`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_________________
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC
`
`Patent Owner.
`_________________
`
`IPR2018-00459
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,561,197
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ......................................................................................... 1
`I.
`II. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................ 4
`A. Real Parties-in-Interest ....................................................................... 4
`B. Related Matters ................................................................................... 4
`C.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) ................................................. 5
`III. TECHNICAL BACKGROUND ................................................................... 6
`A. Nitrogen Scavenging Drugs ................................................................ 6
`1.
`Phenylacetate ............................................................................. 6
`2.
`Sodium Phenylbutyrate ............................................................ 8
`3.
`Glyceryl Tri-[4-Phenylbutyrate] ............................................. 9
`PAA Toxicity ...................................................................................... 10
`B.
`Phenylacetate Saturability ................................................................ 13
`C.
`D. Dose Optimization Based on the PAA:PAGN Ratio Was Known 15
`IV. SUMMARY OF THE ’197 PATENT AND ITS PROSECUTION
`HISTORY ..................................................................................................... 16
`A.
`Specification ....................................................................................... 16
`B. Claims ................................................................................................. 18
`C. Overview of Prosecution History ..................................................... 19
`D. Differences Between Petitioner’s Unpatentability Arguments and
`Arguments Raised During Prosecution ........................................... 25
`PAYMENT OF FEES (37 C.F.R. § 42.103) .............................................. 27
`V.
`VI. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ............................ 27
`VII. PERSON OF ORDINARY SKILL IN THE ART .................................... 27
`VIII. CLAIM CONSTRUCTION ........................................................................ 28
`IX. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b)) .......... 29
`A.
`Scope and Content of Prior Art ....................................................... 29
`1.
`Enns 2010 ................................................................................. 29
`2. MacArthur ............................................................................... 31
`3.
`Piscitelli .................................................................................... 35
`B. Claims 1 and 2 are Unpatentable as Obvious ................................. 37
`C.
`Lack of Secondary Considerations .................................................. 44
`1.
`No Unexpected Results ........................................................... 45
`
`
`
`

`

`
`
`No Commercial Success .......................................................... 46
`2.
`No Teaching Away .................................................................. 47
`3.
`X. CONCLUSION ............................................................................................ 50
`
`
`
`
`
`
`
`
`ii
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`PAGE
`
`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) ............................................................................ 38
`
`Biomarin Pharm., Inc. v. Genzyme Therapeutic Products Ltd. P’ship,
`
`IPR2013-00534, Paper 81 (P.T.A.B. Feb. 23, 2015) ....................................... 3, 43
`
`Celltrion, Inc. v. Genentech, Inc.,
`
`IPR2017-01374, Paper 15, at 17-18 (P.T.A.B. Dec. 1, 2017) .............................. 44
`
`Cuozzo Speed Techs. LLC v. Lee,
`
`136 S. Ct. 2131 (2016) .......................................................................................... 28
`
`Hoffmann-La Roche Inc. v. Apotex Inc.,
`
`748 F.3d 1326 (Fed. Cir. 2014) ............................................................................ 45
`
`In re Applied Materials, Inc.,
`
`692 F.3d 1289 (Fed. Cir. 2012) ....................................................................... 3, 43
`
`Innovention Toys, LLC v. MGA Entm’t, Inc.,
`
`637 F.3d 1314 (Fed. Cir. 2011) ............................................................................ 11
`
`KSR Int’l Co. v. Teleflex Inc.,
`
`550 U.S. 398 (2007) .............................................................................................. 27
`
`
`
`iii
`
`

`

`
`
`Limelight Networks, Inc. v. Massachusetts Institute of Technology,
`
`IPR2017-00249, Paper 9 (P.T.A.B. May 18, 2017) ............................................. 26
`
`Mayo Collaborative Services v. Prometheus Labs. Inc.,
`
`132 S. Ct. 1289 (U.S. 2012) ........................................................................... 24, 25
`
`Pfizer, Inc. v. Apotex Inc.,
`
`480 F.3d 1348 (Fed. Cir. 2007) ............................................................................ 44
`
`PharmaStem Therapeutics, Inc. v. ViaCell, Inc.,
`
`491 F.3d 1342 (Fed. Cir. 2007) ............................................................................ 44
`
`Unified Patents, Inc. v. Berman,
`
`IPR2016-01571, Paper 10 (P.T.A.B. Dec. 14, 2016) ........................................... 25
`
`Statutes
`
`35 U.S.C. § 101 ........................................................................................................ 25
`
`35 U.S.C. § 102 ........................................................................................... 30, 31, 35
`
`35 U.S.C. § 103 ................................................................................................. 29, 50
`
`35 U.S.C. § 311 .......................................................................................................... 1
`
`35 U.S.C. § 312 .......................................................................................................... 1
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314 .......................................................................................................... 1
`
`35 U.S.C. § 315 .......................................................................................................... 1
`
`35 U.S.C. § 316 .......................................................................................................... 1
`
`
`
`iv
`
`

`

`
`
`35 U.S.C. § 317 .......................................................................................................... 1
`35 U.S.C. § 317 .......................................................................................................... 1
`
`35 U.S.C. § 318 .......................................................................................................... 1
`35 U.S.C. § 318 .......................................................................................................... 1
`
`35 U.S.C. § 319 .......................................................................................................... 1
`35 U.S.C. § 319 .......................................................................................................... 1
`
`35 U.S.C. § 325 ........................................................................................................ 25
`35 U.S.C. § 325 ........................................................................................................ 25
`
`
`Rules
`
`Rules
`
`37 C.F.R. § 42 ................................................................................. 1, 4, 5, 27, 28, 29
`37 CPR. § 42 ................................................................................. 1, 4, 5, 27, 28, 29
`
`
`
`
`
`v
`
`

`

`
`
`List of Exhibits
`
`Ex. No.
`
`Description
`
`Ex. 1001
`
`U.S. Patent No. 9,561,197 to Scharschmidt et al. (“ʼ197 patent”)
`
`Ex. 1002
`
`Declaration of Keith Vaux, M.D.
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1005
`
`Ex. 1006
`
`Ex. 1007
`
`Ex. 1008
`
`Ex. 1009
`
`Enns, G.M., Alternative waste nitrogen disposal agents for urea
`cycle disorders, 135-152 (Small Molecule Therapy for Genetic
`Disorders, Cambridge University Press, Jess G. Thoene, Ed.
`2010) (“Enns 2010”)
`
`MacArthur et al., Pharmacokinetics of sodium phenylacetate
`and sodium benzoate following intravenous administration as
`both a bolus and continuous infusion to healthy adult
`volunteers, Molec. Gen. and Metab. 81 (2004) S67-S73
`(“MacArthur”)
`
`Simell et al., Waste Nitrogen Excretion Via Amino Acid
`Acylation: Benzoate and Phenylacetate in Lysinuric Protein
`Intolerance, 20 Pediatric Research, 1117-1121 (1986)
`(“Simell”)
`
`Enns et al., Survival After Treatment with Phenylacetate and
`Benzoate for Urea-Cycle Disorders, 356 New England Journal
`of Medicine 2282– 92 (2007) (“Enns 2007”)
`
`U.S. Patent Publication No. 2010/0008859, filed January 7,
`2009, published January 14, 2010 (the “ʼ859 Publication”)
`
`Batshaw et al., Alternative Pathway Therapy for Urea Cycle
`Disorders: Twenty Years Later, 38 J. Pediatrics: S46-S55
`(2001) (“Batshaw”)
`
`Thibault et al., A Phase I and Pharmacokinetic Study of
`Intravenous Phenylacetate in Patients with Cancer, 54 Cancer
`Research, 1690-1694, (1994) (“Thibault”)
`
`
`
`vi
`
`

`

`Ex. 1010
`
`Ex. 1011
`
`Ex. 1012
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1017
`
`Ex. 1018
`
`Ex. 1019
`
`
`
`Piscitelli et al., Disposition of Phenylbutyrate and its
`Metabolites, Phenylacetate and Phenylacetylglutamine, 35 J.
`Clin. Pharmacol., 368-373 (1995) (“Piscitelli”)
`
`Brusilow, Phenylacetylglutamine May Replace Urea as a
`Vehicle for Waste Nitrogen Excretion, 29 Pediatric Research,
`147-150 (1991) (“Brusilow ʼ91”)
`
`Zeitlin et al., Evidence of CFTR Function in Cystic Fibrosis
`after Systemic Administration of 4-Phenylbutyrate, 6 Molec.
`Ther., July 2002 (“Zeitlin”)
`
`Center for Drug Evaluation and Research, NDA 203284,
`Summary Review
`
`U.S. Patent Application Publication 2012/0022157, to
`Scharschmidt et al. (“Scharschmidt”)
`
`McGuire et al., Pharmacology and Safety of Glycerol
`Phenylbutyrate in Healthy Adults and Adults with Cirrhosis, 51
`Hepatology, 2077-2085 (2010) (“McGuire”)
`
`Excerpts from Molecular Genetics and Metabolism 105 (2012)
`273-366 (March 2012)
`Ravicti® Product Label
`BUPHENYL label, Physician’s Desk Reference, 60th ed. (2006),
`3327-28
`AMMONUL label, Physician’s Desk Reference, 60th ed. (2006),
`3323-26
`
`Ex. 1020
`
`Prosecution History of U.S. Patent No. 9,561,197
`
`Ex. 1021
`
`Curriculum vitae of Keith Vaux, M.D.
`
`Ex. 1022
`
`Thompson et al., Pharmacokinetics of Phenylacetate
`Administered as a 30-min Infusion in Children With Refractory
`Cancer, Cancer Chemother. Pharmacol. (2003) 52: 417-423
`
`
`
`vii
`
`

`

`
`
`Ex. 1023
`EX. 1023
`
`IPR2017-01769 Paper 7 (Horizon Patent Owner Preliminary
`IPR2017-01769 Paper 7 (Horizon Patent Owner Preliminary
`Response)
`
`Response) Ex. 1024
`
`Ex. 1024
`
`Declaration of Tiffany Mahmood
`Declaration of Tiffany Mahmood
`
`
`
`
`
`viii
`viii
`
`

`

`
`
`I.
`
`INTRODUCTION
`
`Lupin Ltd. and Lupin Pharmaceuticals Inc. (“Petitioner” or “Lupin”) petition
`
`for Inter Partes Review (“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42
`
`of all claims (claims 1 and 2) of Patent Owner Horizon Therapeutics, LLC’s
`
`(“Horizon”) U.S. Patent No. 9,561,197 (the “ʼ197 patent,” Ex. 1001).
`
`The ʼ197 patent claims are directed to a method of treating a urea cycle
`
`disorder in a subject by administering a dosage of glyceryl tri-[4-phenylbutyrate] (a
`
`nitrogen scavenging drug) in an amount effective to achieve a specific target ratio
`
`of two metabolites, phenylacetic acid (“PAA”) and phenylacetylglutamine
`
`(“PAGN”).
`
`The ’197 patent explains that in the body, glyceryl tri-[4-phenylbutyrate]
`
`metabolizes to phenylbutyrate, which in turn metabolizes to PAA, which in turn
`
`metabolizes to PAGN. (Ex. 1001 (’197 patent), 2:22-55.) In patients with urea
`
`cycle disorders, the clinical benefit of glyceryl tri-[4-phenylbutyrate] derives from
`
`the ability of PAGN to replace urea as a vehicle for carrying waste nitrogen out of
`
`the body, which avoids the buildup of toxic ammonia in patients with defective
`
`urea cycle functionality. (Id., 2:58-62.) The ’197 patent also explains that PAA
`
`was known to cause toxicity when present in high levels in circulation. (Id., 3:22-
`
`34.) Therefore, the patent explains that the purported invention is a method of
`
`adjusting the dose of drug to minimize the risk of PAA toxicity while maximizing
`
`
`
`

`

`
`
`the drug effectiveness, i.e., nitrogen removal via the PAGN metabolite. (See id.,
`
`e.g., 3:35-39; 3:43:46.)
`
`The problem for Horizon, however, is that all of the above was known and
`
`taught in the prior art. It was well-known that the clinical benefit of nitrogen
`
`scavenging drugs such as glyceryl tri-[4-phenylbutyrate] derives from their ability
`
`to excrete waste nitrogen via PAGN. (See, e.g., Ex. 1004 (MacArthur), S71-72;
`
`Ex. 1006 (Enns 2007), 2282, 2290; Ex. 1008 (Batshaw), S47; Ex. 1003 (Enns
`
`2010), 150.) The prior art was also replete with teachings that PAA can be toxic,
`
`including in urea cycle disorder patients. (See, e.g., Ex. 1004 (MacArthur), S72;
`
`Ex. 1005 (Simmel), 1120; Ex. 1009 (Thibault), 1693-1694; Ex. 1012 (Zeitlin),
`
`120-121; Ex. 1008 (Batshaw), S48; Ex. 1006 (Enns), 2290; Ex. 1018
`
`(BUPHENYL Label), 2; Ex. 1019 (AMMONUL Label), 4; Ex. 1003 (Enns 2010),
`
`147.) And the prior art expressly taught that the dose of nitrogen scavenging drugs
`
`should be optimized “to maximize nitrogen removal, while minimizing the risk of
`
`toxicity, especially due to [PAA].” (Ex. 1004 (MacArthur), S67 (Abstract); see
`
`also Ex. 1012 (Zeitlin), 121 (teaching dose optimization of nitrogen scavenging
`
`drug BUPHENYL to avoid PAA accumulation); Ex. 1022 (Thompson), 423). In
`
`other words, the prior art expressly taught persons of ordinary skill in the art to
`
`optimize the PAA:PAGN ratio in optimizing the dose of nitrogen scavenging
`
`drugs.
`
`
`
`2
`
`

`

`
`
`As Lupin’s expert Dr. Vaux explains, Piscitelli demonstrated that dose
`
`optimization changed the PAA to PAGN ratio in vivo in a predictable way. (Ex.
`
`1002 (Vaux Decl.), ¶¶ 67, 72.) Thus, the experimentation needed to optimize to
`
`achieve a target PAA:PAGN range is “nothing more than the routine application of
`
`well-known problem-solving strategy . . . the work of a skilled artisan, not of an
`
`inventor.” Biomarin Pharm., Inc. v. Genzyme Therapeutic Products Ltd. P’ship,
`
`IPR2013-00534, Paper 81, at 14 (P.T.A.B. Feb. 23, 2015) (citations and quotations
`
`omitted), aff’d 825 F.3d 1360 (Fed. Cir. 2016). At most, Horizon has simply
`
`performed the optimization suggested in the prior art, and is attempting to patent
`
`the results of that routine optimization by claiming a particular numerical ratio of
`
`PAA:PAGN. However, as the Federal Circuit has stated, where the “general
`
`conditions of a claim are disclosed in the prior art, it is not inventive to discover
`
`the optimum or workable ranges by routine experimentation,” which is all that
`
`Horizon seeks to do here. In re Applied Materials, Inc., 692 F.3d 1289, 1295 (Fed.
`
`Cir. 2012) (quoting In re Aller, 220 F.2d 454, 456 (C.C.P.A. 1955).
`
`Accordingly, IPR should be instituted and the ’197 patent claims should be
`
`cancelled.
`
`
`
`3
`
`

`

`
`
`II. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`A. Real Parties-in-Interest
`
`Petitioner certifies that Lupin Ltd. and Lupin Pharmaceuticals Inc. are the
`
`real parties-in-interest.
`
`B. Related Matters
`
`On August 16, 2017, Horizon served Lupin Pharmaceuticals, Inc. and Lupin
`
`Ltd. with a complaint in the District Court for the District of New Jersey (Case No.
`
`2:17-cv-05900) alleging infringement of the ’197 patent. Horizon is also asserting
`
`the ’197 patent against Par Pharmaceutical, Inc. (“Par”) in the District of New
`
`Jersey (Case No. 2:17-cv-05901).
`
`Horizon is also asserting other patents against Lupin and Par that are not
`
`formally related to the ’197 patent, but likewise relate to methods of treating urea
`
`cycle disorders. Specifically, Horizon is asserting U.S. Patent 9,095,559 against
`
`Lupin in the District of New Jersey (Case No. 1:15-cv-07624). This patent was the
`
`subject of IPR2016-00829, filed by Lupin. In a Final Written Decision dated
`
`September 26, 2017 (Paper 42), the Board cancelled all claims of the ’559 Patent.
`
`Horizon has filed a notice of appeal of this decision.
`
`Horizon is asserting U.S. Patents 9,254,278 and 9,326,966 against Lupin in
`
`the District of New Jersey (Case No. 1:16-cv-04438). It is also asserting U.S.
`
`Patents 8,404,215 and 8,642,012 against Par in the Eastern District of Texas (Case
`
`
`
`4
`
`

`

`
`
`No. 2-14-cv-00384). Each of these patents was or is the subject of an IPR. The
`
`’278 Patent is the subject of IPR2017-01159, filed by Lupin, which was instituted
`
`and is pending. The ’966 Patent is the subject of IPR2017-01160, filed by Lupin,
`
`which was instituted and is pending. The ʼ215 Patent was the subject of IPR2015-
`
`01127, filed by Par, to which IPR2016-00284, filed by Lupin, was joined. In a
`
`Final Written Decision dated September 29, 2016, the Board cancelled all claims
`
`of the ’215 Patent. (See IPR2015-01127, Paper 49.) Horizon did not appeal this
`
`decision. The ʼ012 Patent was the subject of IPR2015-01117, filed by Par, to
`
`which IPR2016-00283 filed by Lupin, was joined. In a Final Written Decision
`
`dated November 3, 2016, the Board found that petitioners had not carried their
`
`burden of demonstrating unpatentability. (See IPR2015-01117, Paper 53.) Par is
`
`appealing this decision.
`
`C. Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4))
`
`Lead counsel is Elizabeth J. Holland (Reg. No. 47,657), and backup counsel
`
`are Cynthia Lambert Hardman (Reg. No. 53,179) and Andrew E. Riley (Reg. No.
`
`61,228), all of Goodwin Procter LLP, The New York Times Building, 620 Eighth
`
`Avenue, New York, NY 10018, (212) 813-8800 (telephone), (212) 355-3333
`
`(facsimile). Counsels’ email addresses are eholland@goodwinlaw.com,
`
`chardman@goodwinlaw.com, and ariley@goodwinlaw.com.
`
`
`
`5
`
`

`

`
`
`Please address all correspondence and service to counsel listed above.
`
`Petitioner consents to service by email at the above email addresses.
`
`III. TECHNICAL BACKGROUND
`The urea cycle is the major pathway for the metabolism and excretion of
`
`waste nitrogen from the body. (Ex. 1002 (Vaux Decl.), ¶ 24.) In the urea cycle,
`
`enzymes and transporters synthesize urea from ammonia, and the urea is then
`
`excreted to remove excess nitrogen. (Ex. 1007 (’859 Publication), [0005] and Fig.
`
`1; Ex. 1003 (Enns 2010), 141 and Fig. 10-2.) Urea cycle disorders occur when
`
`enzymes or transporters in the urea cycle are deficient. (Ex. 1002 (Vaux Decl.), ¶¶
`
`24-26; Ex. 1003 (Enns 2010), 135.) These deficiencies can lead to elevated plasma
`
`ammonium levels and hyperammonemia, which can cause lethargy, coma, and
`
`even brain damage. (Ex. 1002 (Vaux Decl.), ¶¶ 24-26; Ex. 1018 (BUPHENYL
`
`Label), 2; Ex. 1003 (Enns 2010), 136-39.)
`
`A. Nitrogen Scavenging Drugs
`1.
`Phenylacetate
`It was well known before the priority date of the ʼ197 patent that treatment
`
`options for treating urea cycle disorders included the use of nitrogen scavenging
`
`drugs. (Ex. 1002 (Vaux Decl.), ¶¶ 27-29; Ex. 1003 (Enns 2010), 140.) Among the
`
`
`
`6
`
`

`

`
`
`early nitrogen scavenging drugs used was phenylacetate (“PAA”)1. (Ex. 1008
`
`(Batshaw), S47.) In the body, enzymes conjugate PAA with glutamine to form
`
`phenylacetylglutamine (“PAGN”). (Id.) Each mole of PAA removes two moles of
`
`nitrogen from the body. (Id.) This is depicted graphically below:
`
`
`Figure 1. Sequestration of nitrogen by PAA. (Ex. 1002 (Vaux Decl.), ¶ 30.)2
`
`
`1 The ’197 patent defines PAA as “phenylacetic acid.” (Ex. 1001 (’197 patent),
`
`2:4-10; 2:38-55.) A person of ordinary skill in the art would understand that
`
`“phenylacetic acid” encompasses either phenylacetic acid or its conjugate base,
`
`phenylacetate. (Ex. 1002 (Vaux Decl.), n.1.) As used herein, PAA means either
`
`phenylacetic acid or phenylacetate.
`
`2 “PBA” in figure 1 refers to phenylbutyrate. The ’197 patent defines PBA as
`
`“phenylbutyrate.” (Ex. 1001 (’197 patent), 2:10-55.) A person of ordinary skill in
`
`
`
`7
`
`

`

`
`
`Before the ’197 patent priority date, PAA was (and still is) commercially
`
`available together with sodium benzoate (another nitrogen scavenging drug) as
`
`AMMONUL. (Ex. 1019 (AMMONUL Label); Ex. 1003 (Enns 2010), 142, 147.)
`
`AMMONUL, an intravenous preparation, is indicated for the treatment of
`
`hyperammonemia in urea cycle disorders. (Ex. 1019 (AMMONUL Label), 2; see
`
`also Ex. 1002 (Vaux Decl.), ¶¶ 28, 35.)
`
`2.
`Sodium Phenylbutyrate
`One drawback of PAA is its offensive odor.3 (Ex. 1008 (Batshaw), S47; Ex.
`
`1011 (Brusilow ’91), 147; Ex. 1003 (Enns 2010), 146.) Accordingly, a prodrug of
`
`PAA, sodium phenylbutyrate, has replaced PAA for chronic use. (Ex. 1008
`
`(Batshaw), S47.)
`
`Prior to the priority date of the ’197 patent, sodium phenylbutyrate was (and
`
`still is) commercially available as BUPHENYL. (Ex. 1018 (BUPHENYL Label);
`
`Ex. 1003 (Enns 2010),144, 147.) BUPHENYL, an oral therapy, is indicated as
`
`adjunctive therapy in the chronic management of patients with certain urea cycle
`
`the art would understand that “phenylbuytrate” encompasses either phenylbutyrate
`
`or its conjugate acid, phenylbutyric acid. (Ex. 1002 (Vaux Decl.), n.1.) As used
`
`herein, PAA means either phenylbutyric acid or phenylbutyrate.
`
`3 It is secreted as a defensive weapon by the stinkpot turtle. (Ex. 1011 (Brusilow
`
`’91), 147; see also Ex. 1002 (Vaux Decl.), ¶ 36.)
`
`
`
`8
`
`

`

`
`
`disorders. (Ex. 1018 (BUPHENYL Label), 2; see also Ex. 1002 (Vaux Decl.), ¶¶
`
`8, 30.)
`
`As a prodrug of PAA, in the body phenylbutyrate rapidly oxidizes to form
`
`PAA, which as noted above, conjugates with glutamine to form PAGN, which in
`
`turn is excreted in urine. (Ex. 1002 (Vaux Decl.), ¶ 30.) Like PAA, each mole of
`
`phenylbutyrate removes two moles of nitrogen. (Id.) This is depicted graphically
`
`in Figure 1, above.
`
`3. Glyceryl Tri-[4-Phenylbutyrate]
`Sodium phenylbutyrate has two major drawbacks. First, for an adult with a
`
`urea cycle disorder, the standard dose of sodium phenylbutyrate requires that the
`
`patient ingest 40 tablets per day. (Ex. 1003 (Enns 2010), 150.) This high pill
`
`burden led to problems with patient compliance. Second, the daily dose of sodium
`
`phenylbutyrate involves a substantial amount of sodium—more than the
`
`recommended daily amount for adult consumption—and is thus a disadvantage to
`
`many patients who need to restrict their daily dose of sodium. (Ex. 1018
`
`(BUPHENYL Label), 2 (Warnings section); Ex. 1002 (Vaux Decl.), ¶ 46.)
`
`In view of these drawbacks, a pre-prodrug of PAA, glyceryl tri-[4-
`
`phenylbutyrate], was introduced. Glyceryl tri-[4-phenylbutyrate] is hydrolyzed by
`
`human pancreatic lipases to release three molecules of PBA, which in turn are
`
`oxidized to form three molecules of PAA and, in turn, three molecules of PAGN.
`
`
`
`9
`
`

`

`
`
`(Ex. 1007 (’859 Publication), [0023]; Ex. 1002 (Vaux Decl.), ¶ 45.) Each
`
`molecule of glyceryl tri-[4-phenylbutyrate] therefore carries out six atoms of
`
`nitrogen (two nitrogen per PAGN molecule). (Ex. 1007 (’859 Publication),
`
`[0022]-[0023]; Ex. 1002 (Vaux Decl.), ¶ 45.)
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`Glyceryl tri-[4-phenylbutyrate] is presently commercially available as
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`RAVICTI. (Ex. 1017 (RAVICTI Label).)
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`PAA Toxicity
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`B.
`It was widely reported in the prior art that PAA could be neurotoxic at high
`
`levels in a variety of populations. (Ex. 1002 (Vaux Decl.), ¶¶ 37-38, 41, 48, 52-
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`54.) For example, following PAA infusions in cancer patients, neurotoxicity due
`
`to PAA accumulation was observed:
`
`Drug-related toxicity was clearly related to the serum
`phenylacetate concentration. Three episodes of CNS toxicity,
`limited to confusion and lethargy and often preceded by emesis,
`occurred in patients treated at dose levels 3 and 4 [200 and 400
`µg/mL, respectively]. They were associated with drug
`concentrations of 906, 1044, and 1285 µg/mL (1078 ± 192
`µg/mL), respectively.
`
`(Ex. 1009 (Thibault), 1693.)
`
`PAA toxicity was also observed following infusions of AMMONUL
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`(sodium PAA/sodium benzoate) in healthy individuals. (Ex. 1004 (MacArthur),
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`S67, S72; see also discussion of MacArthur in Section IX.A.2 below.) MacArthur
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`notes the neurologic toxicities reported by Thibault, and then states: “Similarly, in
`
`our study, the high dose regimen was poorly tolerated by the normal volunteers
`
`due to nausea, vomiting, and somnolence . . . .” (Ex. 1004 (MacArthur), S72.)
`
`In patients with lysinuric protein intolerance (a type of urea cycle disorder),
`
`toxicity was noted following PAA infusions. (Ex. 1005 (Simmel), 1120; Ex. 1002
`
`(Vaux Decl.), ¶¶ 53-54.)4 Simmel indicated that a safe upper PAA concentration is
`
`4 To the extent Horizon argues (as it did in prior IPRs) that a person of ordinary
`
`skill in the art would not have considered Simell because LPI is not a urea cycle
`
`disorder, this argument should be rejected. Although not one of the classical urea
`
`cycle disorders, LPI was traditionally categorized as a mild urea cycle disorder.
`
`(Ex. 1002 (Vaux Decl.), n.2.) Simell itself unambiguously refers to LPI as a urea
`
`cycle disorder: “We studied metabolic changes caused by these substances and
`
`their pharmacokinetics in a biochemically different urea cycle disorder, lysinuric
`
`protein intolerance (LPI) . . . .” (Ex. 1005 (Simell), 1117 (Abstract) (emphasis
`
`added).) Further, references such as Batshaw and Enns 2010 review therapies for
`
`urea cycle disorders, and discuss Simell’s pharmacokinetic data. (Ex. 2009
`
`(Batshaw), S47, S48; Ex. 1003 (Enns 2010), 145.) Accordingly, to the extent
`
`Horizon questions Simell’s relevance, such arguments should be rejected. See
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`Innovention Toys, LLC v. MGA Entm’t, Inc., 637 F.3d 1314, 1321 (Fed. Cir. 2011)
`
`(“‘A reference is reasonably pertinent if . . . it is one which, because of the matter
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`3.0-3.5 mM5 in patients with lysinuric protein intolerance, and indicated that
`
`plasma concentrations measured in patients with urea cycle enzyme deficiencies
`
`indicate that somewhat higher peak PAA values (exceeding 4 mM) are acceptable.6
`
`(Ex. 1005 (Simmel), 1120; Ex. 1002 (Vaux Decl.), ¶¶ 53-54.)
`
`The FDA-approved labels for commercially-available, prior art nitrogen
`
`scavenging drugs used in urea cycle disorder patients contain warnings about PAA
`
`toxicity. For example, the BUPHENYL label states: “Neurotoxicity was reported
`
`in cancer patients receiving intravenous phenylacetate, 250–300 mg/kg/day for 14
`
`days, repeated at 4-week intervals. Manifestations were predominately
`
`somnolence, fatigue, and lightheadedness; with less frequent headache, dysgeusia,
`
`hypoacusis, disorientation, impaired memory, and exacerbation of a pre-existing
`
`neuropathy.” (Ex. 1018 (BUPHENYL Label), 2.) The AMMONUL label reports
`
`with which it deals, logically would have commended itself to an inventor’s
`
`attention in considering his problem.’” (quoting In re Clay, 966 F.2d 656, 659
`
`(Fed. Cir. 1992)).
`
`5 3.5 mM PAA is equivalent to 476 µg/mL. (Ex. 1002 (Vaux Decl.), ¶ 53.)
`
`6 While Simell indicates that higher plasma PAA levels may be acceptable in
`
`certain urea cycle disorder patients, a POSA would not have read Simell to state
`
`that PAA toxicity is not a concern for such patients. (See, e.g., Ex. 1002 (Vaux
`
`Decl.), n.3.)
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`similar information. (Ex. 1019 (AMMONUL Label), 4.) These labels demonstrate
`
`that PAA toxicity was a concern to those of skill in the art. (Ex. 1002 (Vaux
`
`Decl.), ¶ 37.) Indeed, other articles pertaining to urea cycle disorder treatments
`
`likewise report on PAA toxicity. (See, e.g., Ex. 1006 (Enns 2007), 2290; Ex. 1008
`
`(Batshaw), S48; Ex. 1003 (Enns 2010), 147.)
`
`In a prior paper submitted to the Board, Horizon conceded that PAA toxicity
`
`was known and factored into dosing decisions in urea cycle disorder patients. (Ex.
`
`1023 (IPR2017-01769 Paper 7 (HPOPR)), pages 36-37 of 64 (“Phenylacetic acid
`
`(‘PAA’), the active agent of scavenging medications including glycerol
`
`phenylbutyrate, was known to be associated with neurotoxicity and other adverse
`
`side effects.”) And consistent with the prior art teachings regarding PAA
`
`neurotoxicity, the RAVICTI label (which is not prior art), contains a prominent
`
`warning about PAA neurotoxicity and includes a discussion of the same. (Ex.
`
`1017 (RAVICTI Label), 1, 4-5.)
`
`Phenylacetate Saturability
`
`C.
`PAA toxicity was especially a concern for persons of ordinary skill in the art
`
`because it was known that the metabolic step that converts PAA to PAGN can
`
`become saturated, leading to an accumulation of PAA in the body. (Ex. 1002
`
`(Vaux Decl.), ¶¶ 38, 42, 49, 52, 64, 66, 71, 76, 79; Ex. 1003 (Enns 2010), 144,
`
`146, 147.) For example, MacArthur reports that “[t]he clearance of phenylacetate
`
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`appears to be much slower and, unlike benzoate, clearance can become saturated
`
`at the plasma levels attained with doses used to treat hyperammonemia.” (Ex.
`
`1004 (MacArthur), S72 (emphasis added).) Similarly, in a paper titled “Survival
`
`after Treatment with Phenylacetate and Benzoate for Urea-Cycle Disorders,” Dr.
`
`Gregory Enns and co-authors warned: “Continuous high rates of intravenous
`
`infusion may result in plasma phenylacetate levels that saturate the capacity for
`
`conversion of phenylacetate to phenylacetylglutamine [PAGN], leading to rapid
`
`accumulation of phenylacetate and subsequent toxicity.” (Ex. 1006 (Enns 2007),
`
`2290 (emphasis added); see also Ex. 1003 (Enns 2010), 144 (“Both phenylacetate
`
`and benzoate demonstrate saturable, nonlinear elimination, with a decrease in
`
`clearance with increased dose.”)) Similarly, following administration of oral
`
`phenylbutyrate, Zeitlin observed that “Accumulation of phenylacetate in the
`
`plasma was observed in one individual in the 30 g [BUPHENYL] cohort. This
`
`suggests that in this subject, phenylbutyrate may have saturated the metabolic
`
`pathway to conversion to phenylacetylglutamine [PAGN], thus suggesting a
`
`maximum tolerated dose of 20 g daily.” (Ex. 1012 (Zeitlin), 121 (emphasis
`
`added).)
`
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`D. Dose Optimization Based on the PAA:PAGN Ratio Was Known
`MacArthur and others expressly taught the use of the plasma PAA:PAGN
`
`ratio to optimize dose, which Horizon now claims in the ’197 patent. (Ex. 1002
`
`(Vaux Decl.), ¶ 42.) MacArthur stated this concept no less than three times:
`
`• “Dose optimization is required to maximize nitrogen removal, while
`
`minimizing the risk of toxicity, especially due to PAA.” (Ex. 1004
`
`(MacArthur), S67 (Abstract).)
`
`• “Also important is maintaining the plasma levels of phenylacetate and
`
`benzoate below the levels associated with toxicity, while providing
`
`enough of these scavenging agents to maximize waste nitrogen
`
`removal.” (Id., S72.)
`
`• “[A]dministration of phenylacetate needs to be optimized to lessen the
`
`risk of attaining inappropriately high plasma phenylacetate levels,
`
`while maximizing its conversion to PAG[N].”7 (Id.)
`
`Zeitlin also expressly recognized that dose should be adjusted to optimize
`
`drug dosage, PAA, and PAGN. (Ex. 1002 (Vaux Decl.), ¶ 52.) Zeitlin observed
`
`accumulation of PAA in the plasma of one patient, and stated that “phenylbutyrate
`
`may have saturated the metabolic pathwa