`
`
`
`
`
` Paper No. 10
`
`
` Filed: September 28, 2017
`
`
`
`Trials@uspto.gov
`571.272.7822
`
`
`
`
`
`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 IPR2017-01160
`Patent 9,326,966 B2
`____________
`
`
`
`Before GRACE KARAFFA OBERMANN, DEBORAH KATZ, and
`RAMA G. ELLURU, and, 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.
`
`9,326,966 B2 (Ex. 1003 (“the ’966 patent”) (Paper 3 (“Pet.”))). Horizon
`
`
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`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
`
`unless Petitioner shows that there is “a reasonable likelihood that the
`
`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
`
`unpatentability of claims 1–11 and 13 and we institute review as to those
`
`claims. Patent Owner filed a statutory disclaimer of claims 12, 14, and 15
`
`under 35 U.S.C. § 253(a). Accordingly, we do not institute review as to
`
`those claims. See 37 C.F.R. § 42.107(e).
`
`Our findings of fact and conclusions of law are based on the record
`
`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
`
`challenged claim. If a final decision is issued in this case, it will be based on
`
`the full record developed during trial.
`
`A.
`
`Related proceedings
`
`The challenged ’966 patent is part of a family of patents involved in
`
`litigations and other inter partes reviews. The great grandparent of the
`
`application that issued as the ’966 patent became patent 8,404,215 (“the
`
`’215 patent”). The grandparent of the application that issued as the
`
`’966 patent became patent 9,095,559 (“the ’559 patent”). The parent of the
`
`application that issued as the ’966 patent became patent 9,254,278 (“the
`
`’278 patent”). Each of these patents is or was the subject of a petition for
`
`inter partes review.
`
`Specifically, the ’215 patent was the subject of IPR2015-01127, filed
`
`by Par Pharmaceutical, Inc. (“Par”). IPR2016-00284 filed by Petitioner, was
`
`
`
`2
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`instituted and joined with the IPR2015-01127 proceeding. The claims
`
`challenged in that review are similar to the claims challenged in the present
`
`review, wherein fasting blood ammonia levels are measured, compared to
`
`the upper limited of normal, and an adjusted dose of drug is administered if
`
`“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
`
`claims challenged in the present review, wherein fasting blood ammonia
`
`levels are measured and compared to the upper limit of normal, and an
`
`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
`
`held to be unpatentable. See See Lupin, Ltd. v. Horizon Therapeutics, LLC,
`
`Case IPR2016-00829 (PTAB September 26, 2017) (Paper 42).
`
`Petitioner also filed a petition for review of the claims of the ’278
`
`patent (IPR2017-01159) on the same day the instant petition was filed. That
`
`review is instituted concurrently with this review. See Lupin Ltd. v. Horizon
`
`Therapeutics, LLC, Case IPR2017-01159 (PTAB September 28, 2017)
`
`(Paper 10).
`
`In addition, on July 13, 2017, Par filed petitions for review of the
`
`’559 patent, the ’278 patent, and the ’966 patent (IPR2017-01768, IPR2017-
`
`01767, and IPR2017-01769, respectively). A decision on whether to
`
`institute trial based on these pending petitions has not yet been made.
`
`
`
`3
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`We note that patent 8,642,012 is not related by lineage to the currently
`
`challenged ’966 patent, but the publication of the application from which it
`
`issued (publication 2010/0008859 (Ex. 1007)) is cited by Petitioner as prior
`
`art in the current challenges. The claims of patent 8,642,012 were
`
`challenged in IPR2015-01117, though it was determined that Petitioner
`
`failed to show that the claims were unpatentable. That decision has been
`
`appealed to the Court of Appeals for the Federal Circuit (App. No. 2017-
`
`1451).1
`
`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
`
`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 on
`
`October 19, 2015, asserting infringement of the ’559 patent;
`
`Horizon Therapeutics Inc. v. Lupin Ltd. and Lupin Pharmaceuticals
`
`Inc., Case No. 1:16-cv-4438-RBK-JS (D. N.J.) filed on July 21, 2016,
`
`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
`
`
`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 of the appeal to the
`Federal Circuit. Paper 6, 4.
`
`
`
`4
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`application 15/457,643, filed March 13, 2017.
`
`(See Paper 6.)
`
`B.
`
`The ’966 Patent (Ex. 1003)
`
`The claims of the ’966 patent are directed to methods of using a drug,
`
`glyceryl tri-[4-phenylbutryate] (also called “HPN-100”), to treat subjects
`
`with urea cycle disorders. Patients suffering from urea cycle disorders
`
`(“UCDs”) are unable to remove excess nitrogen waste, which is normally
`
`excreted in the urine. See Ex. 1002 ¶ 27; Ex. 2006 ¶ 34. When the body
`
`functions normally, dietary amino acids are converted first to ammonia and
`
`then to urea in the urea cycle and, finally, excreted in the urine. Ex. 1002
`
`¶ 28. In those with UCDs, the enzymes controlling the urea cycle are
`
`deficient, leading to high levels of ammonia in the blood and toxicity, brain
`
`damage, coma, and even death. See Ex. 1002 ¶ 29; Ex. 2006 ¶¶ 35–36.
`
`C.
`
`Asserted Grounds of Unpatentability
`
`Petitioner challenges the patentability of the ’966 patent claims 1–15
`
`as follows:
`
`
`
`Ground
`1
`
`Legal Basis
`35 U.S.C. § 102
`
`References
`’859 Publication2
`
`2
`
`35 U.S.C. § 103 Blau3, Simell4, and the ’859
`Publication
`
`Claims
`12, 14, and
`15
`1–15
`
`
`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
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`
`II.
`
`Analysis
`
`A. Ground 1
`
`Petitioner argues that claims 12, 14, and 15 would have been
`
`anticipated by the ’859 publication under 35 U.S.C. § 102. Pet. 18–21.
`
`Patent Owner does not present arguments to the contrary and
`
`represents that on June 28, 2017 it statutorily disclaimed claims 12, 14, and
`
`15 of the ’966 patent. Accordingly, Petitioner’s Ground 1 is moot and we do
`
`not institute a trial based on challenges to these claims. See 37 C.F.R.
`
`§ 42.107.
`
`B. Ground 2
`
`Petitioner argues that claims 1–15 would have been obvious under
`
`35 U.S.C. § 103 over Blau, Simell, and the ’859 publication. Pet. 22–42.
`
`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 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.
`
`Claim 1 of the ’966 patent recites:
`
`A method of treating a subject with a urea cycle disorder who
`has previously been administered an initial dosage of glyceryl tri-[4-
`phenylbutyrate] and who has a fasting plasma ammonia level less than
`
`
`
`6
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`the upper limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the subject;
`(b) comparing the fasting plasma ammonia level to the upper
`limit of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate] that is greater than the initial dosage if the fasting
`plasma ammonia level is greater than half the upper limit of normal
`for plasma ammonia level,
`wherein the upper limit of normal for plasma ammonia level is
`in the range of 26-64 µmol/L.
`
`Ex. 1003, 24:11–25.
`
`Independent claim 6 is similar to claim 1 but is directed to treating a
`
`“pediatric subject” and does not restrict the upper limit of normal to a
`
`specific range. Ex. 1003, 24:38–50. Independent claim 9 is almost identical
`
`to claim 6, but is directed to an “adult subject.” Ex. 1003, 24:57–25:2.
`
`For reasons that follow, based on the information presented in the
`
`Petition and Preliminary Response, we are persuaded that Petitioner is
`
`reasonably likely to prevail at trial on Ground 2.
`
`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. 15. The ’859 publication also
`
`teaches administering nitrogen scavenging drugs to adults and children. See
`
`Ex. 1007 ¶¶ 16 and 195. See Pet. 27. Furthermore, the ’859 publication
`
`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,
`
`232; see Pet. 24–25.
`
`
`
`7
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`The ’859 publication teaches comparing a patient’s plasma ammonia
`
`level to the upper limit of normal plasma ammonia level. Ex. 1007 ¶ 201
`
`see Pet. 16. The ’859 publication teaches that “plasma levels of ammonia
`
`are acceptable when they are at or below a level considered normal for the
`
`subject, and commonly this would mean plasma ammonia level is below
`
`about 40 µmol/L.” Ex. 1007 ¶ 94; see also id. ¶¶ 182, 226. See Pet. 30.
`
`The ’859 publication teaches increasing the dosage of nitrogen
`
`scavenging drugs when ammonia control is inadequate. See Ex. 1007 ¶¶ 91,
`
`92, 94–99; see Pet. 30–31. 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 identified as “between 26 to
`
`35 µmol/L.” Ex. 1007 ¶ 94; see also id. ¶ 201; see Pet. 30.
`
`Simell and Blau both teach measuring plasma ammonia levels after a
`
`fast. See Ex. 1005, abstract and 1117–18; Ex. 1006, 273 (Table 11.9); see
`
`Pet. 27–29.
`
`Exhibits 1010 and 1015 teach that measuring plasma ammonia is
`
`recommended after the patient has fasted. Ex. 1010, 4; Ex. 1015 at S11; see
`
`Pet. 28, n.4.
`
`Petitioner’s witness, Dr. Vaux, testifies that one 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. Ex. 1002 ¶ 134 (citing Ex. 1006, 268, Table 11.5; Ex. 1012, 213; Ex.
`
`1017, 164, Table II; Ex. 1016, S58, Ex. 1015, S19); see Pet. 33.
`
`Dr. Vaux testifies that
`
`
`
`8
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`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
`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.
`
`Ex. 1002 ¶ 122; see Pet. 26–27.
`
`Dr. Vaux testifies that because it was desired to maintain plasma
`
`ammonia at normal levels, but it was known that plasma ammonia levels
`
`vary due to time of day or eating:
`
`for a patient with fasting plasma ammonia levels approaching 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.
`
`Ex. 1002 ¶ 90; see also id. ¶ 134. See Pet. 33.
`
`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
`
`
`
`9
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`settings, HPN-100 doses well above the approved PBA dosage are expected
`
`to be beneficial . . . .” Id.; see also Ex. 1007 ¶ 203. See Pet. 18.
`
`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. See
`
`Ex. 1002 ¶ 29; see Pet. 7.
`
`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, including guidance on
`
`when to take plasma ammonia samples for measurement and guidance on
`
`choosing an effective dosage of nitrogen scavenging drug and how to adjust
`
`the dosage. See Pet. 22–23 (citing Ex. 1002 ¶¶ 114–117).
`
`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. 24–27. 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
`
`Pet. 24–33.
`
`Petitioner argues further that those of skill in the art would have had a
`
`reasonable expectation of success in combining the references to achieve the
`
`claimed method because the steps of the method are well-known and routine
`
`in the art and the claims do not require any particular efficacy. Pet. 34. In
`
`addition, Petitioner argues that the ordinary artisan would have had a
`
`
`
`10
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`reasonable expectation of success in combining the cited references to
`
`achieve the limitations of the claims because when HPN-100 was
`
`administered to subject 1006 in Example 3 of the ’859 publication, the
`
`subject demonstrated plasma ammonia levels of less than one half the upper
`
`limit of normal. Pet. 39 (citing Ex. 1007, table following ¶ 201); see also
`
`¶ 226.
`
`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
`
`we consider the claims to encompass adjusting drug dosage even when the
`
`subject’s plasma ammonia levels are only slightly less than the upper limit
`
`of normal.
`
`2.
`
`Patent Owner argues that Petitioner’s obviousness analysis depends
`
`on Dr. Vaux’s testimony, but because his testimony is contrary to the prior
`
`art and Dr. Vaux is not one of ordinary skill in the art, it is unsupported.
`
`Prelim. Resp. 12–14 and 26–30. 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
`
`
`
`11
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`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
`
`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 override application of Rule 37 C.F.R. § 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.
`
`
`
`12
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`
`Patent Owner also argues that a trial should not be instituted because
`
`an ordinarily skilled artisan would not have been motivated to increase the
`
`dosage of HPN-100 based on normal plasma ammonia levels, as recited in
`
`the preambles of independent claims 1, 6, and 9. Prelim. Resp. 17–30.
`
`According to Patent Owner, Petitioner fails to cite any single prior art
`
`reference suggesting a person or ordinary skill in the art should administer
`
`increased dosages of drug when a patient already has a normal plasma
`
`ammonia level or to target a plasma level within the range of normal values.
`
`Prelim. Resp. 17.
`
`At this point in the proceeding we are not persuaded that Petitioner is
`
`not reasonably likely to prevail because the challenges are based on
`
`obviousness. Petitioner need not show that a single reference expressly
`
`teaches increasing the dosage of HPN-100 as claimed in order to prevail. 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 because the prior art teaches that a
`
`goal of treatment for UCDs was to maintain plasma ammonia levels at or
`
`below a level considered to be normal. See Pet. 32–33 (citing Ex. 1002
`
`¶¶ 134, Ex. 1007 ¶¶ 83 and 94).
`
`Patent Owner cites to several references, including the
`
`’859 publication, the ’157 publication (Ex. 2012), Häberle (Ex. 2019), and
`
`Brusilow ’84 (Ex. 1004), to argue that the teachings in the prior art were to
`
`increase drug dosages only when plasma ammonia levels were above the
`
`upper limit of normal. Prelim. Resp. 20–22. At this point in the proceeding,
`
`these references are not persuasive because Dr. Vaux testifies that ordinarily
`
`
`
`13
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`skilled artisans would have considered it obvious to have increased drug
`
`dosages at plasma levels for reasons other than those reported in these
`
`references. See Ex. 1002 ¶ 122.
`
`Patent Owner characterizes the prior art as “teaching away” from the
`
`claimed methods because it establishes that normal plasma ammonia levels
`
`were acceptable and only addresses increasing the dosage of medication
`
`when levels were well above the upper limit of normal. Prelim. Resp. 17–
`
`18. For example, Patent Owner interprets paragraph 94 of the ’859
`
`publication as teaching that when levels were normal or below normal, no
`
`more drug would be required. Id. at 19. Patent Owner cites to other
`
`portions of the ’859 publication for similar teachings (see Ex. 1007 ¶ 85 (“a
`
`plasma ammonia level that was normal, e.g., a level of less than about 40
`
`µmol/L, or of not greater than 35 µmol/L, would indicate the treatment was
`
`effective.”)) and for teachings that drug levels should be increased when
`
`plasma ammonia levels are above normal (see Ex. 1007 ¶¶ 73, 83).
`
`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
`
`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
`
`reference, or would be led in a direction divergent from the path that was
`
`taken by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994).
`
`Patent Owner does not provide a sufficient explanation why teachings in the
`
`’859 publication that plasma levels are effective when within the normal
`
`range or to increase drug dosage when plasma ammonia levels are above
`
`normal would not necessarily discourage one of ordinary skill from
`
`increasing drug dosages at other plasma ammonia levels. Patent Owner has
`
`
`
`14
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`not cited to prior art that clearly discourages increasing drug dosages when
`
`plasma ammonia levels are anywhere 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,
`
`e.g. Prelim. Resp. 19–21 (citing Ex. 2012, Ex. 2019, Ex. 1004). Dr. Vaux’s
`
`testimony and the evidence he cites in support demonstrate that there was a
`
`reason to adjust drug dosage at lower plasma ammonia levels.
`
`We have considered Patent Owner’s arguments that the prior art
`
`taught possible side effects of too much nitrogen scavenging drugs but do
`
`not find them to be persuasive. See Prelim. Resp. 22–23 (citing Ex. 2013,
`
`2031, 2032). In light of the evidence that Petitioner cites regarding the
`
`relative safety of HPN-100, we are not persuaded by Patent Owner’s
`
`argument at this point in the proceeding. See Pet. 18 (citing Ex. 1007 ¶¶ 86
`
`and 203).
`
`Patent Owner argues that before the time of the invention described in
`
`the ’966 patent, those of ordinary skill in the art would have rejected the
`
`concept of a “baseline” ammonia level and would have considered increases
`
`to be too unreliable to be the basis for increasing drug dosages, especially
`
`when a patient was within normal plasma ammonia levels. Prelim.
`
`Resp. 23–24. We are not persuaded by this argument at this point in the
`
`proceeding because the claimed methods do not depend on the determination
`
`of a “baseline” plasma ammonia level. Instead, at this time, we credit
`
`Dr. Vaux’s testimony that one of ordinary skill in the art would have
`
`increased drug dosages when a patient’s plasma ammonia levels were
`
`approaching the upper limit of normal to prevent a patient from exceeding
`
`
`
`15
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`the upper limit of normal. Specifically, as discussed above, at this point in
`
`the proceeding, we are persuaded by Dr. Vaux’s testimony that 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 because this testimony is supported by the prior art.
`
`See Ex. ¶ 122; Ex. 1006, 268, Table 11.5; Ex. 1012, 213; Ex. 1017, 164,
`
`Table II; Ex. 1016, S58, Ex. 1015, S19.)
`
`Patent Owner also argues that variation in plasma ammonia levels
`
`would have indicated that plasma ammonia levels are an unreliable indicator
`
`of the effectiveness of an overall treatment program, not an indication to
`
`increase drug dosages. Prelim. Resp. 24–25 (citing Ex. 2006 ¶ 93, 101);
`
`Ex. 1012, 1006, 2012, 2015. At this point in the proceeding, we are
`
`persuaded that those of skill in the art would have relied on plasma ammonia
`
`levels, even if they would have relied on other indicators as well, because
`
`the ’859 publication teaches relying, at least in part, on plasma ammonia
`
`levels to adjust drug dosages. Ex. 1007 ¶¶ 88–92, 95–99, 107–108, 226,
`
`232; see Pet. 15–16. We note that the challenged claims employ the
`
`transitional term “comprising,” thus allowing for other determinations of
`
`drug dosage.
`
`Patent Owner also argues that Petitioner has failed to show that a
`
`person of ordinary skill in the art would have been motivated to combine the
`
`cited prior art because there are significant differences between them.
`
`Prelim. Resp. 30–35. At this point in the proceeding, we are not persuaded
`
`by Patent Owner’s arguments because Petitioner cites Simell and Blau for
`
`their teachings regarding measurement of ammonia levels after a patient has
`
`
`
`16
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`fasted, not for their teachings about drug dosing with particular drugs or for
`
`particular situations or conditions.
`
`Patent Owner argues that Petitioner has failed to establish a
`
`reasonable expectation of success in combining the references cited because
`
`Petitioner fails to show why the claimed method would be successful in
`
`treating UCDs, that is, in reducing the incidence and frequency of
`
`hyperammonemia. Prelim. Resp. 37–38. We are not persuaded by this
`
`argument at this point in the proceeding because the challenged claims do
`
`not require any specific degree of efficacy or treatment of any specific
`
`aspect of UCDs. As Petitioner notes, Example 3 of the ’859 publication
`
`demonstrates that administration of HPN-100 can lower plasma ammonia
`
`levels, a known treatment for UCDs. See Pet. 17–18 (citing Ex. 1007, table
`
`following ¶ 201).
`
`3.
`
`Claims 4, 7, 10, and 13 of the ’966 patent recite the additional method
`
`step wherein the measuring, comparing, and administering steps (a) to (c) of
`
`independent claims 1, 6, 9, and 12, respectively, are repeated until the
`
`subject exhibits a fasting plasma ammonia level at or below half the upper
`
`limit of normal for plasma ammonia level. See Ex. 1003, 24:32–35 (claim
`
`4), 24:51–54 (claim 7), 25:3–6 (claim 10), 26:7–10 (claim 13).
`
`Petitioner argues that these claims would have been obvious over the
`
`prior art, citing the knowledge that maintenance of plasma ammonia levels
`
`within the normal range was a goal of those in the art (see Pet. 38 (citing
`
`Ex. 1007 ¶¶ 83, 46, 74, 182, 209, 226, Ex. 1016, S58)) and the knowledge
`
`that plasma ammonia levels vary throughout the day (see Pet. 38–39 (citing
`
`Ex. 1006, 286, Table 11.5, Ex. 1015, S19)). Because, according to
`
`
`
`17
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`Dr. Vaux, it was also known that there is no minimum level of plasma
`
`ammonia required for normal body function (see Ex. 1002 ¶ 29) and HPN-
`
`100 was known to be well tolerated (see Ex. 1007 ¶ 226), Petitioner argues
`
`that it would have been obvious to repeat the steps of the independent claims
`
`of the ’966 patent until the fasting plasma ammonia level was at or below
`
`half the upper limit of normal for plasma ammonia level. Pet. 39.
`
`Based on this evidence, 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 baseline ammonia levels so that plasma
`
`ammonia could be maintained within normal levels, even after eating.
`
`Pet. 19–20.
`
`Patent Owner raises arguments similar to those against the challenges
`
`to the independent claims of the ’966 patent. For the reasons discussed
`
`above, based on the information presented in the Petition and Preliminary
`
`Response, we are persuaded that Petitioner is reasonably likely to prevail at
`
`trial on this ground.
`
`4.
`
` We are persuaded by the information presented in the Petition and
`
`Preliminary Response that there is a reasonable likelihood Petitioner will
`
`prevail on the challenges raised in Ground 2.
`
`III. CONCLUSION
`
`We are persuaded that there is a reasonable likelihood that Petitioner
`
`will prevail as to the unpatentability of claims 1–11 and 13 of Patent
`
`
`
`18
`
`
`
`Case IPR2017-01160
`Patent 9,326,966 B2
`
`Owner’s ’966 patent under 35 U.S.C. § 103(a) over Blau, Simell and the
`
`’859 publication.
`
`Our findings of fact and conclusions of law are based on the record
`
`developed thus far, prior to Patent Owner’s Response. This is not a final
`
`decision as to the patentability of any challenged claim. If a final decision is
`
`issued in this case, it will be based on the full record developed during trial.
`
`For the reasons given, it is
`
`IV. ORDER
`
`ORDERED that an inter partes review is instituted as to claims 1–11
`
`and 13 of Patent Owner’s ’966 patent under 35 U.S.C. § 103(a) over Blau,
`
`Simell, and the ’859 publication;
`
`FURTHER ORDERED that pursuant to 35 U.S.C. § 314(a), inter
`
`partes review of the ’966 Patent is hereby instituted commencing on the
`
`entry date of this Order, and pursuant to 35 U.S.C. § 314(c) and 37 C.F.R.
`
`§ 42.4, notice is hereby given of the institution of a trial.
`
`
`
`
`
`
`
`
`
`
`
`Petitioner:
`
`Elizabeth J. Holland
`Cynthia Lambert Ha
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
