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.
`
`IPR2017-01160
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,326,966
`PURSUANT TO H 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
`
`r. Gregory Enns
`April 23, 2018
`Exhibit No. 1027
`13
`Megan F. Alvarez
`RPR, CSR No. 12470
`
`1 of 50
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS INC.
`
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC
`
`Patent Owner.
`
`IPR2017-01160
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,326,966
`PURSUANT TO H 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
`
`r. Gregory Enns
`April 23, 2018
`Exhibit No. 1027
`13
`Megan F. Alvarez
`RPR, CSR No. 12470
`
`1 of 50
`
`
`
`I.
`II.
`
`C.
`
`INTRODUCTION
`1
`SUMMARY OF '966 PATENT AND ITS PROSECUTION HISTORY 2
`Independent Claims
`A.
`2
`Prosecution History
`B.
`5
`III. BACKGROUND ON THE UREA CYCLE, UCDs, AND NITROGEN
`SCAVENGING DRUGS
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`PAYMENT OF FEES (37 C.F.R. § 42.103)
`V.
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8)
`Real Parties -in- Interest
`A.
`Related Matters
`B.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`C.
`Information (37 C.F.R. § 42.8(b)(4))
`VII. PERSON OF ORDINARY SKILL IN THE ART
`VIII. CLAIM CONSTRUCTION
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`IX.
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b))
`Overview of Prior Art
`A.
`Ground 1: Claims 12, 14, and 15 are Anticipated By the '859
`B.
`Publication
`Ground 2: Claims 1 -15 are Unpatentable as Obvious Over Blau,
`Simell, and the '859 Publication, in View of the POSA's Knowledge
`22
`22
`22
`24
`24
`27
`29
`
`TABLE OF CONTENTS
`
`Page
`
`5
`8
`8
`8
`8
`8
`
`9
`9
`10
`
`13
`14
`
`18
`
`1.
`2.
`3.
`
`4.
`5.
`
`Overview of Applied Prior Art
`Motivation to Combine Applied Prior Art
`Independent Claims 1, 6, and 9
`Preambles of Independent Claims 1, 6, and 9
`(a)
`Part (a) of Independent Claims 1, 6, and 9
`(b)
`Part (b) of Independent Claims 1, 6, and 9
`(c)
`Part (c) of Independent Claims 1, 6, and 9
`(d)
`Additional Limitation of Claim 1
`(e)
`Independent Claim 12
`Dependent Claims 2 and 3
`
`31
`34
`35
`37
`
`2 of 50
`
`
`
`6.
`
`Dependent Claims 4, 7, 10, and 13
`Dependent Claims 5, 8, 11, 14, and 15
`7.
`Lack of Secondary Considerations
`8.
`CONCLUSION
`
`X.
`
`37
`40
`40
`42
`
`ii
`
`3 of 50
`
`
`
`List of Exhibits
`
`Ex. No.
`
`Description
`
`Ex. 1001
`
`U.S. Patent No. 9,254,278 to Scharschmidt et al. ( "'278 Patent ")
`
`Ex. 1002
`
`Declaration of Keith Vaux, M.D.
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1005
`
`Ex. 1006
`
`Ex. 1007
`
`Ex. 1008
`
`Ex. 1009
`
`Ex. 1010
`
`Ex. 1011
`
`U.S. Patent No. 9,326,966 to Scharschmidt et al. ( "'966 Patent ")
`
`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
`'84").
`
`Simell, et al., Waste Nitrogen Excretion Via Amino Acid
`Acylation. Benzoate and Phenylacetate in Lysinuric Protein
`Intolerance, 20 Pediatric Research, 1117 -1121 (1986). ("Simell').
`
`Blau, Duran, Blaskovics, Gibson (editors), Physician's Guide to
`the Laboratory Diagnosis of Metabolic Diseases, 261 -276 (2d ed.
`1996). ("Blau").
`
`U.S. Patent Publication No. 2010/0008859, filed January 7, 2009,
`published January 14, 2010. (the "'859 Publication ").
`
`Scientific Discussion for Ammonaps, EMEA 2005, available at
`http: / /www.ema. europa.eu/ docs /en_GB /document_library /EPAR -
`Scientific Discussion /human/000219 /WC500024748.pdf.
`( "Scientific Discussion ").
`
`Dixon, et al., Intercurrent Illness in Inborn Errors of Intermediary
`Metabolism, 67 Archives of Disease in Childhood, 1387 -1391
`(1992). ("Dixon").
`
`UMass Memorial Laboratories, Lab Updates, February 2007,
`Measurement of Ammonia in Blood
`
`Brusilow, Phenylacetylglutamine May Replace Urea as a Vehicle
`for Waste Nitrogen Excretion, 29 Pediatric Research, 147 -150
`(1991). ( "Brusilow '91").
`
`iii
`
`4 of 50
`
`
`
`Ex. 1012
`
`Ex. 1013
`
`Ex. 1014
`
`Ex. 1015
`
`Ex. 1016
`
`Ex. 1017
`
`Ex. 1018
`
`Ex. 1019
`
`Ex. 1020
`
`Ex. 1021
`
`Ex. 1022
`
`Ex. 1023
`
`Ex. 1024
`
`Ex. 1025
`
`Yajima, et al., Diurnal Fluctuation of Blood Ammonia Levels in
`Adult -Type Citrullinemia, 137 Tohoku J. Exp. Med., 213 -220
`(1982). ("Yajima').
`
`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').
`
`Kasumov, et al., New Secondary Metabolites of Phenylbutyrate in
`Humans and Rats, 32 Drug Metabolism and Disposition, 10 -19
`(2004). ("Kasumov").
`
`Barsotti, Measurement of Ammonia in Blood, 138 J Pediatrics,
`S11- S20 (2001). ("Barsotti").
`
`Berry, et al., Long -term management of patients with urea cycle
`disorders, Journal of Pediatrics, Vol. 138, No. 1, S56 -S61 (2001).
`( "Berry ")
`
`Levin, et al., Hyperammonaemia A Variant Type of Deficiency of
`Liver Ornithine Transcarbamylase, Arch. Dis. Childh., 1964, 44.
`162 (1968).
`
`Prosecution History of U.S. Patent No. 8,404,215.
`
`Excerpt from Stedman's Medical Dictionary (Lippincott
`Williams & Wilkins 2006).
`
`Buphenyl® label, Physician's Desk Reference, 60th ed. (2006) at
`3327 -28.
`
`Ammonul® label, Physician's Desk Reference, 60th ed. (2006) at
`3323 -26.
`
`Prosecution History of U.S. Patent No. 9,254,278 .
`
`Curriculum vitae of Keith Vaux, M.D.
`
`U.S. Patent No. 5,968,979 ( "Brusilow '979 Patent ").
`
`Prosecution History of U.S. Patent No. 9,326,966.
`
`iv
`
`5 of 50
`
`
`
`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. 9,326,966 ( "the '966 Patent," Ex. 1003).
`
`The '966 Patent is directed to methods of administering and adjusting the
`
`dosage of the nitrogen scavenging drug glyceryl tri -[4- phenylbutyrate] (also known
`
`as glycerol phenylbutyrate and HPN -100) in patients with urea cycle disorders
`
`( "UCDs "), based on measurement of the fasting plasma ammonia level of a
`
`subject. Nitrogen scavenging drugs, and their use in reducing plasma ammonia
`
`levels in UCD patients, were well known long before the '966 Patent was filed.
`
`The '966 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
`
`to maintain normal ammonia levels has been done for decades.
`
`As shown below, the '966 Patent claims describe nothing more than
`
`conventional practice by physicians that was disclosed in the prior art cited herein
`
`6 of 50
`
`
`
`and known before September 30, 2011, the earliest possible priority date of the
`
`'966 Patent claims. Accordingly, IPR should be instituted and the claims should
`
`be cancelled.
`
`II.
`
`SUMMARY OF '966 PATENT AND ITS PROSECUTION HISTORY
`
`The '966 Patent was filed on December 3, 2015 as a continuation of U.S.
`
`Application No. 14/816,674, filed August 3, 2015, now Patent No. 9,254,278 (the
`
`'278 Patent "), which is a continuation of U.S. Application No. 13/775,000, filed
`
`February 22, 2013, now Patent No. 9,095,559 (the "'559 Patent "), which is a
`
`continuation of U.S. Application No. 13/417,137, filed March 9, 2012, now Patent
`
`No. 8,404,215 (the "'215 Patent "). The '966 Patent claims the benefit of U.S.
`
`Provisional Application No. 61/564,668, filed November 29, 2011, and U.S.
`
`Provisional Application No. 61/542,100, filed September 30, 2011.
`
`For purposes of this IPR only, Petitioner will assume that the '966 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.
`
`A.
`
`Independent Claims
`
`Claims 1, 6, 9, and 12, the four independent claims of the '966 Patent, recite:
`
`1. A method of treating a subject with 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
`
`2
`
`7 of 50
`
`
`
`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,
`
`wherein the upper limit of normal for plasma ammonia level is
`
`in the range of 26 -64 µmol /L.
`
`6. A method of treating a pediatric subject with 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 pediatric
`
`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.
`
`9. A method of treating an adult subject with 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
`
`3
`
`8 of 50
`
`
`
`than the upper limit of normal for plasma ammonia level, the method
`
`comprising:
`
`(a) measuring a fasting plasma ammonia level for the adult
`
`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.
`
`12. A method of treating a patient having a urea cycle disorder
`
`comprising:
`
`(a) administering an initial effective dosage of glyceryl tri -[4-
`
`phenylbutyrate] (HPN -100) to the patient, wherein the initial
`
`effective dosage is calculated based on body surface area of the
`
`patient;
`
`(b) measuring the patient's urinary PAGN and /or fasting plasma
`
`ammonia level to determine whether to change the dosage of
`
`the glyceryl tri -[4- phenylbutyrate] (HPN -100); and
`
`(c) administering a subsequent effective dosage of glyceryl tri -
`
`[4-phenylbutyrate] (HPN -100) to the patient that is either the
`
`same as the initial effective dosage or is an increased dosage,
`
`wherein said increased dosage, if any, is calculated based on the
`
`patient's urinary PAGN and /or fasting plasma ammonia level.
`
`(Ex. 1003 at 24:11 -25; 24:38 -50; 24:57 -25:2; 25:9- 26:6.)
`
`4
`
`9 of 50
`
`
`
`B.
`
`Prosecution History
`
`The prosecution of the ' 966 Patent was brief, lasting five months from filing
`
`to patent issue. Patent Owner filed the application leading to the '966 Patent on
`
`December 3, 2015. The Examiner issued a non -final rejection on February 5,
`
`2016, rejecting all claims for nonstatutory double patenting over claims from the
`
`'278 Patent, the '215 Patent, the '559 Patent, and U.S. Patent No. 8,642,012 (the
`
`"'012 Patent "). (Ex. 1025 at 118 -125.) In response, the applicant canceled some
`
`claims, submitted additional claims, and submitted a terminal disclaimer over the
`
`four patents. (Ex. 1025 at 187 -192.) The Examiner then issued a Notice of
`
`Allowance on March 8, 2016. (Ex. 1025 at 204.)
`
`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 from the body. (Ex. 1002 at IT 27.) 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 ¶ 27.) 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 great -grandparent '215
`
`patent that it was "well known in the art that nitrogen retention disorders are
`
`5
`
`10 of 50
`
`
`
`associated with elevated blood ammonia levels, and that these disorders can be
`
`treated by administering nitrogen scavenging drugs." (Ex. 1018 at 148.) It was
`
`also well known before the priority date of the '966 Patent that treatment options
`
`for treating UCDs included the use of nitrogen scavenging drugs such as sodium
`
`benzoate, sodium phenylbutyrate (also known as NaPBA), and HPN -100. (Ex.
`
`1002 at IN 30 -31; 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. 1020 at 3327.)
`
`Because NaPBA is converted to phenylacetic acid ( "PAA ") in the body, it is
`
`referred to as a PAA prodrug. (Ex. 1007 at [0022]; Ex. 1002 at 32.) In vivo,
`
`NaPBA rapidly oxidizes to form one molecule of 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 If
`
`33.) Each molecule of PAGN carries away two molecules of nitrogen.
`
`Because glyceryl tri -[4- phenylbutyrate] is converted to phenylbutyrate
`
`(PBA) in the body and then to PAA, it is also referred to as a PAA prodrug, or a
`
`PBA prodrug. (Ex. 1007 at [0023]; Ex. 1002 ¶ 32.) Glyceryl tri -[4-
`
`phenylbutyrate] is hydrolyzed by human pancreatic lipases to release three
`
`molecules of phenylbutyrate (PBA), which in turn are oxidized to form three
`
`6
`
`11 of 50
`
`
`
`molecules of PAA and, in turn, three molecules of PAGN. (Ex. 1024 at 4:65 -5:2.)
`
`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 '966 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.
`
`1002 ¶ 35.) "The goal of treatment is to maintain normal levels of plasma
`
`ammonia through the use of the low -protein diet and medication while allowing for
`
`normal growth." (Ex. 1016 at S58; see also Ex. 1007 at, e.g. , [0182] (noting that
`
`subjects treated with HPN -100 can "achieve and maintain normal plasma ammonia
`
`levels ").) Another 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 ¶¶ 36, 37, 39-40; Ex. 1007 at, e.g.,
`
`[0083], [0226]; 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.) There is no minimum level of
`
`blood ammonia that must be maintained for normal body function. (Ex. 1002 If
`
`29.)
`
`7
`
`12 of 50
`
`
`
`As will be discussed further below, the '966 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 '966 Patent, issued on May 3, 2016, 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. 506989.
`
`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 August 8, 2016 Horizon served Lupin Pharmaceuticals, Inc. and Lupin
`
`Ltd. with a complaint in the District Court for the District of New Jersey (Case No.
`
`1:16 -cv- 04438) alleging infringement of the '278 and '966 Patents.
`
`Horizon is also asserting the '559 Patent against Lupin in the District of New
`
`Jersey (Case No. 1:15 -cv- 07624), and the '215 Patent and the '012 Patent against
`
`Par in the Eastern District of Texas (Case No. 2-14-cv-00384).
`
`8
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`13 of 50
`
`
`
`The '559 Patent is the subject of Lupin's IPR2016- 00829, which was
`
`instituted and is pending.
`
`The '215 Patent was the subject of IPR2015- 01127, filed by Par
`
`Pharmaceutical, Inc., 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. Patent Owner has not appealed
`
`this decision.
`
`Concurrently herewith, Lupin is filing an IPR on the '278 Patent.
`
`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). Counsels' email addresses are
`
`eholland @goodwinlaw.com and chardman @goodwinlaw.com.
`
`Please address all correspondence and service to counsel listed above.
`
`Petitioner consents to service by email at the above email addresses.
`
`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 Intl
`
`9
`
`14 of 50
`
`
`
`Co. v. Teleflex Inc., 550 U.S. 398, 420 -21 (2007). Petitioner submits that a POSA
`
`is a physician with an M.D. degree, who did a residency in pediatrics or internal
`
`medicine, and who has specialized training in the treatment of UCDs and other
`
`nitrogen retention disorders. (Ex. 1002 ¶ 19.) A POSA would easily have
`
`understood the prior art references referred to herein and would have been capable
`
`of drawing inferences from them.
`
`VIII. CLAIM CONSTRUCTION
`
`The challenged claims should be given their broadest reasonable
`
`interpretation ( "BRI ") in light of the patent specification. 37 C.F.R. § 42.100(b);
`
`see also Cuozzo Speed Techs. LLC v. Lee, 136 S. Ct. 2131, 2142 (2016). For
`
`purposes of this IPR only, Petitioner adopts the following constructions as the BRI
`
`of each term.
`
`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. 1003 at 12:11 -12.)
`
`Each of independent claims 1, 6, 9, and 12, as well as dependent
`
`claims 4, 7, 10, and 13, 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 '966 Patent
`
`10
`
`15 of 50
`
`
`
`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
`nitrogen
`ingest
`supplements
`any
`and /or
`drugs during the fasting period.
`In
`scavenging
`certain of these embodiments, the subject may
`ingest one or more drugs other than
`nonetheless
`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
`In other embodiments, the subject
`fasting period.
`may ingest small amounts of low calorie beverages,
`such as tea, coffee, or diluted juices.
`
`(Ex. 1003, 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
`In certain
`is overnight.
`level
`
`11
`
`16 of 50
`
`
`
`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.
`
`(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, 6, and 9 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:
`
`"Increasing the dosage of a nitrogen scavenging drug may refer to increasing the
`
`amount of drug per administration (e.g., an increase from a 3 mL dosage to a 6 mL
`
`dosage), increasing the number of administrations of the drug (e.g., an increase
`
`from once -a -day dosing to twice- or three -times -a -day), or any combination
`
`thereof." (Id. at 10:10 -15.) In view of this disclosure, an adjusted dosage that is
`
`"greater than the initial dosage" means a dosage that increases the amount of drug
`
`per administration, an increased number of administrations of the drug, or any
`
`combination thereof.
`
`Claim 12 requires that the "adjusted dosage" is the same as the initial
`
`effective dosage or is an "increased dosage." As discussed above, with regard to
`
`12
`
`17 of 50
`
`
`
`an adjusted dosage of glyceryl tri -[4- phenylbutyrate] that is increased, the
`
`specification states: "Increasing the dosage of a nitrogen scavenging drug may
`
`refer to increasing the amount of drug per administration (e.g., an increase from a 3
`
`mL dosage to a 6 mL dosage), increasing the number of administrations of the drug
`
`(e.g., an increase from once -a -day dosing to twice- or three -times -a -day), or any
`
`combination thereof." (Id. at 10:10 -15.) In view of this disclosure, an adjusted
`
`dosage that is an "increased dosage" means a dosage that increases the amount of
`
`drug per administration, an increased number of administrations of the drug, or any
`
`combination thereof.
`
`In addition, each of the challenged claims contains the transition term
`
`"comprising." Accordingly, while the claims require the claimed method steps,
`
`they do not exclude additional steps.
`
`For purposes of this IPR only, Petitioner will assume that the claims'
`
`preambles are limiting.
`
`Petitioners' positions regarding the scope of the claims should not be
`
`construed as an assertion regarding the appropriate claim scope in other
`
`adjudicative forums, where a different claim interpretation standard may apply.
`
`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 IPR and cancellation of claims 12, 14, and
`
`15 as unpatentable under 35 U.S.C. § 102 as anticipated by the '859 Publication.
`
`13
`
`18 of 50
`
`
`
`In Ground 2, Petitioner requests IPR and cancellation of claims 1 -15 as
`
`unpatentable under 35 U.S.C. § 103 as obvious over Blau, Simell, and the '859
`
`Publication.
`
`Petitioner provides the declaration of Keith Vaux, M.D., an expert in the
`
`field, in support of this petition. (Ex. 1002 ¶¶ 1-4; Ex. 1023.)
`
`A.
`
`Overview of Prior Art
`
`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
`
`drugs sodium benzoate and phenylacetate to children with lysinuric protein
`
`intolerance, which Simell specifies is a type of UCD, following the standardized
`
`induction of hyperammonemia. (Ex. 1002 ¶ 48; Ex. 1005 at Abstract, 1117 -18.)
`
`As part of the protocol, Simell measured fasting blood ammonia levels in the
`
`patients after an 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. (Ex. 1006 at, e.g., 1, Ch. 11.) Blau discloses
`
`"Specimen Collection" 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 artery." (Ex. 1006 at 273 (Table 11.9).) A POSA would
`
`have understood Blau to suggest measuring fasting blood ammonia levels. (Ex.
`
`14
`
`19 of 50
`
`
`
`1002 ¶ 49.) Blau discusses different types of UCDs and laboratory tests that
`
`should be performed when treating a UCD patient. (Ex. 1006 at 261, 270 -71, 273
`
`(Table 11.9).)
`
`The '859 Publication is the publication for Horizon's '012 Patent. (Ex.
`
`1007.) It published on January 14, 2010, and qualifies as prior art under 35 U.S.C.
`
`§ 102(b).
`
`The '859 Publication teaches the oral administration of nitrogen scavenging
`
`drugs to patients with nitrogen retention disorders, including UCDs. (See, e.g., Ex.
`
`1007 at [0002], [0020]-10021], [0189]; Ex. 1002 1173.) These nitrogen scavenging
`
`drugs can be PAA prodrugs, such as HPN -100 or NaPBA. (Ex. 1007 at [0144]-
`
`[0156], [0221] -[0229].) HPN -100 is a preferred embodiment, and is described as
`
`providing better control of ammonia levels than NaPBA in a clinical study of UCD
`
`patients. (Id. at [0036], [0060], [0137], [0202] -[0203], [0209], Figs. 12, 13.)
`
`The '859 Publication states that an initial dosage of a PAA prodrug (such as
`
`HPN -100) "can be calculated by methods known in the art once a patient's dietary
`
`intake of protein is known, and assuming the patient has a relatively normal liver
`
`function." (Id. at [0079].) It also teaches methods of adjusting the dose of HPN-
`
`100 in UCDs, based in part on evaluating plasma ammonia levels. (Id. at [0020]-
`
`[0022], Example 3, [0088] -[0092], [0095]- [0099], [0107] -[0108], [0226], [0232].)
`
`One such method provides: (a) administering an initial dosage of a PAA prodrug
`
`15
`
`20 of 50
`
`
`
`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].)
`
`To determine whether a patient's plasma ammonia levels are acceptable, the
`
`'859 Publication teaches comparing a plasma ammonia level to the ULN of plasma
`
`ammonia for the subject, and notes that the ULN can vary but is typically below
`
`about 40 µmol /L. (Id. at [0063, [0094], [0201]; Ex. 1002 It 44.) It also discloses
`
`that the plasma ammonia level can help assess the effectiveness of the overall drug
`
`and dietary regimen for a particular patient. (Ex. 1007at [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
`
`If 44.)
`
`The '859 Publication describes a clinical study of 10 adult UCD patients
`
`who were switched from NaPBA to a PBA- equimolar dose of glyceryl tri -[4-
`
`16
`
`21 of 50
`
`
`
`phenylbutyrate].1 (Id. at [0195]- [0209].) In the study, the blood ammonia levels of
`
`the patients were first recorded while the patients were taking stable doses of
`
`NaPBA. (Id. at [0195].) The patients were then converted to a PBA -equimolar
`
`dose of HPN -100. (Id) Once the patients reached steady -state on HPN -100, their
`
`ammonia values were again recorded. (Id.) For both drugs, the publication reports
`
`the drug dosage, the maximum observed ammonia value (Cmax), and the time -
`
`normalized area under the curve (TN -AUC) ammonia value for each patient. (Id.
`
`at table following [0201]; see also Ex. 1002 at ¶¶ 45 -47 for a summary of the
`
`clinical study.)
`
`As stated in the publication, the ULN for venous ammonia varied among the
`
`study sites from 26 to 3 5 µmol /L. (Ex. 1007 at [0201].) When taking HPN -100,
`
`many of the patients had TN -AUC ammonia values under 35 µmol /L (the
`
`maximum ULN at any of the study sites), and one patient (Subject 1006) had a
`
`TN -AUC ammonia level of 8.30 µmol/L, which was less than half the ULN
`
`(whether the ULN was 26 µmol /L, 35 µmot /L, or somewhere in between). (Id. at
`
`table following [0201]; Ex. 1002 at If 46, 63.) This same patient also had an
`
`Given that both NaPBA and glyceryl tri -[4- phenylbutyrate] are PAA prodrugs, it
`
`was known that dosages of glyceryl tri- [4- phenylbutyrate] could be calculated
`
`based on an PBA -equimolar amount of NaPBA. (See, e.g., Ex. 1007 at [0025-
`
`0026], [0231].)
`
`17
`
`22 of 50
`
`
`
`ammonia Cmax of 13.0 µmot /L, which is also at or below half the ULN (whether
`
`the ULN was 26 µmol /L, 35 µmol /L, or somewhere in between). (Ex. 1007 at
`
`table following [0201]; Ex. 1002 at ¶ 46, 63.) When this patient was taking
`
`NaPBA, the corresponding ammonia values were much higher (Cmax of 150
`
`µmol /L, TNAUC of 71.5 µmot /L). (Ex. 1007 at table following [0201]; Ex. 1002
`
`at ¶ 46, 63.)
`
`The publication reports that no patients experienced serious adverse events
`
`with HPN -100. (Ex. 1007 at [0203], see also [0086].) The '859 Publication also
`
`explains that after the PAA prodrug is administered, urinary PAGN excretion may
`
`be measured, and the dosage of HPN -100 may be adjusted based on PAGN output.
`
`(Ex. 1007 at, e.g., [0224] -[0227].)
`
`B.
`
`Ground 1: Claims 12, 14, and 15 are Anticipated By the '859
`Publication
`
`The '859 Publication, summarized above, discloses each and every
`
`limitation of claims 12, 14, and 15. Claim 12 reads as follows:
`
`12. A method of treating a patient having a urea cycle disorder comprising:
`
`(a) administering an initial effective dosage of glyceryl tri -[4-
`
`phenylbutyrate] (HPN -100) to the patient, wherein the initial effective
`
`dosage is calculated based on body surface area of the patient;
`
`18
`
`23 of 50
`
`
`
`(b) measuring the patient's urinary PAGN and /or fasting plasma ammonia
`
`level to determine whether to change the dosage of the glyceryl tri -[ 4-
`
`phenylbutyrate] (HPN -100); and
`
`(c) administering a subsequent effective dosage of glyceryl tri -[4-
`
`phenylbutyrate] (HPN -100) to the patient that is either the same as the initial
`
`effective dosage or is an increased dosage, wherein said increased dosage, if
`
`any, is calculated based on the patient's urinary PAGN and /or fasting plasma
`
`ammonia level.
`
`Claims 14 and 15 add that the initial (claim 14) and subsequent (claim 15)
`
`effective dosages of glyceryl tri -[ 4- phenylbutyrate] are administered orally.
`
`With regard to the preamble and part (a) of claim 12, the '859 Publication
`
`teaches a method of treating a patient who has a urea cycle disorder comprising
`
`administering an initial effective dosage of glyceryl tri -[4- phenylbutyrate] (HPN-
`
`100) to the patient, wherein the initial effective dosage is calculated based on body
`
`surface area of the patient. Specifically, the '859 Publication provides that when a
`
`UCD patient is being switched from NaPBA to glyceryl tri -[4- phenylbutyrate], that
`
`patient can be switched to a dosage of glyceryl tri -[4- phenylbutyrate] that does not
`
`exceed the recommended dosing levels for NaPBA. (Ex. 1007 at [0084].) The
`
`label for the use of NaPBA for the chronic treatment of UCDs recommends a daily
`
`dosage range that is based on body surface area (g /m2), and the '859 Publication
`
`19
`
`24 of 50
`
`
`
`similarly provides corresponding dosages of HPN -100 that are calculated
`
`according to body surface area. (Id, "For a subject weighing more than 20 kg, a
`
`dosage range for HPN -100 would be between 8.6 and 11.2 mL /m2. ")
`
`The '859 Publication also discloses part (b) of claim 12, which recites:
`
`"measuring the patient's urinary PAGN and /or fasting plasma ammonia level to
`
`determine whether to change the dosage of the glyceryl tri -[ 4- phenylbutyrate]
`
`(HPN- 100)." Specifically, the '859 Publicatio
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