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`571.272.7822
`
`Paper No. 42
`Filed: September 26, 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, INC.,
`Patent Owner.
`
`Case IPR2016 -00829
`Patent 9,095,559 B2
`
`Before TOM R. SCHEINER, LORA M. GREEN, and DEBORAH KATZ,
`Administrative Patent Judges.
`
`KATZ, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 and 37 C.F.R. § 42.73
`
`I. Introduction
`
`We instituted a trial under 35 U.S.C. § 314 to review challenges
`
`brought by Lupin Ltd. and Lupin Pharmaceuticals, Inc. ( "Lupin" or
`
`"Petitioner ") against claims 1 -15 of U.S. Patent No. 9,095,559 B2 (Ex.
`
`IDr. Gregory Enns
`April 23, 2018
`Exhibit No. 1028
`Megan F. Alvarez
`RPR, CSR No. 12470
`
`1 of 34
`
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`571.272.7822
`
`Paper No. 42
`Filed: September 26, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`LUPIN LTD. and LUPIN PHARMACEUTICALS, INC.,
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`
`Case IPR2016 -00829
`Patent 9,095,559 B2
`
`Before TOM R. SCHEINER, LORA M. GREEN, and DEBORAH KATZ,
`Administrative Patent Judges.
`
`KATZ, Administrative Patent Judge.
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318 and 37 C.F.R. § 42.73
`
`I. Introduction
`
`We instituted a trial under 35 U.S.C. § 314 to review challenges
`
`brought by Lupin Ltd. and Lupin Pharmaceuticals, Inc. ( "Lupin" or
`
`"Petitioner ") against claims 1 -15 of U.S. Patent No. 9,095,559 B2 (Ex.
`
`IDr. Gregory Enns
`April 23, 2018
`Exhibit No. 1028
`Megan F. Alvarez
`RPR, CSR No. 12470
`
`1 of 34
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`Patent 9,095,559 B2
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`1001) ( "the '559 patent ") in the Petition (Paper 3 ( "Pet. ")). See Paper 13
`
`(Institution Decision ( "DI ")).
`
`Horizon Therapeutics, Inc. ( "Horizon" or "Patent Owner ") filed a
`
`preliminary response under 37 C.F.R. § 42.107 (Paper 9 ( "Prelim. Resp. "))
`
`and a response under 37 C.F.R. § 42.120 (Paper 26 ( "PO Resp. ")) to Lupin's
`
`challenges and Lupin filed a Reply (Paper 31 ( "Reply ")).
`
`Lupin also filed a motion to exclude Horizon Exhibits 2019 and 2041
`
`(Paper 35). See also Patent Owner's Opposition to Petitioner's Motion to
`
`Exclude (Paper 37) and Petitioner's Reply in Support of Its Motion to
`
`Exclude Evidence (Paper 38). These exhibits are discussed in footnotes
`
`below.
`
`Horizon does not seek to amend its challenged claims under 37 C.F.R.
`
`§ 42.121.
`
`A hearing was held on July 28, 2017, and a transcript of the oral
`
`argument was made of record (Paper 41).
`
`We conclude that the challenged claims are unpatentable under 35
`
`U.S.C. § 103 over the cited prior art.
`
`A.
`
`Both Lupin and Horizon report that Horizon served Lupin with a
`
`complaint in the District Court for the District of New Jersey (Case No.
`
`1:15 -cv- 07624) alleging that Lupin infringed the '559 patent, as well other
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`related patents. Pet. 7; Prelim. Resp. 2.
`
`Lupin also reports that U.S. Patent No. 8,404,215, which issued from
`
`the parent application of the '559 patent, was the subject of IPR2015- 01127,
`
`filed by Par Pharmaceutical, Inc., and IPR2016- 00284, filed by Lupin, which
`
`was instituted and joined with the IPR2015 -01127 proceeding. The claims
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`2
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`challenged in that review are similar to the claims challenged in the present
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`review, wherein fasting blood ammonia levels are measured, compared to
`
`the upper limit of normal, and an adjusted dose of drug is administered if
`
`"the fasting blood ammonia level is greater than half the upper limit of
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`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.
`
`Lupin reports further that IPR2015 -01117 and IPR2016- 00283,
`
`involving Horizon's U.S. Patent 8,642,0121, were instituted and joined.
`
`That patent is not related by lineage to the '559 patent and it was held that
`
`Petitioner did not show that the challenged claims were unpatentable. See
`
`Par Pharm., Inc. v. Horizon Therapeutics, LLC, Case IPR2015 -01117
`
`(PTAB November 3, 2016) (Paper 53).
`
`We note that Lupin has recently filed petitions for review of the
`
`claims of U.S. Patent Nos. 9,254,278 and 9,326,966 (IPR2017 -01159 and
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`IPR2017- 01160, respectively), which are related as being issued from
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`continuations of the application from the currently challenged '559 patent.
`
`In addition, on July 13, 2017, Par Pharmaceutical, Inc. filed petitions
`
`for review of U.S. Patent Nos. 9,095,559, 9,254,278, and 9,326,966
`
`(IPR2017- 01768, IPR2017- 01767, and IPR2017- 01769, respectively).
`
`Decisions on whether to institute trial based on these pending petitions
`
`has not yet been issued.
`
`1 The application that became U.S. Patent 8,642,012 was published as U.S.
`Patent Publication 2010/0008859, which was cited as prior art in Petitioner's
`challenges. See Ex. 1007.
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`B.
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`The claims of the '559 patent are directed to methods of using a drug,
`
`glyceryl tri -[4- phenylbutryate] ( "HPN- 100 "), to treat subjects with urea
`
`cycle disorders. Individuals suffering from urea cycle disorders ( "UCDs ")
`
`are unable to remove excess nitrogen waste, which is normally excreted in
`
`the urine. Ex. 1002 If 30; Ex. 2006 IN 31 -32. 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. 100241131; Ex.
`
`2006 ¶ 31. In individuals with UCDs, the enzymes controlling the urea
`
`cycle are deficient, leading to high levels of ammonia in the blood. Ex. 1002
`
`If 32; Ex. 2006 ¶¶ 32 -33. This accumulation of ammonia at high
`
`concentrations in the body is toxic. Ex. 1002 ¶ 32; Ex. 2006 1133. Patent
`
`Owner's witness, Dr. Gregory M. Enns2, testifies that "[i]ncreased blood
`
`ammonia levels manifest mainly as central nervous system dysfunctions
`
`such as stupor, convulsions, and coma." Ex. 2006 1133.
`
`The claims of the '599 patent are directed to methods wherein HPN-
`
`100 is administered at an initial or increased dose when a patient's fasting
`
`2 Dr. Enns testifies that he is a Professor at the Stanford University School of
`Medicine. Ex. 2006 If 8. Dr. Enns also testifies that he is Board Certified in
`Clinical Genetics and Clinical Biochemical Genetics by the American Board
`of Medical Genetics and Genomics. Ex. 2006 IF 7. Dr. Enns testifies that he
`has cared for approximately 70 to 100 UCD patients over the course of his
`career and that for the UCD patients he manages he prescribes nitrogen
`scavenging medications on nearly all patients who have not undergone liver
`transplantation. Ex. 2006 If 11. To manage the care of his patients, Dr. Enns
`testifies that he adjusts the dose of nitrogen scavenging medication as well
`as tailors dietary treatment and provides emergency management. Ex. 2006
`If 11. We find Dr. Enns to be qualified to provide opinions on the subject
`matter at issue.
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`plasma ammonia level is less than the upper limit of the normal range for
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`ammonia, but greater than half that upper limit.
`
`Claim 1 of the '559 patent is representative of the claims challenged
`
`in Petitioner's Ground 1 and 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.
`
`Ex. 1001, 24:28 -39 (emphasis added). Independent claim 2, the only other
`
`independent claim challenged in Ground 1, is similar to claim 1, differing in
`
`the preamble among other small differences.
`
`Claim 3 is challenged in Petitioner's Ground 2 and recites:
`
`A method of administering glyceryl tri- [4-
`phenylbutyrate] to a subject having a urea cycle disorder, the
`method comprising:
`(a) measuring a first fasting plasma ammonia level for
`the subject:
`(b) comparing the first fasting plasma ammonia level to
`the upper limit of normal for plasma ammonia level; and
`(c) administering an initial dosage of glyceryl tri-[4-
`phenylbutyrate] to the subject if the fasting plasma ammonia
`level is greater than half the upper limit of normal for plasma
`ammonia level and less than the upper limit of normal for
`plasma ammonia level.
`
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`Ex. 1001 at 24:49 -60. Claim 3 requires administering an initial dosage of
`
`HPN -100 to a subject if the fasting plasma ammonia level is greater than
`
`half, but less than the upper limit of normal for plasma ammonia.
`
`C.
`
`We instituted trial on the grounds of unpatentability asserted by
`
`Petitioner. Both grounds were on the basis of obviousness under 35 U.S.C.
`
`§ 103 and are as follows:
`
`Ground
`
`1
`
`2
`
`Claims
`References
`Blau (Ex. 1006)3, Simell (Ex. 1005)4, and 1, 2, 4, 5, 7 -10,
`12, and 13
`the '859 Publication (Ex. 1007)5
`3, 6, 11, 14, and
`Blau, Simell, the '859 publication, and
`Brusilow '84 (Ex. 1004)6
`15
`
`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.
`
`3 PHYSICIAN'S GUIDE TO THE LABORATORY DIAGNOSIS OF METABOLIC
`DISEASES, 261 -76 (Nenad Blau et al. eds., 2d ed. 1996).
`4 Simell et al., Waste Nitrogen Excretion Via Amino Acid Acylation:
`Benzoate and Phenylacetate in Lysinuric Protein Intolerance, 20 PEDIATRIC
`RESEARCH 1117 -21 (1986).
`5 U.S. Patent Publication 2010/0008859 Al was filed on January 7, 2009,
`and published on January 14, 2010.
`6 Brusilow et al., Treatment of Episodic Hyperammonemia in Children with
`Inborn Errors of Urea Synthesis, 310 THE NEW ENGLAND JOURNAL OF
`MEDICINE 1630 -34 (1984).
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`6
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`The Supreme Court explains 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. See KSR Intl Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
`
`To determine obviousness,
`
`[o]ften, it will be necessary for a court to look to interrelated teachings
`of multiple patents; the effects of demands known to the design
`community or present in the marketplace; and the background
`knowledge possessed by a person having ordinary skill in the art, all
`in order to determine whether there was an apparent reason to
`combine the known elements in the fashion claimed by the patent at
`issue. To facilitate review, this analysis should be made explicit... .
`As our precedents make clear, however, the analysis need not seek out
`precise teachings directed to the specific subject matter of the
`challenged claim, for a court can take account of the inferences and
`creative steps that a person of ordinary skill in the art would employ.
`
`Id. at 418. We analyze the evidence presented by Petitioner and Patent
`
`Owner in light of the Supreme Court's guidance.
`
`A.
`
`The following findings of fact, like others in this opinion, are
`
`supported by a preponderance of the evidence.
`
`Petitioner points to the '859 publication for its teaching that nitrogen
`
`scavenging drugs, including HPN -100, were known to treat UCDs. See Pet.
`
`22 -23; Ex. 1007 IN 88 -91, 95 -99, 107 -108, 226, and 232; Ex. 1002 ¶ 53.
`
`The '859 publication provides that HPN -100 is a phenylbutyric acid
`
`( "PBA ") pro -drug of choice for individual management of patients with
`these disorders. Ex. 1007 If 108; see Pet. 21 -22 (citing Ex. 1002 If 53). The
`
`'859 publication also teaches that increased dosages of nitrogen scavenging
`
`drugs could be used to control plasma ammonia levels. Ex. 1007 ¶ 83; see
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`Pet. 21 -22. Thus, we agree with Petitioner and find that those of skill in the
`
`are would have known to use the drug recited in the challenged claims to
`
`treat subjects with a UCD.
`Petitioner also cites to the '859 publication for its teaching that
`
`measuring plasma or blood levels of ammonia was known to be useful for
`
`determining the effectiveness of the overall drug and dietary regimen for a
`
`particular patient. Ex. 1007 ¶¶ 88 -91; see Pet. 22, citing Ex. 1002 ¶ 53.
`
`Specifically, the '859 publication teaches
`The plasma or blood level of ammonia is optionally also
`determined, in addition to measuring urinary PAGN, to assess
`the effectiveness of the overall drug and dietary regimen for a
`particular patient. If the ammonia control is inadequate, the
`dosage of the nitrogen scavenging drug may need to be
`increased if that can be done, or the patient's dietary protein
`intake can be decreased if that is feasible.
`
`Ex. 1007 ¶ 83. Furthermore, the '859 publication teaches a method of
`
`individually adjusting the dose of a nitrogen scavenging drug, including
`
`HPN -100, for a patient who had previously been treated with a drug,
`
`including a) administering drug, b) measuring the amount of nitrogen waste
`
`excreted, and
`c) optionally measuring blood ammonia to determine if the
`initial dosage is sufficient to control blood ammonia levels, or
`to establish a suitable average ammonia level: and
`
`d) adjusting the initial dosage of the new drug as needed to
`provide an adjusted dosage based upon ammonia control,
`dietary protein, and the amount of total waste nitrogen excreted
`by the patient.
`
`The level of ordinary skill in the art is discussed on pages 14 -15.
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`Ex. 1007 IN 95 -99. See also id. at ¶ 226 ( "The physician may also monitor
`the plasma ammonia levels and dietary protein intake in the patient to
`
`ascertain whether the patient's dietary protein intake and drug treatment
`
`combined are producing the appropriate therapeutic effect ") and If 232
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`( "Subsequent dose adjustment would be based on repeated measurement of
`
`urinary PAGN as well as assessment of dietary protein and plasma
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`ammonia. "). See Pet. 22 -23, citing Ex. 1002 If 53. From these teachings,
`
`we agree with the Petitioner and find that the '859 publication teaches using
`
`plasma ammonia levels to make adjustments in nitrogen scavenging drug
`
`levels.
`
`Petitioner also argues that the '859 publication indicates that
`
`maintaining stable plasma ammonia levels is desirable. For example,
`
`Petitioner cites to the teaching in the '859 publication that "when the subject
`
`is treated with the prodrug, which can be HPN -100, the subject will typically
`
`achieve and maintain normal plasma ammonia levels." Ex. 1007 If 182; see
`
`Reply 3. Similarly, the '859 publication teaches that only 2 -3 doses of
`
`HPN -100 can provide "a stable level of plasma ammonia," and compares
`
`this number to the 3 -6 doses necessary with a different drug, PBA. See Ex.
`
`1007 ¶ 46; Reply 3. From these teachings, we agree with the Petitioner and
`
`find that maintenance of normal plasma ammonia levels was a goal for those
`
`of ordinary skill in the art.
`
`The '859 publication discusses normal plasma ammonia levels. For
`
`example, the '859 publication teaches
`
`that for patients having ammonia levels above about 40 µmol /L
`when treated with sodium PBA, HPN -100 at equimolar dosages
`provided superior control of ammonia, and consistently reduced
`ammonia levels to below about 40 µmol /L. Thus for patients
`whose ammonia levels are abnormal (e.g. above about 40
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`µmol /L) when treated with sodium PBA, it is expected that
`better ammonia control can be achieved with an equimolar
`amount of HPN -100.
`
`Ex. 1007 ¶ 209; see Pet. 18. Similarly, 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 1194. See Pet. 18; see
`
`also Ex. 1007 ¶ 226 ( "Dietary protein intake or drug dosage or both could be
`
`adjusted to attain a normal or desired plasma ammonia level, e.g., a level
`
`below about 40 µmol /L. "). Based on these teachings we agree with
`
`Petitioner and find that those of ordinary skill in the art knew plasma
`
`ammonia levels below a level considered to be normal were acceptable, even
`
`desirable.
`
`The '859 publication refers to plasma ammonia levels at the upper
`
`limits of normal, stating that "[i]n certain clinical tests described herein the
`
`upper limit of normal for the subjects was between 26 and 35 µmol /L, and it
`
`is recognized in the art that a normal ammonia level will vary depending
`upon exactly how it is measured ...." Ex. 1007 IT 94. Elsewhere, the '859
`
`publication provides that a normal plasma ammonia level is "a level of less
`
`than about 40 µmol /L, or of not greater than 35 µmol /L ...." Ex. 1007
`
`if 85; see PO Resp. 16 -17. These teachings indicate to us that recitation of
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`specific plasma ammonia levels are not necessarily useful in determining the
`
`upper limit of normal because reported plasma ammonia levels may vary
`
`depending on how they are measured.
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`Nevertheless, 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. 10; PO Resp. 21. We determine that the plain meaning and
`
`the broadest reasonable interpretation of the claim term "less than the upper
`
`limit of normal" is 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).
`
`We also find, from the statement "a plasma ammonia level of less
`
`than about 40 µmol /L, or of not greater than 35 µmol /L would indicate the
`
`treatment was effective" (Ex. 1007 If 74; see also id. ¶ 85), that treatment
`
`would be considered effective by those in the art when plasma ammonia
`
`levels are below a level considered to be the upper limit of normal.
`
`In summary, the '859 publication teaches that those of skill in the art
`
`would have known to use HPN -100 to treat subjects with UCDs. It also
`
`teaches that measuring plasma or blood level of ammonia was known to be
`
`useful in determining the effectiveness of a drug regimen for a particular
`
`patient and that measuring blood ammonia was a known step in adjusting
`
`drug dosages. The '859 publication teaches that maintaining normal plasma
`
`ammonia levels was desirable in the art. Although specific measurements of
`
`s Patent Owner notes that the parties do not dispute the meaning of any of
`the claim terms. PO Resp. 2. Because the meaning of the terms in the
`challenged claims are evident from their ordinary meaning and not
`controversial, we need not provide a separate analysis of them. See
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011)
`( "claim terms need only be construed `to the extent necessary to resolve the
`controversy.' Vivid Techs., Inc. v. Am. Sci. & Eng'g, Inc., 200 F.3d 795, 803
`(Fed. Cir. 1999). ").
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`plasma ammonia do not necessarily indicate the upper limit of normal
`
`consistently across different ways of measuring it, the '859 publication
`
`teaches that treatment would have been considered to be effective when
`
`plasma ammonia levels were less than what is determined to be the upper
`
`limit of normal in a given case.
`
`In addition to the ' 859 publication, Petitioner relies on Blau and
`
`Simell for the teaching to collect blood from UCD patients after a fast in
`
`order to measure plasma ammonia levels. Ex. 1006 at 273 (Table 11.9); Ex.
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`1005 at 1118; see Pet. 25 -26 (citing Ex. 1002 IN 58, 59); see also id. 1002
`
`If 46, n.2 (citing Ex. 1015 at S11). Anticipating Patent Owner's argument
`
`that Blau relates to diagnosis not treatment of UCDs, Petitioner also cites to
`
`Exhibits 1010 and 1015 as evidence that it was generally recommended to
`
`measure plasma ammonia after a fast. See Pet. 16, n.2. Exhibit 1010 is a
`
`"Lab Update" about measurement in ammonia in blood, and Exhibit 1015 is
`
`a publication entitled "Measurement of ammonia in blood." Both state that
`
`most methods recommend collecting a sample from patients who have fasted
`
`for at least 6 hours. See Ex. 1010, 4; Ex. 1015, 1. From this evidence, we
`
`agree with Petitioner that those of skill in the art would have known that
`
`measuring fasting serum ammonia levels, as taught in at least Simell and
`
`Blau, was known to be useful with the methods taught in the '859
`
`publication.
`
`In regard to Ground 2, which challenges claim 3 and the claims that
`
`depend on it, Petitioner cites Brusilow ' 84 for its teaching of measuring a
`
`patient's fasting plasma ammonia level when he or she is admitted,
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`presumably to a hospital, and, in response to elevated levels, treating with
`
`the nitrogen scavenging drugs sodium benzoate and phenylacetate. See Pet.
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`35-36, citing Ex. 1004 at 1631; see Ex. 1002 ¶ 77. We agree with Petitioner
`
`and find that Brusilow ' 84 teaches it was known to initiate drug therapy
`
`when a patient presented with plasma ammonia levels above the upper limit
`
`of normal. Pet. 39-41, citing Ex. 1002 ¶ 83.
`
`B.
`
`Petitioner also relies on the testimony of Dr. Vaux to demonstrate the
`
`obviousness of the challenged claims. Dr. Vaux testifies that the objective
`
`of therapy with nitrogen scavenging drugs was known to be maintenance of
`
`ammonia levels within normal limits. Ex. 1002 ¶ 54; see Pet. 24. This
`
`testimony is reflected in the prior art, which teaches: "The goal of treatment
`
`is to maintain normal levels of plasma ammonia through the use of low
`
`protein diet and medication while allowing for normal growth." Ex. 1016 at
`
`S58.
`
`Petitioner also relies on Dr. Vaux's testimony that ammonia levels
`
`were known to vary during the day, for example after eating or because of
`
`the time. See Pet. 24 -25, citing Ex. 1002 1155. We credit Dr. Vaux's
`
`testimony on this issue because it is supported by the prior art. Specifically,
`
`the prior art teaches that "postprandial" ammonia levels were known to be
`
`"30 -60 tmol /L higher depending on time and N load." Ex. 1006, 268, Table
`
`11.5; see Ex. 1002 IT 55. Similarly, it was reported in the prior art that the
`
`circadian rhythm has an effect on plasma ammonia levels. Ex. 1012, 213,
`
`abstract. See also Ex. 1017, 164, Table II (providing plasma ammonia levels
`
`after protein ingestion at different hours after protein load) and Ex. 1016 at
`
`S58.
`
`In light of this knowledge, Dr. Vaux testifies:
`
`In order to maintain plasma ammonia levels within normal
`limits, a person of ordinary skill in the art would have been
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`motivated to administer more drug to reduce the ammonia
`levels, even in cases where the fasting plasma ammonia level
`was above half the ULN but below the ULN. A person of
`ordinary skill in the art would have been motivated to maintain
`a patient at normal plasma ammonia levels, and would have
`known that variation of ammonia levels due to time of day
`and /or ingestion of food would risk taking the patient outside of
`normal levels. (Ex. 1006 at 268, Table 11.5.) For example, for
`a patient with fasting plasma ammonia levels 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 ¶ 55 (emphasis added); see also id. ¶¶ 51, 65; Pet. 24 -25, 28 -29.
`
`Dr. Vaux's testimony indicates there would have been a reason for those of
`
`ordinary skill in the art to have modified prior art methods of increasing
`
`nitrogen scavenging drug dosage when a patient's plasma ammonia levels
`
`were approaching the upper limit of normal but had not yet exceeded it.
`
`According to Dr. Vaux, those of ordinary skill in the art would have
`
`understood that increasing the dosage would maintain ammonia levels in the
`
`normal range after a meal or when influenced by daily rhythms.
`
`Patent Owner argues that Dr. Vaux's testimony should be given little
`
`weight because Dr. Vaux is not board certified in clinical genetics or clinical
`
`biochemical genetics and has not published or spoken publicly about the
`
`treatment of UCDs. According to Patent Owner, Dr. Vaux is not qualified
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`as one of ordinary skill in the art on the subject matter of this review. PO
`
`Resp. 20, 36.
`
`Patent Owner and Petitioner define a person of ordinary skill in the art
`
`as having similar qualifications (compare Pet. 8 -9, citing Ex. 1002 if 19 with
`
`PO Resp. 15 -16, citing Ex. 2006 ¶ 26), but Patent Owner argues that the
`
`ordinarily skilled artisan must additionally have "at least three years of
`
`residency /fellowship training in Medical Genetics, including Biochemical
`
`Genetics, followed by certification in Clinical Genetics and Clinical
`
`Biochemical Genetics by the American Board of Medical Genetics and
`
`Genomics." PO Resp. 15 -16, citing Ex. 2006 If 26. We agree with the
`
`qualifications on which the parties agree and find that one of ordinary skill
`
`in the art would have an M.D. or equivalent degree, with a residency and
`
`specialized training in the diagnosis or treatment of inherited metabolic
`
`disorders, such as UCDs and other nitrogen retention disorders. See Pet. 8-
`
`9; PO Resp. 15 -16. We also agree with Patent Owner that one of ordinary
`
`skill in the art would have experience treating patients with nitrogen
`
`retention disorders, including UCDs. See PO Resp. 16.
`
`We are not persuaded by Patent Owner's argument that the lack of
`
`specific residency /fellowship training or certification, disqualifies Dr. Vaux
`
`from providing opinion testimony on the motivations, understandings, and
`
`actions of those of ordinary skill in the art. Dr. Vaux testifies that he is "a
`
`medical doctor with specialty training in Pediatrics and Clinical Genetics"
`
`and is currently Professor and Clinical Chief of the Division of Medical
`
`Genetics in the Department of Medicine at UC San Diego. Ex. 1002 If 1.
`
`He also testifies:
`
`Since 1994, I have regularly diagnosed and treated patients with
`urea cycle disorders ( "UCD "), and continue to do so today. In
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`treating UCD patients, I regularly prescribe nitrogen scavenging
`drugs and treat patients who are maintained on therapy with
`nitrogen scavenging drugs.
`
`Ex. 1002 ¶ 1. Thus, Dr. Vaux has actually treated UCD patients for at least
`
`five years (a requirement recited by Patent Owner, see PO Resp. 16),
`
`including prescribing drugs. Patent Owner does not direct us to evidence
`
`that Dr. Vaux's testimony is untruthful or that his treatment of UCD patients
`
`is ineffective, indicating that he does not understand how to treat them.
`
`Accordingly, even if Dr. Vaux does not have the specialized certificates or
`
`particular training that Patent Owner argues are necessary, he has done the
`
`job for over twenty years of one who would carry out the claimed methods.
`
`We consider this experience more relevant than certificates or training.
`
`Thus, we determine that Dr. Vaux is qualified to provide opinions about the
`
`motivations, understandings, and actions of one of ordinary skill in the art.
`
`C.
`
`Even if Dr. Vaux were not qualified as one of ordinary skill in the art
`
`about the subject matter of this proceeding, we still would accord weight to
`
`his testimony because we find it to be supported by the prior art. For
`
`example, despite Patent Owner's arguments that "no support exists for Dr.
`
`Vaux's contention that a goal of nitrogen scavenging therapy is to maintain a
`
`stable plasma ammonia level" (see PO Resp. 34), the '859 publication
`
`teaches that when treating with HPN -100 "the subject will typically achieve
`
`and maintain normal plasma ammonia levels." Ex. 1007 ¶ 182. Similarly,
`
`Berry (Ex. 1016) cited by Dr. Vaux, teaches that "[t]he goal of treatment is
`
`to maintain normal levels of plasma ammonia through the use of low -protein
`
`diet and medication while allowing for normal growth." Ex. 1016, S58. We
`
`find that these prior art references support Dr. Vaux's testimony that
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`"[m]aintenance of plasma ammonia levels within normal limits is one of the
`
`objectives of therapy with nitrogen scavenging drugs." Ex. 1002 ¶ 54. We
`
`note that even Dr. Enns, Patent Owner's witness, testifies that "a number of
`
`references repeat the idea that the goal is to maintain plasma ammonia
`
`within normal limits." Ex. 2006 ¶ 114, citing Ex. 1020 at 3328; Ex. 1016 at
`
`S58; Ex. 2021 at 33.
`
`Patent Owner argues that Dr. Vaux's testimony is not supported
`
`because "the prior art does not state that the goal of maintaining a normal
`
`plasma ammonia level means staying within normal during the entire course
`
`of every day." PO Resp. 34. We disagree that this accurately characterizes
`
`Dr. Vaux's testimony or that the invention as recited in the'559 patent
`
`claims would have been obvious only if skilled artisans had a goal of
`
`constant maintenance throughout the "entire course of every day." Instead,
`
`the challenged claims merely recite administering an adjusted dosage of
`
`drug.
`
`We are also not persuaded by Dr. Enns's testimony that the known
`
`variability in plasma ammonia levels made it too difficult to try to achieve
`
`stability in plasma ammonia levels when treating UCDs. PO Resp. 34,
`
`citing Ex. 2006 ¶¶ 41, 43, 86 -87. Because the prior art expressly provides
`
`for a goal of maintaining normal levels of plasma ammonia at least in part
`
`with medication (see Ex. 1016, S58), we are not persuaded that Dr. Vaux's
`
`testimony lacks support.
`
`Patent Owner argues further that there is no support for Dr. Vaux's
`
`assumption that a physician would have taken any action when a patient had
`
`a normal plasma ammonia level or that the action would have been to
`
`increase drug dosage. PO Resp. 34, citing Ex. 2006 ¶¶ 86 -87; see also PO
`
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`Resp. 39 -41 (citing Ex. 2006 If 13 -14). We disagree because the '859
`
`publication teaches that "plasma levels of ammonia are acceptable when
`they are at or below a level considered normal for the subject ...." Ex.
`
`1007 If 94. Thus, the '859 publication teaches that a known goal of
`
`treatment is plasma levels that are below normal, not just below the upper
`
`limit of normal.
`
`Patent Owner argues that the prior art teaches only adjusting drug
`
`dosages when plasma ammonia levels are far above the upper limit of
`
`normal, not within the normal range, citing several references in support. PO
`
`Resp. 38-46. For example, Patent Owner cites to Brusilow '84 (Ex. 1004)
`
`to show that ordinarily skilled artisans were concerned only when plasma
`
`ammonia levels were three times normal or higher. PO Resp. 41 (citing Ex.
`
`1004, 1631 and Ex. 2006 If 67 -68). We do not consider Brusilow '84 to
`
`support Patent Owner's argument because treatment of one or several
`
`patients with high plasma levels of ammonia does not indicate skilled
`
`artisans would always wait until plasma ammonia reached those levels.
`
`Patent Owner also cites to Berry (Ex. 1016) for its discussion of
`
`adjusting the dose of nitrogen scavenging drugs only when plasma ammonia
`
`levels are more than three times the upper range of normal. PO Resp. 43
`
`(citing Ex. 1016, S58 -S59); Ex. 2006 IN 80, 114, and 119. The portion of
`
`Berry cited by Patent Owner, though, refers to prophylactic treatment when
`
`a patient is ill and therefore may not be indicative of all dosing decisions.
`
`See Reply 7 -8. In addition, Berry includes teachings to adjust drug dosage
`
`at plasma levels within the claimed range because it applies to any plasma
`
`level below three times the upper range of normal, a range that includes
`
`below the upper limit of normal. Reply 7 -8. Accordingly, we are not
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`persuaded, based on Berry's teachings, that those of ordinary skill in the art
`
`would not have had a reason to adjust drug dosage when plasma ammonia
`
`levels were below the upper limit of normal.
`
`For similar reasons, we are not persuaded by Patent Owner's citations
`
`to Batshaw (Ex. 2009), Feillet (Ex. 2018), and Barsotti (Ex. 1015). See PO
`
`Resp. 44 (citing Ex. 2006 ¶¶ 116, 119). Batshaw states: "The aim of long-
`
`term therapy has been to maintain metabolic control with plasma ammonia
`concentrations less than twi
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