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, INC.
`
`Patent Owner.
`_________________
`
`IPR2016-00829
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,095,559
`PURSUANT TO §§ 35 U.S.C. 311-319 AND 37 C.F.R. § 42
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
`
`
`
`

`
`
`
`TABLE OF CONTENTS
`
`Page
`
`INTRODUCTION ......................................................................................... 1
`I.
`II. OVERVIEW ................................................................................................... 1
`A.
`Summary of the ʼ559 Patent .................................................................. 1
`B.
`Summary of the Prosecution History of the ʼ559 Patent ...................... 2
`III. BACKGROUND ON THE UREA CYCLE, UCDs, AND NITROGEN
`SCAVENGING DRUGS ............................................................................... 4
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) .............................. 6
`V.
`PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................ 6
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................ 7
`A.
`Real Parties-in-Interest .......................................................................... 7
`B.
`Related Matters ...................................................................................... 7
`C.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) .................................................... 8
`VII. PERSON OF ORDINARY SKILL IN THE ART ...................................... 8
`VIII. CLAIM CONSTRUCTION .......................................................................... 9
`A.
`Broadest Reasonable Interpretation Standard ....................................... 9
`B.
`Claim Construction for the ʼ559 Patent .............................................. 10
`IX. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b)) .......... 13
`A. Ground 1: Claims 1, 2, 4, 5, 7-10, 12, and 13 Are Unpatentable as
`Obvious Over Blau, Simell, and the ʼ859 Publication ........................ 15
`1.
`Overview of Prior Art Applied in Ground 1 ............................. 15
`2. Motivation to Combine Applied Prior Art ................................ 19
`3.
`Lack of Secondary Considerations ........................................... 20
`4.
`Independent Claims 1 and 2 ...................................................... 22
`(a)
`Preambles of Independent Claims 1 and 2 ..................... 22
`(b)
`Part (a) of Independent Claims 1 and 2 .......................... 25
`(c)
`Part (b) of Independent Claims 1 and 2 .......................... 26
`(d)
`Part (c) of Independent Claims 1 and 2 .......................... 27
`Dependent Claim 4 ................................................................... 30
`Dependent Claim 5 ................................................................... 31
`Dependent Claim 7 ................................................................... 32
`
`5.
`6.
`7.
`
`
`
`

`
`
`
`8.
`Dependent Claim 8 ................................................................... 32
`9.
`Dependent Claim 9 ................................................................... 33
`10. Dependent Claim 10 ................................................................. 34
`11. Dependent Claims 12 and 13 .................................................... 35
`B. Ground 2: Claims 3, 6, 11, 14, and 15 are Unpatentable as Obvious in
`View of Blau, Simell, the ʼ859 Publication, and Brusilow ʼ84 ........... 35
`1.
`Overview of Prior Art Applied in Ground 2 ............................. 35
`2. Motivation to Combine Prior Art Applied in Ground 2 ........... 37
`3.
`Lack of Secondary Considerations ........................................... 38
`4.
`Independent Claim 3 ................................................................. 38
`(a)
`Preamble of Independent Claim 3 .................................. 38
`(b)
`Part (a) of Independent Claim 3 ..................................... 39
`(c)
`Part (b) of Independent Claim 3 ..................................... 40
`(d)
`Part (c) of Independent Claim 3 ..................................... 42
`5.
`Dependent Claim 6 ................................................................... 44
`6.
`Dependent Claim 11 ................................................................. 44
`7.
`Dependent Claims 14 and 15 .................................................... 45
`X. CONCLUSION ............................................................................................ 46
`
`
`
`
`
`
`
`ii
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`

`
`
`
`List of Exhibits
`
`Ex. No.
`
`Description
`
`Ex. 1001
`
`U.S. Patent No. 9,095,559 to Scharschmidt et al. (“ʼ559 patent”)
`
`Ex. 1002
`
`Declaration of Keith Vaux, M.D.
`
`Ex. 1003
`
`Curriculum vitae of Keith Vaux, M.D.
`
`Ex. 1004
`
`Brusilow, et al., Treatment of Episodic Hyperammonemia in
`
`Children with Inborn Errors of Urea Synthesis, 310 The New
`
`England Journal of Medicine, 1630-1634 (1984). (“Brusilow
`
`ʼ84”).
`
`Ex. 1005
`
`Simell, et al., Waste Nitrogen Excretion Via Amino Acid
`
`Acylation: Benzoate and Phenylacetate in Lysinuric Protein
`
`Intolerance, 20 Pediatric Research, 1117-1121 (1986). (“Simell”).
`
`Ex. 1006
`
`Blau, Duran, Blaskovics, Gibson (editors), Physician’s Guide to
`
`the Laboratory Diagnosis of Metabolic Diseases, 261-276 (2d ed.
`
`1996). (“Blau”).
`
`Ex. 1007
`
`U.S. Patent Publication No. 2010/0008859, filed January 7, 2009,
`
`published January 14, 2010. (the “ʼ859 Publication”).
`
`Ex. 1008
`
`Scientific Discussion for Ammonaps, EMEA 2005, available at
`
`http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
`
`
`
`iii
`
`

`
`
`
`_Scientific_Discussion/human/000219/WC500024748.pdf.
`
`(“Scientific Discussion”).
`
`Ex. 1009
`
`Dixon, et al., Intercurrent Illness in Inborn Errors of Intermediary
`
`Metabolism, 67 Archives of Disease in Childhood, 1387-1391
`
`(1992). (“Dixon”).
`
`Ex. 1010
`
`UMass Memorial Laboratories, Lab Updates, February 2007,
`
`Measurement of Ammonia in Blood
`
`Ex. 1011
`
`Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle
`
`for Waste Nitrogen Excretion, 29 Pediatric Research, 147-150
`
`(1991). (“Brusilow ʼ91”).
`
`Ex. 1012
`
`Yajima, et al., Diurnal Fluctuation of Blood Ammonia Levels in
`
`Adult-Type Citrullinemia, 137 Tohoku J. Exp. Med., 213-220
`
`(1982). (“Yajima”).
`
`Ex. 1013
`
`Batshaw, et al., Treatment of Carbamyl Phosphate Synthetase
`
`Deficiency with Keto Analogues of Essential Amino Acids, 292
`
`The New England J. Medicine, 1085-1090 (1975). (“Batshaw”).
`
`Ex. 1014
`
`Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
`
`Humans and Rats, 32 Drug Metabolism and Disposition, 10-19
`
`(2004). (“Kasumov”).
`
`
`
`iv
`
`

`
`
`
`Ex. 1015
`
`Barsotti, Measurement of Ammonia in Blood, 138 J Pediatrics,
`
`S11- S20 (2001). (“Barsotti”).
`
`Ex. 1016
`
`Berry, et al., Long-term management of patients with urea cycle
`
`disorders, Journal of Pediatrics, Vol. 138, No. 1, S56–S61 (2001).
`
`(“Berry”).
`
`Ex. 1017
`
`Levin, et al., Hyperammonaemia A Variant Type of Deficiency of
`
`Liver Ornithine Transcarbamylase, Arch. Dis. Childh., 1964, 44.
`
`162 (1968).
`
`Ex. 1018
`
`Prosecution History of U.S. Patent No. 8,404,215.
`
`Ex. 1019
`
`Excerpt from Stedman’s Medical Dictionary (Lippincott
`
`Williams & Wilkins 2006).
`
`Ex. 1020
`
`Buphenyl® label, Physician’s Desk Reference, 60th ed. (2006) at
`
`3327-28.
`
`Ex. 1021
`
`Ammonul® label, Physician’s Desk Reference, 60th ed. (2006) at
`
`3323-26.
`
`Ex. 1022
`
`Prosecution History of U.S. Patent No. 9,095,559 (part 1 of 2).
`
`Ex. 1023
`
`Prosecution History of U.S. Patent No. 9,095,559 (part 2 of 2).
`
`
`
`v
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`

`
`
`
`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 claims 1 to 15 of U.S. Patent No. 9,095,559 (“the ʼ559 patent,” Ex. 1001).
`
`II. OVERVIEW
`
`A.
`
`Summary of the ʼ559 Patent
`
`The ʼ559 patent is directed to methods of administering and adjusting the
`
`dosage of tri-[4-phenylbutyrate], a nitrogen scavenging drug, based on the fasting
`
`plasma ammonia level of a subject. Nitrogen scavenging drugs, and their use in
`
`reducing plasma ammonia levels in patients with nitrogen retention disorders, were
`
`well known long before the ʼ559 patent was filed. The use of the nitrogen
`
`scavenging drugs glyceryl tri-[4-phenyl-butyrate] (also known as “HPN-100”),
`
`phenylbutyric acid (“PBA”), sodium phenylbutyrate (“NaPBA”), sodium benzoate,
`
`and combinations thereof, to treat patients with urea cycle disorders (“UCDs”) and
`
`hepatic encephalopathy, was specifically disclosed in the prior art.
`
`The ʼ559 patent discloses a purportedly novel method of measuring a fasting
`
`plasma ammonia level of a subject who has received glyceryl tri-[4-phenyl-
`
`butyrate], comparing this fasting plasma ammonia level to an upper limit of normal
`
`(“ULN”) for plasma ammonia level, and then adjusting the dosage of glyceryl tri-
`
`[4-phenyl-butyrate] if the measured fasting plasma ammonia level is between half
`
`
`
`

`
`
`
`of the ULN and the ULN for plasma ammonia level. Increasing the dose of
`
`nitrogen scavenging drugs to lower a subject’s fasting plasma ammonia level and
`
`maintain normal levels has been done for decades.
`
`As shown below, the claims of the ʼ559 patent describe nothing more than
`
`conventional practice by physicians that was disclosed in the prior art cited herein
`
`and known before September 30, 2011, the earliest possible priority date (“priority
`
`date”) of the ʼ559 patent. Accordingly, IPR should be instituted.
`
`B.
`
`Summary of the Prosecution History of the ʼ559 Patent
`
`The application leading to the ʼ559 patent was filed on February 22, 2013.1
`
`(Ex. 1001.) The Examiner issued a non-final rejection on January 9, 2015,
`
`rejecting the claims for nonstatutory double patenting. (Ex. 1022 at 295–98.) In
`
`1 The ʼ559 patent was filed on February 22, 2013, as a divisional of U.S.
`
`Application No. 13/417,137, filed March 9, 2012, now Patent No. 8,404,215 (the
`
`“ʼ215 patent”). The ʼ559 patent claims the benefit of U.S. Provisional Application
`
`No. 61/564,668, filed on November 29, 2011, and U.S. Provisional Application
`
`No. 61/542,100, filed September 30, 2011. The ʼ559 patent is assigned to Horizon
`
`Therapeutics, Inc. (“Horizon” or “Patent Owner”). For purposes of this IPR only,
`
`Petitioner will assume that the ʼ559 patent claims are entitled to the earliest
`
`possible claimed priority date, which is the September 30, 2011 filing date of U.S.
`
`Provisional Application No. 61/542,100.
`
`
`
`2
`
`

`
`
`
`response, the applicant submitted a terminal disclaimer. (Ex. 1022 at 325.) The
`
`Examiner then issued a Notice of Allowance on May 20, 2015, stating the
`
`following reasons for allowance:
`
`Following a diligent search it was determined that the prior art neither
`
`teaches nor provides adequate motivation to arrive at the instantly
`
`claimed method 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-phenyl-butyrate], 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-phenyl-butyrate], wherein the adjusted dosage is greater than the
`
`initial dosage if the fasting blood ammonia level is greater than half
`
`the upper limit of normal for plasma ammonia level.
`
`(Ex. 1022 at 349–50.)
`
`On June 5, 2015, the applicant submitted a Request for Continued
`
`Examination, and amended the claims to specify that “the fasting plasma ammonia
`
`level is greater than half the upper limit of normal for plasma ammonia level and
`
`less than the upper limit of normal for plasma ammonia level or that the subject
`
`
`
`3
`
`

`
`
`
`with a urea cycle disorder has previously been administered an initial dosage of
`
`glyceryl tri-[4-phenyl-butyrate] and has a fasting plasma ammonia level less than
`
`the upper limit of normal for plasma ammonia level.” (Ex. 1023 at 484–485.) The
`
`applicant also added new dependent claims, specifying the oral administration of
`
`glyceryl tri-[4-phenyl-butyrate].
`
`The Examiner then issued a Notice of Allowance on June 18, 2015,
`
`repeating the same reasons for allowance quoted above. (Ex. 1023 at 498–99.)
`
`As shown below, the claimed subject matter that the Examiner believed was
`
`absent from the prior art was in fact well known.
`
`III. BACKGROUND ON THE UREA CYCLE, UCDs, AND NITROGEN
`SCAVENGING DRUGS
`
`The urea cycle is the major pathway for the metabolism and excretion of
`
`waste nitrogen. (Ex. 1002 at ¶ 30.) In the urea cycle, enzymes and transporters
`
`synthesize urea from ammonia, and the urea is then excreted to remove excess
`
`nitrogen. (Ex. 1007 at [0005] and Fig. 1.) UCDs occur when enzymes or
`
`transporters in the urea cycle are deficient. (Ex. 1002 at ¶ 30.) These deficiencies
`
`can lead to elevated plasma ammonium levels and hyperammonemia, which can
`
`cause lethargy, coma, and even brain damage. (Id.; Ex. 1008 at 1.)
`
`The applicant admitted during prosecution of the parent ʼ215 patent that it
`
`was “well known in the art that nitrogen retention disorders are associated with
`
`elevated blood ammonia levels, and that these disorders can be treated by
`
`
`
`4
`
`

`
`
`
`administering nitrogen scavenging drugs.” (Ex. 1018 at 148.) It was also well
`
`known before the priority date of the ʼ559 patent that treatment options for UCDs
`
`included the use of nitrogen scavenging drugs such as sodium benzoate, PBA,
`
`HPN-100, and NaPBA. (Ex. 1007 at [0015]–[0016], [0020]–[0021]; Ex. 1009 at
`
`1389; Ex. 1020; Ex. 1021.) BUPHENYL® (sodium phenylbutyrate, NaPBA) was
`
`FDA-approved in 1996, and is indicated as adjunctive therapy in the chronic
`
`management of patients with certain UCDs. (Ex. 1002 ¶ 33; Ex. 1020 at 3327.)
`
`In vivo, NaPB rapidly oxidizes to form one molecule of phenylacetic acid
`
`(“PAA”), which in turn conjugates with glutamine to form phenylacetylglutamine
`
`(“PAGN”), which is then excreted in the urine. (Ex. 1009 at 1389; Ex. 1007 at
`
`[0003], [0021]–[0037]; Ex. 1002 ¶ 34.) Each molecule of PAGN carries away two
`
`molecules of nitrogen. (Ex. 1007 at [0023]; Ex. 1002 ¶ 34.) Glyceryl tri-[4-
`
`phenylbutyrate] is hydrolyzed to release three molecules of phenylbutyrate, which
`
`in turn are oxidized to form three molecules of PAA and, in turn, three molecules
`
`of PAGN. Each molecule of glyceryl tri-[4-phenylbutyrate] therefore carries out
`
`six molecules of waste nitrogen (two nitrogen per PAGN molecule). (Ex. 1007 at
`
`[0022].)
`
`It was well known before the priority date of the ʼ559 patent that treating
`
`patients with UCDs involved achieving a balance between diet, amino acid
`
`supplementation, and use of nitrogen scavenging drugs. (Ex. 1016 at S56; Ex.
`
`
`
`5
`
`

`
`
`
`1002 ¶ 32.) One critical aspect of therapy was monitoring fasting plasma ammonia
`
`levels, and if the levels were elevated, administering nitrogen scavenging drugs to
`
`decrease plasma ammonia values and bring and maintain them within normal
`
`ranges for the subject. (Ex. 1002 ¶¶ 29, 33, 35–41, 48; Ex. 1007 at, e.g., [0083];
`
`Ex. 1004 at 1631, 1632 (Fig. 1); Ex. 1005 at 1118; Ex. 1006 at 273 (Table 11.9);
`
`Ex. 1008 at 10; Ex. 1015 at S11.)
`
`It was also well known before the priority date of the ʼ559 patent that an
`
`effective dosage of a PAA prodrug could be determined by taking into account the
`
`conversion of PAA prodrugs to urinary PAGN, which was reported in the prior art
`
`to be 60–75%. (Ex. 1002 ¶ 36; Ex. 1007 at [0020], [0043], [0223].) Therefore,
`
`the ʼ559 patent describes nothing more than applying well known principles for
`
`treating UCD patients.
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`
`Petitioner certifies that (1) the ʼ559 patent, issued on August 4, 2015, is
`
`available for IPR; and (2) Petitioner is not barred or estopped from requesting an
`
`IPR on the grounds identified in this Petition.
`
`V.
`
`PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`Petitioner authorizes required fees to be charged to Deposit Acct. 504494.
`
`
`
`6
`
`

`
`
`
`VI. 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 January 13, 2016 and January 14, 2016, Horizon served Lupin
`
`Pharmaceuticals, Inc. and Lupin Ltd., respectively, with a complaint in the District
`
`Court for the District of New Jersey (Case No. 1:15-cv-07624) alleging that
`
`Petitioner is infringing the ʼ559 patent, the parent ʼ215 patent, and Horizon’s U.S.
`
`Patent 8,642,012.
`
`The parent ʼ215 patent is the subject of IPR2015-01127, filed by Par
`
`Pharmaceutical, Inc., which has been instituted. Lupin filed IPR2016-00284
`
`against the ’215 patent, together with a motion for joinder with IPR2015-01127.
`
`Lupin’s IPR is pending a decision on institution and joinder.
`
`Par and Lupin also filed IPR2015-01117 and IPR2016-00283, respectively,
`
`against Horizon’s U.S. Patent 8,642,012, although that patent is not related to the
`
`ʼ559 patent.
`
`Horizon is also asserting the parent ʼ215 patent and U.S. Patent 8,642,012
`
`against Par in the Eastern District of Texas (Case No. 2-14-cv-00384).
`
`
`
`7
`
`

`
`
`
`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
`
`is Cynthia Lambert Hardman (Reg. No. 53,179), both of Goodwin Procter LLP,
`
`The New York Times Building, 620 Eighth Avenue, New York, NY 10018, (212)
`
`813-8800 (telephone), (212) 355-3333 (facsimile). Ms. Holland’s email address is
`
`eholland@goodwinprocter.com, and Ms. Hardman’s email address is
`
`chardman@goodwinprocter.com.
`
`Please address all correspondence and service to counsel listed above.
`
`Petitioner consents to service by email, directed to counsel at the email addresses
`
`identified above.
`
`VII. PERSON OF ORDINARY SKILL IN THE ART
`
`A person of ordinary skill in the art (“POSA”) is a hypothetical person who
`
`is presumed to know all of the relevant prior art, has ordinary creativity, is not an
`
`automaton, and is capable of combining teachings of the prior art. See KSR Int’l
`
`Co. v. Teleflex Inc., 550 U.S. 398, 420–21 (2007). With respect to the ʼ559 patent,
`
`Petitioner submits that a POSA is a physician with an M.D. degree, with a
`
`residency in pediatrics or internal medicine, and specialized training in the
`
`diagnosis or treatment of inherited metabolic disorders, such as UCD and other
`
`nitrogen retention disorders. (Ex. 1002 ¶ 19.) A POSA would easily have
`
`
`
`8
`
`

`
`understood the prior art references referred to herein and would have been capable
`
`
`
`of drawing inferences from them.
`
`VIII. CLAIM CONSTRUCTION
`
`A. Broadest Reasonable Interpretation Standard
`
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
`
`given their broadest reasonable interpretation in light of the specification of the
`
`ʼ559 patent. The Patent Trial and Appeal Board (“Board”) interprets claims using
`
`the “broadest reasonable construction in light of the specification of the patent in
`
`which [they] appear[].” 37 C.F.R. § 42.100(b); Office Patent Trial Practice Guide,
`
`77 Fed. Reg. 48756, 48766 (Aug. 14, 2012).
`
`Under this standard, claim terms are generally given their ordinary and
`
`customary meaning, as would be understood by a POSA in the context of the entire
`
`disclosure. See In re Translogic Tech., Inc. 504 F.3d 1249, 1257 (Fed. Cir. 2007).
`
`If a special definition for a claim term is proffered, it must be described in the
`
`specification “with reasonable clarity, deliberateness, and precision.” In re
`
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Absent such a special definition,
`
`limitations are not to be read from the specification into the claims. See In re Van
`
`Guens, 988 F.2d 1181, 1184 (Fed. Cir. 1993).
`
`
`
`9
`
`

`
`B. Claim Construction for the ʼ559 Patent
`
`
`
`According to the specification, “upper limit of normal” (“ULN”), which
`
`appears in each of the challenged claims, means “the highest level in the range of
`
`normal values.” (Ex. 1001 at 12:11–12.)
`
`Each of independent claims 1, 2, and 3, as well as dependent claims 5,
`
`6, and 8, recite a “fasting” plasma ammonia level. In the medical context, the
`
`plain and ordinary meaning of the term “fast” means abstaining from food.
`
`See, e.g., Stedman’s Medical Dictionary (Lippincott Williams & Wilkins
`
`2006) (Ex. 1019). The specification of the ʼ559 patent is consistent with
`
`this, making clear that fasting means that the subject preferably does not
`
`ingest any food, and in certain embodiments, some non-food substances
`
`(such as certain supplements, beverages, etc.):
`
`During the fasting period, the subject preferably does
`
`not ingest any food. In certain embodiments, the
`
`subject may also refrain from ingesting certain non-
`
`food substances during the fasting period. For
`
`example, in certain embodiments the subject does
`
`not ingest any supplements and/or nitrogen
`
`scavenging drugs during the fasting period. In
`
`certain of these embodiments, the subject may
`
`
`
`10
`
`

`
`
`
`nonetheless ingest one or more drugs other than
`
`nitrogen scavenging drugs during the fasting period.
`
`In certain embodiments, the subject does not ingest
`
`any high calorie liquids during the fasting period. In
`
`certain of these embodiments, the subject does not
`
`ingest any liquids other than water during the
`
`fasting period. In other embodiments, the subject
`
`may ingest small amounts of low calorie beverages,
`
`such as tea, coffee, or diluted juices.
`
`(Ex. 1001, at 10:30–44.) The patent specifies that the fasting period is at least
`
`four hours:
`
`In certain embodiments of the methods disclosed
`
`herein, the fasting period for obtaining a fasting
`
`blood ammonia level is overnight. In certain
`
`embodiments, the fasting period is 4 hours or more, 5
`
`hours or more, 6 hours or more, 7 hours or more, 8
`
`hours or more, 9 hours or more, 10 hours or more, 11
`
`hours or more, or 12 hours or more, and in certain
`
`embodiments the fasting period is 4-8 hours, 6-8
`
`hours, or 8-12 hours.
`
`
`
`11
`
`

`
`
`
`(Id., at 10:23–29.) In view of specification and the plain and ordinary meaning of
`
`the term fasting, “fasting” plasma ammonia level means a plasma ammonia
`
`level from a person who has not eaten food for at least four hours.
`
`Claims 1, 2, and 6 require that the “adjusted dosage” is “greater than the
`
`initial dosage.” With regard to an adjusted dosage of glyceryl tri-[4-
`
`phenylbutyrate] that is greater than the initial dosage, the specification states:
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`“Increasing the dosage of a nitrogen scavenging drug may refer to increasing the
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`amount of drug per administration (e.g., an increase from a 3 mL dosage to a 6 mL
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`dosage), increasing the number of administrations of the drug (e.g., an increase
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`from once-a-day dosing to twice- or three-times-a-day), or any combination
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`thereof.” (Id. at 10:20–25.) In view of this disclosure, an adjusted dosage that is
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`“greater than the initial dosage” means a dosage that increases the amount of drug
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`per administration, an increased number of administrations of the drug, or any
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`combination thereof.
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`In addition, each of the challenged claims contains the transition term
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`“comprising.” Accordingly, while the claims require the claimed method steps,
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`they do not exclude additional steps.
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`Petitioners’ positions regarding the scope of the claims should not be
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`construed as an assertion regarding the appropriate claim scope in other
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`adjudicative forums, where a different claim interpretation standard may apply.
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`12
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`IX. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b))
`
`In Ground 1, Petitioner requests inter partes review and cancellation of
`
`claims 1, 2, 4, 5, 7-10, 12, and 13 as unpatentable under 35 U.S.C. § 103 as
`
`obvious over Blau, Simell, and the ʼ859 Publication.
`
`In Ground 2, Petitioner requests inter partes review and cancellation of
`
`claims 3, 6, 11, 14, and 15 as unpatentable under 35 U.S.C. § 103 as obvious over
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`Blau, Simell, the ʼ859 Publication, and Brusilow ʼ84.
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`Petitioner provides the declaration of Keith Vaux, M.D. in support of the
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`grounds for challenging the claims. (Ex. 1002.) Dr. Vaux is an expert in the field.
`
`(Ex. 1002 ¶¶ 1–4; Ex. 1003.)
`
`Claims 1–3, the three independent claims of the ʼ559 patent, recite:
`
`1. 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-
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`[4-phenylbutyrate] and who has a fasting plasma ammonia level less
`
`than the upper limit of normal for plasma ammonia level, the method
`
`comprising:
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`(a) measuring a fasting plasma ammonia level for the subject;
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`(b) comparing the fasting plasma ammonia level to the upper
`
`limit of normal for plasma ammonia level; and
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`13
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`(c) administering an adjusted dosage of glyceryl tri-[4-
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`phenylbutyrate], wherein the adjusted dosage is greater than the
`
`initial dosage if the fasting plasma ammonia level is greater
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`than half the upper limit of normal for plasma ammonia level.
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`2. A method of treating a subject with a urea cycle disorder who has
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`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] that 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.
`
`3. A method of administering glyceryl tri-[4-phenylbutyrate] to a
`
`subject having a urea cycle disorder, the method comprising:
`
`(a) measuring a first fasting plasma ammonia level for the
`
`subject;
`
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`14
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`
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`(b) comparing the first fasting plasma ammonia level to the
`
`upper limit of normal for plasma ammonia level; and
`
`(c) administering an initial dosage of glyceryl tri-[4-
`
`phenylbutyrate] to the subject if the fasting plasma ammonia
`
`level is greater than half the upper limit of normal for plasma
`
`ammonia level and less than the upper limit of normal for
`
`plasma ammonia level.
`
` (Ex. 1001 at 24:21–60.)
`
`A. Ground 1: Claims 1, 2, 4, 5, 7-10, 12, and 13 Are Unpatentable as
`Obvious Over Blau, Simell, and the ʼ859 Publication
`1. Overview of Prior Art Applied in Ground 1
`Simell (Ex. 1005) was published in 1986, and qualifies as prior art under 35
`
`U.S.C. § 102(b). It discloses methods of administering the nitrogen scavenging
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`drugs sodium benzoate and phenylacetate to children with lysinuric protein
`
`intolerance, a type of UCD, following the standardized induction of
`
`hyperammonemia. (Ex. 1002 ¶ 45; Ex. 1005 at Abstract, 1117–18.) As part of the
`
`protocol, Simell measured fasting blood ammonia levels in the patients after an
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`overnight fast. (Ex. 1005 at 1118.)
`
`Blau (Ex. 1006) was published in 1996, and qualifies as prior art under 35
`
`U.S.C. § 102(b). Blau is a physician’s guide to the laboratory diagnosis of
`
`metabolic diseases, including UCDs. Blau discloses “Specimen Collection”
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`15
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`guidelines that require ammonia levels to be measured “at least 4 h after end of the
`
`last meal or stopping intravenous [amino acid] supply from a central vein or
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`artery.” (Ex. 1006 at 273 (Table 11.9).) A POSA would have understood Blau to
`
`suggest measuring fasting blood ammonia levels. (Ex. 1002 ¶ 46.) Blau discusses
`
`different types of UCDs and laboratory tests that should be performed when
`
`treating a UCD patient.2 (Ex. 1006 at 261, 270–71, 273 (Table 11.9).)
`
`2 To the extent Patent Owner argues that Blau relates solely to using fasting plasma
`
`ammonia levels for diagnosing UCDs but not for treating them, this purported
`
`criticism should be rejected. Prior to September 2011, it was routine for
`
`practitioners to obtain fasting blood samples on which to perform ammonia testing,
`
`no matter what the purpose of the testing (e.g. for both treatment and diagnosis).
`
`This is confirmed by Ex. 1015 at S11, as well as by Ex. 1010. Exhibit 1010, a Lab
`
`Update concerning “Measurement of Ammonia in Blood,” was published by
`
`UMass Memorial Medical Center in Worcester, Massachusetts, in February 2007,
`
`and is available at https://www.ummlabs.org/ClientNews.asp. UMass Memorial’s
`
`“Lab Updates” are publicly-available announcements regarding clinical tests,
`
`procedures, and results. See http://www.umassmemoriallabs.org/test-
`
`resources/updates. Exhibit 1010 specifies that for measurement of blood ammonia,
`
`most methods recommend collecting a sample from patients who have fasted for at
`
`least 6 hours. (Id.; Ex. 1002 at n. 4.) It also teaches that measurements should be
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`
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`The ʼ859 Publication is the publication for U.S. Patent No. 8,642,012, which
`
`is also assigned to Horizon. (Ex. 1007.) It was published on January 14, 2010, and
`
`qualifies as prior art under 35 U.S.C. § 102(b). It teaches methods of adjusting the
`
`dose of a nitrogen scavenging drug, including the drugs sodium phenylbutyrate and
`
`glyceryl tri-[4-phenylbutyrate], in subjects with UCDs who had previously been
`
`administered a dosage of the nitrogen scavenging drug, based in part on evaluating
`
`plasma ammonia levels. (Ex. 1007 at [0020]–[0022], Example 3, [0088]–[0091],
`
`[0095]–[0099], [0107]–[0108], [0226], [0232].) One such method provides: (a)
`
`administering an initial dosage of a PAA prodrug according to the patient’s dietary
`
`protein load; (b) measuring the amount of total waste nitrogen excreted following
`
`administration of the drug; (c) measuring blood ammonia to determine if the
`
`increase in urinary excretion of total waste nitrogen is sufficient to control blood
`
`ammonia levels; and (d) adjusting the initial dosage to provide an adjusted dosage
`
`of the drug based upon ammonia control, dietary protein, and the amount of total
`
`waste nitrogen excreted, or the amount of waste PAGN excreted. (Id. at [0088]–
`
`[0091].) Either or each of these parameters can be monitored to assess the dosage
`
`of drug. (Id. at [0091].)
`
`
`taken at the same time of day and under the same circumstances, due to a diurnal
`
`variation in blood ammonia levels. (Ex. 1010; Ex. 1002 n. 4.)
`
`
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`17
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`

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`
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`To determine whether the plasma ammonia levels are acceptable, the ʼ859
`
`Publication teaches comparing a plasma ammonia level to the ULN of plasma
`
`ammonia for the subject, and defines that ULN as about 35 or 40 μmol/L. (See id.
`
`at [0063], Fig. 13, [0094], [0201].) It also discloses that the plasma ammonia level
`
`can help assess the effectiveness of the overall drug and dietary regimen for a
`
`particular patient. (Id. at [0083], [0088]–[0092], [0095]–[0099], [0226], [0232].)
`
`If the ammonia control is inadequate, the dosage of the nitrogen scavenging drug
`
`may be increased. (Id. at [0083], [0232]; Ex. 1002 ¶ 43.)
`
`The ʼ859 Publication teaches treating a UCD patient with a PAA prodrug,
`
`such as HPN-100 or NaPBA. (Ex. 1007 at [0144]–[0156], [0221]–[0229].) HPN-
`
`100 is a preferred embodiment. (Id. at [0036].) It is described as providing better
`
`control of ammonia levels than NaPBA in a clinical study of UCD patients. (Id. at
`
`[0060], [0137], [0202]–[0203], [0209], Figs. 12, 13.)
`
`The ʼ859 Publication further teaches that when HPN-100 or NaPBA is
`
`administered to a patient, it is converted to urinary PAGN at a rate