IN THE UNITED STATES DISTRICT COURT
`FOR THE EASTERN DISTRICT OF TEXAS
`MARSHALL DIVISION
`
`HYPERION THERAPEUTICS, INC.,
`
`Plaintiff,
`
`v.
`
`PAR PHARMACEUTICAL, INC.,
`
`Defendant.
`
`)
`)
`)
`) C.A. No. 2:14-cv-00384-JRG-RSP
`)
`)
`)
`)
`)
`)
`
`PAR PHARMACEUTICAL, INC.’S INITIAL INVALIDITY
`CONTENTIONS AND NON-INFRINGEMENT CONTENTIONS FOR
`U.S. PATENT NOS. 8,404,215 AND 8,642,012
`
`Pursuant to Local Patent Rules 3-3, 3-4, and 3-8 of the Local Rules for the United States
`
`Eastern District of Texas, defendant Par Pharmaceutical, Inc. (“Par”) serves its Initial Invalidity
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`Contentions and accompanying document production to plaintiff Hyperion Therapeutics, Inc.
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`(“Hyperion”) for U.S. Patent Nos. 8,404,215 (“the ’215 patent”) and 8,642,012 (“the ’012
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`patent”) (collectively the “patents-in-suit”).
`
`These contentions are based upon information obtained by Par as of the date of this
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`document, and Par’s discovery and investigation in connection with this action continues. Par
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`reserves the right to supplement or amend these contentions based on information learned
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`through discovery, any claim construction entered by the Court, plaintiffs’ response to Par’s
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`contentions, and expert discovery. Par incorporates by reference each of the invalidity
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`contentions articulated in its Detailed Statement of the Factual and Legal Basis for Par
`
`Horizon Exhibit 2005
`Par v. Horizon
`IPR2017-01768
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`Page 1 of 9
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`1.
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`
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`Claim 1 of the ʼ215 Patent Is Obvious over the Prior Art
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`The alleged invention of claim 1 is invalid because it is obvious over the prior art. The
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`prior art set forth in Appendix A, either alone or in combination with one another, render these
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`claims obvious. The following combinations are examples of invalidating combinations.
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`a)
`
`The Combination of the ʼ859 Publication and Endo
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`The method of claim 1 of the is generally directed to increasing the dose of a nitrogen
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`scavenging drug if the blood ammonia level is too high, where too high is a blood level greater
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`than one half of the upper limit of normal.
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`Claim 1. A method for adjusting the dosage of a nitrogen scavenging drug
`in a subject who has previously been administered an initial dosage of the
`nitrogen scavenging drug, comprising:
`
`a) measuring a fasting blood ammonia level for the subject;
`
`b) comparing the fasting blood ammonia level to the upper limit of normal
`for blood ammonia level; and
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`c) administering an adjusted dosage of the nitrogen scavenging drug,
`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
`blood ammonia level.
`
`(bold emphasis added). Although the alleged discovery by the inventors was that a nitrogen
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`scavenging drug should be administered to patients even if the blood ammonia level is within
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`otherwise normal upper limits, the claims are not restricted to only increasing the drug dosage
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`when the blood ammonia levels are between one-half the upper limit of normal and the upper
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`limit of normal. In other words, claim 1 presumably covers a method of increasing the dose
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`when the fasting blood ammonia level is greater than one half the upper limit of normal, but also,
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`increasing the dose when the fasting blood level is greater than the upper limit of normal, or even
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`increasing the dose when the blood level is at extremely high levels and well-beyond the upper
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`limit of normal.
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`One of ordinary skill in the art would increase the dose of the nitrogen scavenging agent
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`if the fasting blood ammonia level of a patient was at the upper limit of normal, simply to protect
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`the patient from dangerously high levels. One of ordinary skill in the art was also motivated to
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`increase the dose of the nitrogen scavenging agent if the fasting blood ammonia level was at, or
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`above, one half of the upper limit of normal.3
`
`U.S. Publication 2010/0008859 (“the ’859 publication”) teaches a method for
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`determining when to increase a dosage of a nitrogen scavenging drug in a subject. (’859
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`publication at [0020], [0039].)4 In particular, it teaches adjusting the schedule and dose of orally
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`administered nitrogen scavenging drugs for patients already receiving the nitrogen scavenging
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`drug. (Id. at [0044].) The prior art method comprises: a) measuring a fasting blood ammonia
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`level (id. at [0212]) for the subject (id. at [0213]); b) comparing the fasting blood ammonia level
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`to the upper limit of normal for blood ammonia level (id. at [0201]), plasma upper limit of
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`normal (id. at [0094]), to determine whether to increase the dose of a nitrogen scavenging drug
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`(id. at [0041]), wherein the dose needs to be increased if the fasting blood ammonia level is
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`3
`
`It would have been obvious to a person of ordinary skill in the art to increase the drug
`dose even when the blood ammonia level was within normal limits, but above one half of the
`upper limit of normal because protein rich foods can impact circulating ammonia levels. It was
`known to lower circulating ammonia levels to ensure the value remains away from the upper
`limit of normal. Claim 1, however, is broader and covers even higher levels instances where the
`fasting blood ammonia levels are higher than even normal limits.
`4
`The ʼ859 publication is prior art to the ʼ215 patent under 35 U.S.C. § 102(b) based on its
`January 14, 2010, publication date.
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`greater than half the upper limit of normal for blood ammonia level. If the ammonia control is
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`inadequate, the dosage of the nitrogen scavenging drug can be increased. (Id. at [0083].)
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`Endo, F. et al., Clinical Manifestations of Inborn Errors of the Urea Cycle and Related
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`Metabolic Disorders during Childhood, J. Nutrition 1606, 1606S, 1608S (2004) (“Endo 2004”),
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`along with many other prior art references, teaches increasing the dose of a nitrogen scavenging
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`drug when a person’s blood ammonia levels are high, including greater than 100 μg/dL.5 See
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`also, e.g., Batshaw, M. L., et al., Alternative Pathway Therapy for Urea Cycle Disorders: Twenty
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`Years Later, 138 J. Pediatrics S46, S51 (2001) (“Batshaw 2001”) (“The aim of long-term therapy
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`is to maintain metabolic control with plasma ammonia concentrations less than twice normal”);
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`The Urea Cycle Disorders Conference Group, Consensus Statement from a Conference for the
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`Management of Patients with Urea Cycle Disorders, J. Pediatrics (Supplement) S1, S3 (2001)
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`(“UCD Conference Group 2001”) (“An elevated ammonia level during a clinic visit . . . does
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`require adjustment of therapy or better compliance with recommended treatment regimen.”); Lee
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`2010 at 226 (providing that increasing dose of a nitrogen scavenging drug may improve
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`ammonia levels); Maestri, N.E., et al., Long-Term Survival of Patients with Argininosuccinate
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`Synthetase Deficiency, 127 J. Pediatrics 929, 932 (1993) (“Maestri 1993”) (providing, generally,
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`that larger dosage of sodium phenylbutyrate reduced hyperammonemic episodes).
`
`5
`
`Endo discloses summary data showing the relationship between circulating blood
`ammonia levels and mental injuries. It states that feeding is not possible when a patient has high
`circulating blood ammonia levels at onset, and therefore, the data in Figure 3 represent fasted
`levels. Id. at 1609S. The data in Figure 3 show that only patients with blood ammonium levels
`of less than 200 µg/dL consistently had good-moderate outcomes.
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`The following chart compares claim 1 to the prior art.
`
`Claim 1 of the ʼ215 Patent
`A method for adjusting the dosage of a
`nitrogen scavenging drug in a subject who
`has previously been administered an initial
`dosage of the nitrogen scavenging drug,
`comprising:
`
`’859 publication and Endo
`The ’859 publication teaches a method of adjusting
`the dose of a nitrogen scavenging drug in a subject
`who had previously been administered an initial
`dosage of the nitrogen scavenging drug. (’859
`publication at et sequence, including [0016],
`[0020], [0044], [0091], [0108].)
`
`a) measuring a fasting blood ammonia
`level for the subject;
`
`The ’859 publication discloses measuring blood
`ammonia levels and includes analysis from fed and
`fasting subjects.6 (See, e.g., id. at [0091], [0212].)
`
`b) comparing the fasting blood ammonia
`level to the upper limit of normal for blood
`ammonia level; and
`
`The ’859 publication generally discloses
`comparing a blood ammonia level to the upper
`limit of normal for the blood ammonia level. (See
`id. at [0060], [0063], [0094], and [0201]; see also
`Figure 13 (reproduced below).)
`
`c) administering an adjusted dosage of the
`nitrogen scavenging drug, 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 blood ammonia level.
`
`The ’859 publication discloses the need to adjust
`the dosage of an ammonia scavenging drug based
`on patient to patient variability depending on the
`severity of liver disease or the inherited enzymatic
`defect. Dose adjustments are required to
`compensate for the individual patient
`characteristics. (See id. at [0041], [0083].)
`
`Endo teaches administering an adjusted dosage
`greater than the initial dosage if the fasting blood
`ammonia level is high, i.e., greater than half the
`upper limit of normal. (See Endo at 1606S,
`1608S.)
`
`6
`
`Other prior art references teach that fasting blood ammonia levels should be measured to
`adjust the dosage of a nitrogen scavenging drug. See, e.g., Majeed, K. I., Hyperammonemia,
`eMedicine (last updated Dec. 18, 2001) (stating that plasma ammonium fasting levels should be
`measured for monitoring of condition
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`At the time of the alleged invention, a skilled artisan (e.g., a physician or clinician) would
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`have been motivated to combine the teachings of the prior art references to achieve the claimed
`
`invention, and the skilled artisan would have had a “reasonable expectation of success in doing
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`so.”7 One of ordinary skill in the art would be motivated by the ’859 publication to measure a
`
`fasting blood ammonia level for a subject who had been previously administered a nitrogen
`
`scavenging drug and compare the fasting blood ammonia level to the upper limit of normal. One
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`of ordinary skill in the art was motivated to increase the dose of the nitrogen scavenging agent if
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`the fasting blood ammonia level was above the upper limit of normal because high blood
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`ammonium levels are dangerous. (Endo at 1606S.) This is allegedly covered by the patent, and
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`a single obvious embodiment encompassed by claim 1 renders claim 1 obvious.
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`By way of example, Figure 13 of the ’859 publication compares the efficacy of HPN-100
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`with BUPHENYL by comparing mean plasma levels in 10 UCD patients treated for seven days
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`with sodium PBA followed by seven days with a PBA-equimolar dose of HPN-100. Both HPN-
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`100 and BUPHENYL are nitrogen scavenging drugs. Thus, the ’859 publication teaches
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`measuring the blood ammonia level by measuring the time-normalized area under the curve (TN-
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`AUC). It then compares the values obtained to the upper limit of normal.
`
`7
`
`Pfizer, Inc. v. Apotex, Inc., 480 F.3d at 1361. See, e.g., Alza Corp. v. Mylan
`Laboratories, Inc., 464 F. 3d 1286 (Fed. Cir. 2006) (affirming district court finding of
`obviousness); Syntex (USA) LLC v. Apotex, Inc., 407 F. 3d 1371 (Fed. Cir. 2005) (reversing
`district court finding of nonobviousness.)
`
`20
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`The ’215 patent claim limitation directed to administering an adjusted dosage of the
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`nitrogen scavenging drug greater than the initial dosage if the fasting blood ammonia level is
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`greater than half the upper limit of normal for blood ammonia levels is inherently disclosed by
`
`the prior art. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377 (Fed. Cir. 2003); see
`
`also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320 (Fed. Cir. 2004); Abbott Labs v. Geneva
`
`Pharms., Inc., 182 F.3d 1315, 1319 (Fed. Cir. 1999); Atlas Powder Co. v. Ireco, Inc., 190 F.3d
`
`1342, 1348–49 (Fed. Cir. 1999); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331,
`
`1343–44 (Fed. Cir. 2005).
`
`Endo teaches administration of nitrogen scavenging agents to decrease blood nitrogen
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`levels and motivates the reduction of the blood ammonia levels when the fasting blood ammonia
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`level is greater than normal blood ammonia levels. Endo teaches that high blood ammonia levels
`
`cause problems.
`
`When blood ammonium levels exceed 100 µg/dL, appetite loss, nausea,
`insomnia, agitation, and personality changes emerge. With levels ~150–
`200 µg/dL, seizures and severe loss of consciousness occur. Sudden
`elevations of ammonium from normal levels cause a unique flapping
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`tremor of the hands. When levels exceed 200–400 µg/dL, severe coma and
`respiratory failure lead to life-threatening conditions.
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`(Endo at 1606S.) Endo teaches the reduction of blood nitrogen levels in patients with high blood
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`ammonia levels, e.g., 200 µg/dL – 500 µg/dL, which are apparently fasting ammonia levels. (Id.
`
`at 1608S (“When ammonium levels decrease and feeding becomes possible.”).) Endo indicates
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`that when fasting ammonia levels stabilize, treatment should reduce ammonia levels further, and
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`it teaches the importance of reducing the circulating level of ammonia to below even
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`asymptomatic levels. (See id.)8 A person of ordinary skill in the art would have been motivated
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`to combine the teachings of Endo and the ’859 publication to provide a method of measuring
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`fasting blood ammonia levels, comparing it to a predetermined value (the “upper limit of
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`normal”), and then adjusting the dose to a greater dose than the initial dose if the fasting blood
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`ammonia level is greater than half the upper limit of normal for blood ammonia levels.
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`b)
`
`The Combination of Geraghty and Dixon
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`Claim 1 of the ʼ215 patent is also obvious over additional prior art, including Geraghty,
`
`M.T. and Brusilow, S.W., Disorders of the Urea Cycle, in LIVER DISEASE IN CHILDREN 836
`
`(Frederick Suchy, et al. eds., 2d ed. 2001) (“Geraghty”) in combination with Dixon, M. A. and
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`Leonard, J.V., Intercurrent Illness in Inborn Errors of Intermediary Metabolism, 67 Archives of
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`Disease in Childhood 1387, 1389–90 (1992) (“Dixon”). Based on at least these prior art
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`references, it would have been obvious to a person of ordinary skill in the art at the time of the
`
`8
`
`Both Endo and the ʼ859 publication are directed to the same field – urea cycle disorders.
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`22
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`Page 8 of 9
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`Dated: November 13, 2014
`
`/s/Michael J. Freno
`
`Michael E Jones
`State Bar No. 10929400
`mikejones@potterminton.com
`POTTER MINTON
`A Professional Corporation
`110 N College Avenue, Suite 500
`Tyler, TX 75702
`Telephone: 903-597-8311
`Facsimile: 903-593-0846
`
`Michael J. Freno
`K&L Gates LLP
`925 Fourth Avenue, Suite 2900
`Seattle, WA 98104-1158
`Telephone: 206-370-7947
`michael.freno@klgates.com
`
`Peter Giunta
`K&L Gates LLP
`599 Lexington Avenue
`New York, NY 10022-6030
`peter.giunta@klgates.com
`
`Harold M. Storey
`Seed IP Law Group PLLC
`701 Fifth Avenue, Suite 5400
`Seattle, WA 98104
`(206) 622-4900
`harolds@seedip.com
`
`ATTORNEYS FOR DEFENDANT
`PAR PHARMACEUTICAL, INC.
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`Page 9 of 9
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