Trials@uspto.gov
`571.272.7822
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` Paper No. 10
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` Filed: September 28, 2017
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`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.
`____________
`
`Case IPR2017-01159
`Patent 9,254,278 B2
`____________
`
`
`
`Before GRACE KARAFFA OBERMANN, DEBORAH KATZ, and RAMA
`G. ELLURU, Administrative Patent Judges.
`
`KATZ, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`I.
`
`BACKGROUND
`
`Lupin Ltd. and Lupin Pharmaceuticals, Inc. (“Petitioner”) filed a
`
`request for an inter partes review (“IPR”) of claims 1–15 of U.S. Patent No.
`
`9,254,278 B2 (Ex. 1001 (“the ’278 patent”) (Paper 3 (“Pet.”)). Horizon
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`

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`Case IPR2017-01159
`Patent 9,254,278 B2
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`Therapeutics, Inc. (“Patent Owner”) filed a Preliminary Response (Paper 7
`
`(“Prelim. Resp.”)).
`
`Under 35 U.S.C. § 314(a), an inter partes review may not be instituted
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`unless Petitioner shows that there is “a reasonable likelihood that the
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`petitioner would prevail with respect to at least 1 of the claims challenged in
`
`the petition.” Petitioner makes that showing with respect to the grounds for
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`unpatentability of claims 1–15. Therefore, we institute review as to
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`claims 1–15.
`
`Our findings of fact and conclusions of law are based on the record
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`developed thus far, prior to Patent Owner’s Response under 37 C.F.R.
`
`§ 42.120. This is not a final decision as to the patentability of any
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`challenged claim. If a final decision is issued in this case, it will be based on
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`the full record developed during trial.
`
`A.
`
`Related proceedings
`
`The challenged ’278 patent is part of a family of patents involved in
`
`litigations and other inter partes reviews. The grandparent of the application
`
`that became the ’278 patent issued as patent 8,404,215 (“the ’215 patent”).
`
`The parent of the application that became the ’278 patent issued as patent
`
`9,095,559 (“the ’559 patent”). The application that became the ’278 patent
`
`is the parent of the application that issued as patent 9,326,966 (“the ’966
`
`patent”). Each of these patents is or was the subject of a petition for inter
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`partes review.
`
`Specifically, the ’215 patent was the subject of IPR2015-01127, filed
`
`by Par Pharmaceutical, Inc. (“Par”). IPR2016-00284 filed by Petitioner, was
`
`instituted and joined with the IPR2015-01127 proceeding. The claims
`
`challenged in that review are similar to the claims challenged in the present
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`
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`2
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`Case IPR2017-01159
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`review, wherein fasting blood ammonia levels are measured, compared to
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`the upper limited of normal, and an adjusted dose of drug is administered if
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`“the fasting blood ammonia level is greater than half the upper limit of
`
`normal for blood ammonia level.” See Par Pharm., Inc. v. Horizon
`
`Therapeutics, LLC, Case IPR2015-01127, slip op. at 6–7 (PTAB September
`
`29, 2016) (Paper 49). Those claims were held to be unpatentable.
`
`The ’559 patent was the subject of IPR2016-00829, filed by
`
`Petitioner. The claims challenged in that review also are similar to the
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`claims challenged in the present review, wherein fasting blood ammonia
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`levels are measured and compared to the upper limit of normal, and an
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`adjusted dose of drug is administered relative to the upper limit of normal
`
`for fasting plasma ammonia levels. See Prelim. Resp. 5. Those claims were
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`held to be unpatentable. See Lupin, Ltd. v. Horizon Therapeutics, LLC, Case
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`IPR2016-00829 (PTAB September 26, 2017) (Paper 42).
`
`Petitioner also filed a petition for review of the claims of the ’966
`
`patent (IPR2017-01160) on the same day the instant petition was filed. That
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`review is instituted concurrently with this review. See Lupin Ltd. v. Horizon
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`Therapeutics, LLC, Case IPR2017-01160 (PTAB September 28, 2017)
`
`(Paper 10).
`
`In addition, on July 13, 2017, Par filed petitions for review of the ’559
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`patent, the ’278 patent, and the ’966 patent (IPR2017-01768, IPR2017-
`
`01767, and IPR2017-01769, respectively). A decision on whether to
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`institute trial based on these pending petitions has not yet been made.
`
`We note that patent 8,642,012 is not related by lineage to the currently
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`challenged ’278 patent, but the publication of the application from which it
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`issued (publication 2010/0008859 (Ex. 1007)) is cited by Petitioner as prior
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`3
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`art in the current challenges. The claims of patent 8,642,012 were
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`challenged in IPR2015-01117, though it was determined that Petitioner
`
`failed to show that the claims were unpatentable. That decision has been
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`appealed to the Court of Appeals for the Federal Circuit (App. No. 2017-
`
`1451).1
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`In addition, the parties report the following infringement suits in the
`
`District of New Jersey:
`
`Horizon Therapeutics Inc. v. Par Pharmaceutical Inc., Case No. 1:16-
`
`cv-3910-RBK-JS (D.N.J.) filed on June 30, 2016, asserting infringement of
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`the ’559 patent, the ’278 patent, and the ’966 patent;
`
`Horizon Therapeutics Inc. v. Lupin Ltd. and Lupin Pharmaceuticals
`
`Inc., Case No. 1:15-cv-07624-RBK-JS (D.N.J. filed Oct. 19, 2015), asserting
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`infringement of the ’559 patent;
`
`Horizon Therapeutics Inc. v. Lupin Ltd. and Lupin Pharmaceuticals
`
`Inc., Civil Action No. 1:16-cv-4438-RBK-JS (D.N.J.) filed on July 21, 2016,
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`asserting infringement of the ’278 patent and the ’966 patent.
`
`Patent Owner reports the following related patent applications:
`
`application 15/074,625, filed March 18, 2016;
`application 15/074,666, filed March 18, 2016;
`application 15/074,691, filed March 18, 2016; and
`application 15/457,643, filed March 13, 2017.
`
`(See Paper 6.)
`
`
`1 Infringement of patent 8,642,012 was asserted in the Eastern District of
`Texas in Hyperion Therapeutics Inc. v. Par Pharmaceutical, Inc., Case No.
`2:14-cv-00384-JRG-RSP (E.D. Tex.) filed on April 23, 2014. That case
`reportedly has been stayed pending the resolution Appeal No. 2017-1451 to
`the Federal Circuit. Paper 5 at 4.
`
`
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`4
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`Case IPR2017-01159
`Patent 9,254,278 B2
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`
`B.
`
`The ’278 Patent (Ex. 1001)
`
`The claims of the ’278 patent are directed to methods of using a drug,
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`glyceryl tri-[4-phenylbutryate] (also called “HPN-100”), to treat subjects
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`with urea cycle disorders. Patients suffering from urea cycle disorders
`
`(“UCDs”) are unable to remove excess nitrogen waste, which is normally
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`excreted in the urine. Ex. 1002 ¶ 30. When the body functions properly
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`dietary amino acids are converted first to ammonia and then to urea in the
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`urea cycle and, finally, excreted in the urine. Id. ¶ 28. In those with UCDs,
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`the enzymes controlling the urea cycle are deficient, leading to high, toxic
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`levels of ammonia in the blood and possibly brain damage, comma, or death.
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`Id. ¶ 29; Ex. 2006 ¶¶ 35–36.
`
`C.
`
`Asserted Grounds of Unpatentability
`
`Petitioner challenges the patentability of ’278 patent claims 1–15
`
`under 35 U.S.C. § 103 over the following references:
`
`
`
`
`
`Ground
`1
`2
`3
`
`References
`’859 Publication2
`Blau3, Simell4, and the ’859 Publication
`Blau, Simell, the ’859 publication, and
`Brusilow ’979 patent5
`
`Claims
`
`1–3
`4–7 and 12–15
`8–11
`
`
`2 U.S. Patent Publication 2010/0008859 A1, was filed on January 7, 2009,
`and published on January 14, 2010 (Ex. 1007).
`3 PHYSICIAN’S GUIDE TO THE LABORATORY DIAGNOSIS OF METABOLIC
`DISEASES, 261–76 (Nenad Blau et al. eds., 2d ed. 1996) (Ex. 1006).
`4 Olli Simell et al., Waste Nitrogen Excretion Via Amino Acid Acylation:
`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20 PEDIATRIC
`RESEARCH 1117–21 (1986) (Ex. 1005).
`5 U.S. Patent 5,968,979, issued October 19, 1999 (Ex. 1024).
`
`
`
`5
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`
`II.
`
`Analysis
`
`Under 35 U.S.C. § 103, subject matter is unpatentable “if the
`
`differences between the subject matter sought to be patented and the prior art
`
`are such that the subject matter as a whole would have been obvious at the
`
`time the invention was made to a person having ordinary skill in the art to
`
`which said subject matter pertains.” In KSR Int’l Co. v. Teleflex Inc., 550
`
`U.S. 398, 421 (2007), the Supreme Court has explained that if the person of
`
`ordinary skill could have arrived at the claimed subject matter using
`
`common sense to combine different teachings of the prior art, that subject
`
`matter is likely obvious, not innovative.
`
`A. Ground 1
`
`Petitioner argues that claims 1–3 would have been obvious over the
`
`’859 publication under 35 U.S.C. § 103. Pet. 14-23.
`
`Claim 1 recites:
`
`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.
`
`Ex. 1001, 24:21–26. Claim 2 of the ’278 patent defines the “upper limit of
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`normal” as 35 µmol/L (Ex. 1001, 24:27–28) and claim 3 requires the HPN-
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`100 be administered orally (id. at 24:29–30).
`
`For reasons that follow, based on the information presented in the
`
`Petition and Preliminary Response, we are persuaded that Petitioner is
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`reasonably likely to prevail at trial on this ground.
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`
`1.
`
`The ’859 publication teaches oral administration of nitrogen
`
`scavenging drugs, including HPN-100, to treat urea cycle disorders. See
`
`Ex. 1007 ¶¶ 2, 20–21, and 189; see Pet. 14. The ’859 publication also
`
`teaches methods of adjusting drug dosage, including HPN-100, based in part
`
`on plasma ammonia levels. See Ex. 1007 ¶¶ 88–92, 95–99, 107–108, 226,
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`232; see Pet. 14–15.
`
`The ’859 publication teaches comparing a patient’s plasma ammonia
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`level to the upper limit of normal plasma ammonia level. Ex. 1007 ¶ 201
`
`see Pet. 15. The ’859 publication teaches further that “plasma levels of
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`ammonia are acceptable when they are at or below a level considered normal
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`for the subject, and commonly this would mean plasma ammonia level is
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`below about 40 µmol/L.” Ex. 1007 ¶ 94; see Pet. 15. In the ’859
`
`publication normal plasma ammonia levels are identified as “below about 40
`
`µmol/L” (Ex. 1007, ¶ 94), but the upper limit of normal plasma ammonia
`
`levels is also identified as “between 26 to 35 µmol/L” (Ex. 1007 ¶ 94; see
`
`also id. ¶ 201; see Pet. 15. The ’859 publication teaches increasing the
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`dosage of nitrogen scavenging drugs when ammonia control is inadequate.
`
`See Ex. 1007 ¶¶ 83 and 232; see Pet. 15.
`
`The ’859 publication includes Example 3, which reports a study of
`
`UCD patients who were treated with sodium PBA, a different nitrogen
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`scavenging drug, and then switched to an equivalent dose of HPN-100 for
`
`one week. See Ex. 1007 ¶ 195; see Pet. 15–17. The results show that one of
`
`the patients (number 1006) had a “mean time normalized area under the
`
`curve” (“TN-AUC”) venous ammonia level of 8.3 µmol/L and an ammonia
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`Cmax of 13.0 µmol/L, which were both less than half the upper limits of
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`normal reported for the patients in the study (26 to 35 µmol/L). See
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`Ex. 1007 ¶¶ 200–201 and table following ¶ 201; see Pet. 15–17 and 19–20.
`
`Dr. Vaux testifies that
`
`[g]iven the ammonia control seen in [patient 1006 in Example 3
`of the ’859 publication] when taking HPN-100, and that fact that
`HPN-100 was reported to be well tolerated (Ex. 1007 at [0203],
`see also [0086]), a person of ordinary skill in the art would have
`been motivated to replicate these results by administering the
`same amount of HPN-100 to other UCD patients, with the
`expectation of achieving low ammonia levels, including levels
`that were less than half the ULN in some patients.
`
`Ex. 1002, ¶ 63.
`
`Petitioner’s witness, Dr. Vaux testifies that
`
`The only difference between this disclosure in the ’859
`Publication and claim 1 of the ’278 Patent is that claim 1
`specifies producing a “fasting” plasma ammonia level that is less
`than half the ULN, whereas the ’859 Publication does not specify
`whether the TNAUC and Cmax values for Subject 1006 are fasted
`values. Nevertheless, as discussed above, a person of ordinary
`skill in the art would have been motivated to keep a patient’s
`baseline ammonia level low, to keep the patient well-controlled
`and to reduce the risk of hyperammonemia. (See supra ¶¶ 36-40.)
`Knowing that ammonia levels increase after the ingestion of
`food, a person of ordinary skill in the art would have been
`motivated to keep the fasting plasma ammonia level low, e.g. less
`than half the ULN, to maximize chances of keeping the patient
`continually within normal plasma ammonia limits despite
`transitory spikes in ammonia level, and because there is no
`minimum level of blood ammonia that must be maintained for
`normal body function. A person of ordinary skill in the art would
`have had a reasonable expectation of success of achieving a
`fasting plasma ammonia level of less than half the ULN,
`particularly because the ʼ859 Publication discloses a dose of
`HPN-100 that achieved this plasma ammonia level in one of the
`study patients (Subject 1006), and because HPN-100 was known
`
`
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`to be a well-tolerated drug. (Ex. 1007 at Table under [0201],
`[0203], [0086].)
`
`
`Ex. 1002, ¶ 64; Pet. 20.
`
`Dr. Vaux further testifies that given the short term and long term
`
`challenges of UCD patients caused by excess ammonia, clinicians try to
`
`maintain plasma ammonia levels as low as possible. Ex. 1002 ¶ 36 (citing
`
`Ex. 1004 at 1631; Ex. 1008 at 10; Ex. 1020 at 3327 (“Laboratory Tests”
`
`section); Ex. 1007 at [0083], [0094]; Ex. 1016 at S58 (“The goal of
`
`treatment is to maintain normal levels of plasma ammonia through the use of
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`low-protein diet and medication while allowing for normal growth. . . . The
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`finding of both an elevated plasma ammonia and glutamine level indicate
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`that body ammonia is elevated and the patient is at risk for
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`hyperammonemic encephalopathy.”)). In addition, Dr. Vaux testifies that
`
`when measuring plasma ammonia levels it was recommended to measure a
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`fasting plasma ammonia level. Ex. 1002 ¶ 37 (citing Ex. 1005 at 1118, Ex.
`
`1006 at Table 11.9, Ex. 1015 at S11, Ex. 1010).
`
`The ’859 publication teaches that the lower plasma ammonia level in
`
`a patient treated with HPN-100 allows for better overnight control of
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`ammonia exposure and “provides more stable ammonia levels, and reduces
`
`the risk of hyperammonemia.” Ex. 1007 ¶ 202.
`
`The ’859 publication teaches that “HPN-100 exhibits no indications of
`
`toxicity at equimolar doses when compared to the approved PBA
`
`[phenylbutyric acid] dosage of 20 g/day and a dose 2-3 times the equivalent
`
`of 20 grams of PBA is unlikely to produce [adverse effects].” Ex. 1007
`
`¶ 86. The ’859 publication also teaches that “[i]n some patients or clinical
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`settings, HPN-100 doses well above the approved PBA dosage are expected
`
`to be beneficial . . . .” Id.; see also Ex. 1007 ¶ 203. See Pet. 17.
`
`Dr. Vaux testifies that there is no minimum level of blood ammonia
`
`that must be maintained for normal body function and that he is not aware of
`
`any negative effects of ammonia levels that are low or even absent.
`
`Ex. 1002 ¶ 29.
`
`Based on the evidence it cites, Petitioner argues that it would have
`
`been obvious to maintain a patient’s plasma ammonia levels within normal
`
`limits and that one of ordinary skill in the art would have been motivated to
`
`administer sufficient drug to reduce ammonia levels and maintain them
`
`within normal levels, even after eating. Pet. 18-19. Citing to the results of
`
`subject 1006 in Example 3 of the ’859 publication, who had plasma levels
`
`reduced to below half the upper limit of normal, Petitioner argues that those
`
`in the art would have been motivated to obtain similar results for the patients
`
`because there is no minimum level of plasma ammonia needed for normal
`
`body function. Pet. 19–20. Petitioner also argues that it would have been
`
`obvious to target a fasting ammonia level because it was known that
`
`ingestion of food could make ammonia levels fluctuate. See id.
`
`2.
`
`We note that although Patent Owner argues that the preamble of each
`
`independent claim of the ’278 patent, including claim 1, requires that the
`
`“subject” receiving the treatment of the claimed method have a fasting
`
`ammonia level less than the upper limit of normal (see Prelim. Resp. 16), at
`
`this point in the proceeding we do not construe claim 1 as requiring the
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`subject to have any specific plasma ammonia level before administration of
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`HPN-100. See Ex. 1001, 24:21–26.
`
`In regard to the evidence cited by Petitioner, Patent Owner argues that
`
`we should not accord any weight to Dr. Vaux’s testimony. According to
`
`Patent Owner, he is not one of ordinary skill in the art because he is not
`
`board certified in clinical genetics or in clinical or medical biochemical
`
`genetics. Prelim. Resp. 15; see also id. 27–31. We do not agree at this point
`
`in the proceeding.
`
`Dr. Vaux testifies that he is Professor and Clinical Chief of the
`
`Division of Medical Genetics in the Department of Medicine at University
`
`of California – San Diego. Ex. 1002 ¶ 1. Dr. Vaux testifies: “Since 1994, I
`
`have regularly diagnosed and treated patients with urea cycle disorders
`
`(‘UCD’), and continue to do so today. In treating UCD patients, I regularly
`
`prescribe nitrogen scavenging drugs and treat patients who are maintained
`
`on therapy with nitrogen scavenging drugs.” (Id.) Although Patent Owner
`
`argues that Dr. Vaux lacks the extensive training and certifications necessary
`
`to manage treatment of UCD patients (Prelim. Resp. 12–15), Dr. Vaux
`
`testifies that he has treated such patients for over twenty years, including
`
`prescribing medication for them. On this record, we are persuaded that Dr.
`
`Vaux is qualified to opine about how one of ordinary skill in the art would
`
`treat UCD patients.
`
`Patent Owner argues that the testimony of its own witness, Dr. Enns,
`
`(Ex. 2006) is more reliable than Dr. Vaux’s and that we can deny institution
`
`based on it because it is substantially the same as his declaration in a prior
`
`inter partes review, IPR2016-00829 (Ex. 2001). See Prelim. Resp. 5.
`
`According to Patent Owner, because of this similarity and because Petitioner
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`cross-examined Dr. Enns in the prior proceeding, Dr. Enns’s testimony need
`
`not be viewed in the light most favorable to Petitioner when deciding
`
`whether to institute a trial as provided in 37 C.F.R. § 41.108(c). See Prelim
`
`Resp. 6. We are not persuaded that the circumstances of Dr. Enns’s prior
`
`cross-examination overrides application of Rule 41.108(c) in this case. For
`
`example, the issues of fact raised in this proceeding may not be exactly the
`
`same as the issues of the prior proceeding. Accordingly, we refuse to deny
`
`institution of a trial in this proceeding because Petitioner has not had an
`
`opportunity to cross-examine Dr. Enns with regard to the specific issues
`
`raised by Petitioner in this proceeding.
`
`Patent Owner also argues that we should refuse to institute a trial
`
`because Petitioner incorrectly relies on the result of one subject reported in
`
`Example 3 of the ’859 publication, when all of the patients, including those
`
`with ammonia levels above half the upper limit of normal and even above
`
`the upper limit of normal were characterized as being “better controlled”
`
`when they took HPN-100. Prelim. Resp. 42. At this point in the
`
`proceeding, we are persuaded that even if the ’859 publication teaches
`
`treating other patients, it also teaches administering drug to a patient to
`
`achieve a plasma ammonia level less than half the upper limit of normal.
`
`That teaching, plus Dr. Vaux’s testimony that those of ordinary skill in the
`
`art would have known to measure plasma ammonia when the patient has
`
`fasted, indicate to us that Petitioner is reasonably likely to prevail in showing
`
`that the methods recited in Patent Owner’s claims 1–3 would have been
`
`obvious.
`
`
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`12
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`
`3.
`
`We are persuaded based on the information presented in the Petition
`
`and Preliminary Response that Petitioner is reasonably likely to prevail.
`
`Accordingly, we institute trial on Ground 1.
`
`B. Ground 2
`
`Petitioner argues that claims 4–7 and 12–15 would have been obvious
`
`over Blau, Simell, and the ’859 publication under 35 U.S.C. § 103. Pet. 24–
`
`44.
`
`Claim 4 recites:
`
`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.
`
`Ex. 1001, 24:31–47. Independent claim 12 is similar to claim 4, but includes
`
`an extra step before the administering step (c) of claim 4 requiring “(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 . . . .” Ex. 1001, 25:17–26:13. In addition, unlike
`
`
`
`13
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`claim 4, claim 12 does not require restricting the subject's dietary protein
`
`intake. See id.
`
`1.
`
`Petitioner cites to the same portions of the ’859 publication discussed
`
`above. In addition, Petitioner cites to the ’859 publication, as well as other
`
`references, for their teaching to adjust protein intake to control ammonia
`
`levels. Pet. 36–37 (citing Ex. 1007 ¶¶ 83 and 226); see also and Exs. 1006,
`
`1016, 1017, 1020, Ex. 1002 ¶ 92. At this point in the proceeding, we agree
`
`that the references teach such adjustment.
`
`Petitioner cites to Simell and Blau for their teachings regarding
`
`measuring plasma ammonia levels after a fast. See Pet. 24 (citing Ex. 1005,
`
`abstract and 1117–18 and Ex. 1006, 273). To anticipate Patent Owner’s
`
`argument that Blau relates to diagnosis, not treatment of UCDs (see Prelim.
`
`Resp. 36), Petitioner cites other evidence for the teaching that measuring
`
`plasma ammonia is recommended after a fast. See Pet. 31, n. 4 (citing
`
`Ex. 1010 at 4; Ex. 1015 at 1). At this point in the proceeding, we agree that
`
`these references indicate it was known to measure plasma ammonia levels
`
`after a fast.
`
`Petitioner argues that those of ordinary skill in the art looking to
`
`adjust the dosage of a nitrogen scavenging drug such as HPN-100 would
`
`have combined the teachings of Simell, Blau, and the ’859 publication
`
`because they teach different aspects of treating UCDs. See Pet. 25–26
`
`(citing Ex. 1002 ¶¶ 72–75).
`
`Petitioner also cites to Dr. Vaux’s testimony that
`
`in order to maintain a patient’s plasma ammonia levels within
`normal limits, a person of ordinary skill in the art would have
`been motivated to administer more drug to reduce ammonia
`
`
`
`14
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`Case IPR2017-01159
`Patent 9,254,278 B2
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`levels even in cases where the fasting plasma ammonia level
`was above half the ULN but below the ULN. For example, in
`the case of a patient with a fasting plasma ammonia level
`approaching the ULN, a person of ordinary skill in the art
`would have desired to maintain the patient at normal ammonia
`levels, and would have known that variation in ammonia levels
`due to time of day and/or ingestion of food would potentially
`take the patient outside of normal levels. Thus, even though the
`patient’s fasting plasma ammonia level was already below the
`ULN, a person of ordinary skill in the art would have been
`motivated to increase the dose of drug to lower the patient’s
`baseline ammonia and to help ensure that the patient routinely
`stayed within normal plasma ammonia limits.
`
`
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`Ex. 1002 ¶ 80, see also id. at ¶ 120; see Pet. 30. Similarly, Dr. Vaux testifies
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`that “for a patient with fasting plasma ammonia levels approaching the
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`[upper limit of normal], a person of ordinary skill in the art would have been
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`motivated to increase the dose of drug to lower the patient’s baseline
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`ammonia and to help ensure that the patient routinely stayed within normal
`
`plasma ammonia limits.” Ex. 1002 ¶ 90; see Pet. 36.
`
`Petitioner argues further that those of ordinary skill in the art would
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`have had a reasonable expectation of success in combining the references to
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`achieve the claimed method because the steps of the method are well-known
`
`and routine in the art. Pet. 37. Petitioner argues, more specifically, that
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`ordinarily skilled artisans would have had a reasonable expectation of
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`success in achieving a fasting plasma ammonia level of less than half the
`
`upper limit of normal because the ’859 publication teaches achieving this
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`level in one of the study subjects reported in Example 3 and because HPN-
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`100 was known to be a well-tolerated drug. Pet. 20 (citing Ex. 1002 ¶¶ 63–
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`64 and Ex. 1007, table following ¶ 201, ¶¶ 86 and 203).
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`Case IPR2017-01159
`Patent 9,254,278 B2
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`In regard to the additional step in claim 12, Petitioner cites to Dr.
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`Vaux’s testimony that it was known in the art to determine an initial dose of
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`HPN-100 based on the molar equivalent of sodium phenylbutyrate. Pet. 40–
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`41 (citing Ex. 1002 ¶ 95); see Ex. 1007 ¶¶ 67, 195, Example 3.
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`2.
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`We note that, at this point in the proceeding, we agree with the parties
`
`that the claim term “upper limit of normal” (“ULN”) means the highest
`
`value in a range of normal values. See Pet. 11; Prelim. Resp. 15–16.
`
`Therefore, we determine, at this time, that “less than the upper limit of
`
`normal” means any value less than the highest value in the range of normal
`
`values. See Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46
`
`(2016) (upholding the use of the broadest reasonable interpretation
`
`standard); see 37 C.F.R. § 42.100(b). Thus, at this point in the proceeding,
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`we consider the claims to encompass adjusting drug dosage even when the
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`subject’s plasma ammonia levels are only slightly less than the upper limit
`
`of normal.
`
`Patent Owner argues that a trial should not be instituted because an
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`ordinarily skilled artisan would not have been motivated to increase the
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`dosage of HPN-100 based on normal plasma ammonia levels, as recited in
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`the preambles of independent claims 4 and 12. Prelim. Resp. 17–31.
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`According to Patent Owner, Petitioner fails to cite any single prior art
`
`reference suggesting that a person or ordinary skill in the art should
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`administer increased dosages of drug when a patient already has a normal
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`plasma ammonia level or to target a plasma level within the range of normal
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`values. Prelim. Resp. 18.
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`Case IPR2017-01159
`Patent 9,254,278 B2
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`At this point in the proceeding, we are not persuaded that Petitioner is
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`not reasonably likely to prevail for this reason because the challenges are
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`based on obviousness. Petitioner need not show that a single reference
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`expressly teaches increasing the dosage of HPN-100 as claimed in order to
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`prevail. As discussed above, at this time, we consider the cited prior art
`
`references and Dr. Vaux’s testimony to show sufficiently that those of skill
`
`in the art would have administered increased drug dosages to patients whose
`
`plasma ammonia levels were approaching the upper limit of normal. The
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`prior art teaches that a goal was to maintain plasma ammonia levels at or
`
`below a level considered to be normal. See Pet. 27–37 (citing Ex. 1002
`
`¶¶ 80 and 90, Ex. 1007 ¶ 94).
`
`Patent Owner cites to several references, including the ’859
`
`publication, the ’157 publication (Ex. 2012), Häberle (Ex. 2019), and
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`Brusilow ’84 (Ex. 1004), to argue that the teachings in the prior art were to
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`increase drug dosages only when plasma ammonia levels were above the
`
`upper limit of normal. Prelim. Resp. 21–22. At this point in the proceeding,
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`these references are not persuasive because Dr. Vaux testifies that ordinarily
`
`skilled artisans would have considered it obvious to have increased drug
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`dosages at plasma levels other than those reported in these references. See
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`Ex. 1002 ¶ 122.
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`Patent Owner characterizes the prior art as “teaching away” from the
`
`claimed methods because it establishes that normal plasma ammonia levels
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`were acceptable and only addresses increasing the dosage of medication
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`when levels were well above the upper limit of normal. Prelim. Resp. 18.
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`For example, Petitioner interprets paragraph 94 of the ’859 publication as
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`teaching that when levels were normal or below normal, no more drug
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`Case IPR2017-01159
`Patent 9,254,278 B2
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`would be required. Prelim. Resp. 20. Patent Owner cites to other portions
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`of the ’859 publication for similar teachings (see Ex. 1007 ¶ 85 (“a plasma
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`ammonia level that was normal, e.g., a level of less than about 40 µmol/L, or
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`of not greater than 35 µmol/L, would indicate the treatment was effective.”))
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`and for teachings that drug levels should be increased when plasma
`
`ammonia levels are above normal (see Ex. 1007 ¶¶ 73, 83).
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`We are not persuaded at this time that the ’859 publication teaches
`
`away from the claimed methods as defined in the case law. “A reference
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`may be said to teach away when a person of ordinary skill, upon reading the
`
`reference, would be discouraged from following the path set out in the
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`reference, or would be led in a direction divergent from the path that was
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`taken by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
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`Patent Owner does not provide a sufficient explanation why teachings in the
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`’859 publication that plasma levels are effective when within the normal
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`range or to increase drug dosage when plasma ammonia levels are above
`
`normal would necessarily discourage one of ordinary skill from increasing
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`drug dosages at other plasma ammonia levels. Patent Owner has not cited to
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`prior art that clearly discourages increasing drug dosages when plasma
`
`ammonia levels are within the normal range.
`
`We also are not persuaded at this point in the proceeding that one of
`
`ordinary skill in the art would have adjusted drug dosages only when a
`
`patient’s plasma ammonia levels are above the upper limit of normal. See,
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`e.g. Prelim. Resp. 21–22 (citing Ex. 2012, Ex. 2019, Ex. 1004). In contrast,
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`Dr. Vaux’s testimony and the evidence he cites in support demonstrate that
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`there was a reason to adjust drug dosage at lower plasma ammonia levels –
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`for example, to maintain normal levels after eating.
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`Case IPR2017-01159
`Patent 9,254,278 B2
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`We have considered Patent Owner’s arguments that the prior art
`
`taught possible side effects of too much nitrogen scavenging drugs but do
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`not find them to be persuasive. See Prelim. Resp. 23–24 (citing Ex. 2031,
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`2032, 2013). In light of the evidence that Petitioner cites regarding the
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`relative safety of HPN-100, we are not persuaded by Patent Owner’s
`
`argument at this point in the proceeding. See Pet. 17 (citing Ex. 1007 ¶¶ 86
`
`and 203).
`
`Patent Owner argues that before the time of the invention described in
`
`the ’278 patent, those of ordinary skill in the art would have rejected the
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`concept of a “baseline” ammonia level and would have considered increases
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`to be too unreliable to be the basis for increasing drug dosages, especially
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`when a patient was within normal plasma ammonia levels. Prelim.
`
`Resp. 23–24. We are no