabolic control with plasma ammonia
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`concentrations less than twice normal”) (Batshaw).)
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`C.
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`Overview of the ’278 Patent
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`The inventors of the ’278 patent recognized the need for improved methods of
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`determining the appropriate dosage of nitrogen scavenging drugs such as glyceryl tri-[4-
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`phenylbutyrate] to use in subjects having UCDs to control plasma ammonia levels and to prevent
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`hyperammonemic episodes. (Ex. 1001 at 2:56-60; Ex. 2006 at ¶ 46.)
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`In response to this need, the inventors investigated the previously unknown relationship
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`between a fasting ammonia level and daily ammonia exposure in the largest group of UCD
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`patients ever studied. (Ex. 1001 at 4:62-5:50, Example 1; Ex. 2006 at ¶ 47.) They discovered
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`from their research data that the patients’ fasting plasma ammonia levels correlated with overall
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`daily ammonia exposure. (Id.) Based on this information, the inventors determined that an
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`ammonia value that does not exceed half the ULN is a clinically useful and practical target that is
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`statistically predictive of average daily ammonia values over twenty-four hours. (Ex. 1001 at
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`4:64-5:15, 5:51-6:1; Ex. 2006 at ¶ 47.)
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`9
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`Example 1 of the ’278 patent details the inventors’ analysis of the relationship between
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`Case No. IPR2017-01159
`U.S. Patent No. 9,254,278
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`fasting ammonia levels and the profile of ammonia levels over twenty-four hours. (Ex. 1001 at
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`14:60-15:15; Ex. 2006 at ¶ 48.) The inventors looked at steady-state and fasting ammonia data
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`from sixty-five patients across two Phase 2 studies and one Phase 3 study, and observed a
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`positive and strong relationship between the fasting ammonia levels and the area under the curve
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`(AUC) over twenty-four hours. (Ex. 1001 at 15:16-64; 16:9-14; Ex. 2006 at ¶ 48.) By
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`employing modeling with Generalized Estimating Equations, they were able to predict the
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`average daily or highest achieved ammonia level based on this fasting plasma ammonia value.
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`(Ex. 1001 at 16:15-17:53, Table 2; Ex. 2006 at ¶ 48.) Based on the results of this modeling, the
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`inventors concluded with 95% confidence that the true probability of having an ammonia value
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`AUC in the 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 17:54-60; Ex. 2006 at
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`¶ 48.) The ability to predict with such statistical confidence the highest potential ammonia a
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`patient may experience during the day and the average twenty-four-hour ammonia level from a
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`single fasting plasma ammonia measurement was previously unknown and has important
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`practical implications for nitrogen scavenging drug dosing guidelines and chronic patient
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`management. (Ex. 1001 at 15:10-15; Ex. 2006 at ¶¶ 49-51.)
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`The inventors used this data to develop methods for treating UCDs and adjusting the
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`dosage of a nitrogen scavenging drug. (Ex. 1001 at 2:64-3:21; Ex. 2006 at ¶ 47.) Independent
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`claims 4, 8 and 12 of the ’278 patent recite novel methods of adjusting the dosage of glyceryl tri-
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`[4-phenylbutyrate] in patients being treated for UCD that require administration of an increased
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`dosage of glyceryl phenylbutyrate to a UCD patient who has a fasting plasma ammonia level that
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`falls in the window between half the ULN and the ULN.
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`10
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`Independent claim 4 recites:
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`U.S. Patent No. 9,254,278
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`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 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.
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`Independent claims 8 and 12 share the same core limitation as claim 4 of administering
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`an increased dosage of glyceryl tri-[4-phenylbutyrate] if subject’s fasting plasma ammonia level
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`is less than the ULN but greater than half the ULN, but do not further recite restricting the
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`subject’s dietary protein intake. Instead, claim 8 recites that the method further comprises
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`monitoring the subject's ammonia levels if the glyceryl tri-[4-phenylbutyrate] is not being
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`adequately 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 phenylbutyrate and that the
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`initial dosage of glyceryl tri-[4-phenylbutyrate] administered is determined by the amount of the
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`initial dosage of sodium phenylbutyrate.
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`Claims 5, 9 and 13 depend from claims 4, 8 and 12, respectively, and further recite
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`repeating the steps of measuring the fasting plasma ammonia level and administering an adjusted
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`11
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`dosage until the patient exhibits a fasting plasma ammonia level at or below half the ULN.
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`Similarly, independent claim 1 is directed to a method of treating a subject with a UCD
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`comprising involving administering a dosage of glyceryl tri-[4-[phenylbutyrate] sufficient to
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`produce a fasting plasma ammonia level less than half the ULN.
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`These patented methods provide significant advantages over previous treatment methods
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`by eliminating the c