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.
`_________________
`
`IPR2017-01159
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 9,254,278
`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
`
`I.
`II.
`
`III.
`
`B.
`
`INTRODUCTION............................................................................................................. 1
`SUMMARY OF THE ʼ278 PATENT AND ITS PROSECUTION HISTORY ........... 2
`A.
`Independent Claims ................................................................................................ 2
`B.
`Prosecution History ................................................................................................. 5
`BACKGROUND ON THE UREA CYCLE, UCDs, AND NITROGEN
`SCAVENGING DRUGS .................................................................................................. 5
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................................. 8
`V.
`PAYMENT OF FEES (37 C.F.R. § 42.103) .................................................................... 8
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8) ................................................................ 8
`A.
`Real Parties-in-Interest ............................................................................................ 8
`B.
`Related Matters ....................................................................................................... 8
`C.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service Information (37
`C.F.R. § 42.8(b)(4)) ................................................................................................ 9
`VII. PERSON OF ORDINARY SKILL IN THE ART ....................................................... 10
`VIII. CLAIM CONSTRUCTION ........................................................................................... 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 1-3 are Unpatentable as Obvious Over the ʼ859 Publication .. 14
`1.
`Overview of Prior Art Applied in Ground 1 ............................................. 14
`2.
`Independent Claim 1 ................................................................................. 17
`3.
`Dependent Claims 2 and 3 ........................................................................ 21
`4.
`Lack of Secondary Considerations ........................................................... 21
`Ground 2: Claims 4-7 and 12-15 are Unpatentable as Obvious Over Blau, Simell,
`and the ʼ859 Publication ....................................................................................... 24
`1.
`Overview of Prior Art Applied in Ground 2 ............................................. 24
`2.
`Motivation to Combine Applied Prior Art ................................................ 25
`3.
`Lack of Secondary Considerations ........................................................... 27
`4.
`Independent Claim 4 ................................................................................. 27
`(a)
`Preamble ....................................................................................... 27
`(b)
`Claim 4, Part (a) ............................................................................ 31
`(c)
`Claim 4, Part (b) ............................................................................ 32
`(d)
`Claim 4, Part (c) ............................................................................ 34
`(e)
`Claim 4, Wherein Clause .............................................................. 36
`Independent Claim 12 ............................................................................... 38
`(a)
`Preamble ....................................................................................... 38
`(b)
`Claim 12, Parts (a) and (b) ............................................................ 40
`
`5.
`
`
`
`

`

`
`
`C.
`
`Claim 12, Part (c) .......................................................................... 40
`(c)
`Claim 12, Part (d) .......................................................................... 41
`(d)
`6.
`Dependent Claims 5 and 13 ...................................................................... 42
`7.
`Dependent Claims 6, 7, 14 and 15 ............................................................ 43
`Ground 3: Claims 8-11 are Unpatentable as Obvious in View Blau, Simell, the
`ʼ859 Publication, and the Brusilow ’979 Patent ................................................... 44
`1.
`Overview of Prior Art Applied in Ground 3 ............................................. 44
`2.
`Motivation to Combine Applied Prior Art ................................................ 45
`3.
`Lack of Secondary Considerations ........................................................... 46
`4.
`Independent Claim 8 ................................................................................. 46
`(a)
`Preamble and Parts (a)-(c) of Independent Claim 8 ...................... 46
`(b) Wherein Clause of Claim 8 ........................................................... 46
`5.
`Dependent Claim 9 ................................................................................... 48
`6.
`Dependent Claims 10 and 11 .................................................................... 48
`CONCLUSION ............................................................................................................... 49
`
`
`
`X.
`
`
`
`
`
`
`ii
`
`

`

`
`
`List of Exhibits
`
`Description
`
`U.S. Patent No. 9,254,278 to Scharschmidt et al. (“ʼ278 Patent”)
`
`Declaration of Keith Vaux, M.D.
`
`U.S. Patent No. 9,326,966 to Scharschmidt et al. (“ʼ966 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
`ʼ84”).
`
`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 “ʼ859 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 ʼ91”).
`
`Ex. No.
`
`Ex. 1001
`
`Ex. 1002
`
`Ex. 1003
`
`Ex. 1004
`
`Ex. 1005
`
`Ex. 1006
`
`Ex. 1007
`
`Ex. 1008
`
`Ex. 1009
`
`Ex. 1010
`
`Ex. 1011
`
`
`
`iii
`
`

`

`
`
`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.
`
`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
`
`
`
`iv
`
`

`

`
`
`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. 9,254,278 (“the ʼ278 Patent,” Ex. 1001).
`
`The ʼ278 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 ʼ278 Patent was filed.
`
`The ʼ278 Patent discloses purportedly novel methods 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 ʼ278 Patent claims 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 of the
`
`ʼ278 Patent claims. Accordingly, IPR should be instituted and the claims should
`
`be cancelled.
`
`II.
`
`SUMMARY OF THE ʼ278 PATENT AND ITS PROSECUTION
`HISTORY
`
`The ʼ278 Patent was filed on August 3, 2015, as a continuation of U.S.
`
`Application No. 13/775,000, filed February 22, 2013, now U.S. 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 U.S. Patent No. 8,404,215 (the “ʼ215
`
`patent”). The ʼ278 Patent claims the benefit of U.S. Provisional Application Nos.
`
`61/564,668, filed November 29, 2011, and 61/542,100, filed September 30, 2011.
`
`For purposes of this IPR only, Petitioner will assume that the ʼ278 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, 4, 8, and 12, the four independent claims of the ʼ278 Patent, recite:
`
`1. A method of treating a subject with a urea cycle disorder, the
`method comprising:
`administering to the subject in need thereof glyceryl tri-[ 4-
`phenylbutyrate] in an amount sufficient to produce a fasting
`plasma ammonia level that is less than half the upper limit of
`normal for plasma ammonia level.
`
`
`
`2
`
`

`

`
`
`4. A method for adjusting the dosage of glyceryl tri-[4-
`phenylbutyrate] in a subject being treated for a urea cycle disorder
`who has previously been administered an initial dosage of glyceryl tri-
`[4-phenylbutyrate] and who has a fasting plasma ammonia level less
`than the upper limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the subject;
`(b) comparing the fasting plasma ammonia level to the upper limit
`of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate], wherein the adjusted dosage is greater than the
`initial dosage if the fasting plasma ammonia level is greater than
`half the upper limit of normal for plasma ammonia level, and
`wherein the method further comprises restricting the subject's dietary
`protein intake.
`
`8. A method for adjusting the dosage of glyceryl tri-[4-
`phenylbutyrate] in a subject being treated for a urea cycle disorder
`who has previously been administered an initial dosage of glyceryl tri-
`[4-phenylbutyrate] and who has a fasting plasma ammonia level less
`than the upper limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the subject;
`(b) comparing the fasting plasma ammonia level to the upper limit
`of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate], wherein the adjusted dosage is greater than the
`
`
`
`3
`
`

`

`
`
`initial dosage if the fasting plasma ammonia level is greater than
`half the upper limit of normal for plasma ammonia level, and
`wherein the method further comprises monitoring the subject's
`ammonia levels if the glyceryl tri-[4-phenylbutyrate] is not being
`adequately digested by the subject's pancreatic lipases.
`
`12. 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 sodium
`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;
`(c) administering an initial dosage of glyceryl tri-[4-
`phenylbutyrate], wherein the initial dosage is determined by the
`amount of the initial dosage of sodium phenylbutyrate, and
`(d) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate], wherein the adjusted dosage is greater than the
`initial dosage of glyceryl tri-[4-phenylbutyrate] if the fasting
`plasma ammonia level is greater than half the upper limit of
`normal for plasma ammonia level.
`
` (Ex. 1001 at 24:21–26, 24:31–47, 24:56-25:7, 25:17–26:13.)
`
`
`
`
`
`4
`
`

`

`B.
`
`Prosecution History
`
`
`
`The prosecution of the ’278 Patent was brief, lasting six months from filing
`
`to patent issue. Patent Owner filed the application leading to the ʼ278 Patent on
`
`August 3, 2015, together with an amendment cancelling the eleven original claims
`
`and adding three new claims. (Ex. 1001.) On November 3, 2015, the Examiner
`
`rejected the claims for nonstatutory double patenting over claims of the
`
`grandparent ’215 Patent, parent ’559 Patent, and U.S. Patent No. 8,642,012 (the
`
`“’012 Patent”). (Ex. 1022 (Office Action (November 3, 2015)) at 97, 100.) In
`
`response, the applicant submitted a terminal disclaimer over these three patents on
`
`November 5, 2015. (Ex. 1022 (Response (November 5, 2015)), at 124.) On
`
`November 20, 2015, the applicants added twelve additional claims. (Ex. 1022
`
`(Response (November 20, 2015)), at 157-60.) On December 23, 2015, the
`
`Examiner allowed the claims. (Ex. 1022 (Notice of Allowance (December 23,
`
`2015)) at 167-69.)
`
`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 ¶ 27.) In the urea cycle, enzymes and
`
`transporters synthesize urea from ammonia, and the urea is then excreted to
`
`remove excess nitrogen. (Id. Ex. 1007 at [0005] and Fig. 1.) UCDs occur when
`
`enzymes or transporters in the urea cycle are deficient. (Ex. 1002 at ¶ 27.) These
`
`
`
`5
`
`

`

`
`
`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 grandparent 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
`
`administering nitrogen scavenging drugs.” (Ex. 1018 at 148.) It was also well
`
`known before the priority date of the ʼ278 Patent that 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 ¶¶ 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 ¶
`
`33.) Each molecule of PAGN carries away two molecules of nitrogen.
`
`
`
`6
`
`

`

`
`
`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
`
`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 ʼ278 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.,
`
`
`
`7
`
`

`

`
`
`[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 ¶
`
`29.)
`
`As will be discussed further below, the ʼ278 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 ʼ278 Patent, issued on February 9, 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.
`
`
`
`8
`
`

`

`
`
`1:16-cv-04438) alleging infringement of the ’278 Patent and one of its child
`
`patents, U.S. Patent No. 9,326,966 (the “’966 Patent”).
`
`Horizon is also asserting the ’559 Patent against Lupin in the District of New
`
`Jersey (Case No. 1:15-cv-07624), and the ʼ215 Patent and the ’012 Patent against
`
`Par in the Eastern District of Texas (Case No. 2-14-cv-00384).
`
`The ’559 Patent is the subject of Lupin’s IPR2016-00829, which was
`
`instituted and is pending.
`
`The ʼ215 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 ’966 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.
`
`
`
`9
`
`

`

`
`
`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 Int’l
`
`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.
`
`
`
`10
`
`

`

`
`
`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 12:7-8.)
`
`Each of independent claims 1, 4, 8, and 12, as well as dependent claims
`
`5, 9, 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 ʼ278 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 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
`
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`11
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`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 10:28–41.) 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.
`(Id., at 10:21–27.) In view of specification and the plain and ordinary meaning of
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`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 4, 8, and 12 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
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`thereof.” (Id. at 10:8-13.) In view of this disclosure, an adjusted dosage that is
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`12
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`“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.
`
`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 1-3 as
`
`unpatentable under 35 U.S.C. § 103 as obvious over the ʼ859 Publication.
`
`In Ground 2, Petitioner requests IPR and cancellation of claims 4-7 and 12-
`
`15 as unpatentable under 35 U.S.C. § 103 as obvious over Blau, Simell, and the
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`ʼ859 Publication.
`
`In Ground 3, Petitioner requests IPR and cancellation of claims 8-11 as
`
`unpatentable under 35 U.S.C. § 103 as obvious over Blau, Simell, the ʼ859
`
`Publication, and the Brusilow ’979 Patent.
`
`
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`13
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`
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`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. Ground 1: Claims 1-3 are Unpatentable as Obvious Over the ʼ859
`Publication
`1. Overview of Prior Art Applied in Ground 1
`The ʼ859 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 ʼ859 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]–[0021], [0189]; Ex. 1002 ¶ 73.) 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].)
`
`
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`14
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`

`
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`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
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`PAGN excreted. (Id. at [0088]–[0091].)
`
`To determine whether a patient’s plasma ammonia levels are acceptable, the
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`ʼ859 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 ¶ 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
`
`¶ 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-
`
`
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`15
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`

`
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`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
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`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 35 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 µmol/L, or somewhere in between). (Id. at
`
`table following [0201]; Ex. 1002 at ¶¶ 46, 63.) This same patient also had an
`
`1 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].)
`
`
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`16
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`

`

`
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`ammonia Cmax of 13.0 µmol/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 µmol/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 ʼ859 Publication also
`
`explains that after the PAA prodrug is administered, urinary PAGN excretion may
`
`be measured, and the dosage of HPN-100 may be a