Paper No. 10
`
`
`
`
`
`Trials@uspto.gov
`571.272.7822 Filed: January 30, 2018
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioners,
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner.
`____________
`
`Case IPR2017-01768
`Patent 9,095,559 B2
`____________
`
`
`
`Before TONI R. SCHEINER, LORA M. GREEN, and DEBORAH KATZ,
`Administrative Patent Judges.
`
`KATZ, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`I. Introduction
`Par Pharmaceutical, Inc. (“Petitioner”) filed a request for an inter
`partes review (“IPR”) of claims 1–15 of U.S. Patent No. 9,095,559 B2
`(Ex. 1001 (“the ’559 patent”) (Paper 3 (“Pet.”)). Horizon Therapeutics, LLC
`(“Patent Owner”) filed a Preliminary Response (Paper 7 (“Prelim. Resp.”)).
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`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 challenges
`of at least claims 1 and 3. Therefore, we exercise our discretion to institute
`review of all the challenged claims.
`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.
`The ’559 Patent (Ex. 1001)
`The claims of the ’559 patent are directed to methods of using a drug,
`glyceryl tri-[4-phenylbutyrate] (also called “GPB” or “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 ¶ 30. 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 urine. See id. ¶ 31.
`In subjects with UCDs, the enzymes controlling the urea cycle are
`deficient, leading to high, toxic levels of ammonia in the blood and possibly
`brain damage, coma, or death. See id. ¶ 32; Ex. 2006 ¶¶ 36–37. To
`ameliorate the deficiency of enzymes, GPB and other so-called “nitrogen
`scavenging drugs” are administered and converted in the body to a
`compound that binds nitrogen and allows it to be excreted. Ex. 1002 ¶¶ 33–
`34; Ex. 2006 ¶¶ 42–43. Patent Owner does not dispute that GPB was a
`
` 
`
`2
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`known nitrogen scavenging drug before 2011, when the applications cited as
`priority documents for the ’278 patent were filed.
`The ’559 patent claims methods related to treating a subject with a
`UCD, taking into consideration the level of ammonia in his or her blood
`(plasma) and comparing this level to the half of the “upper limit of normal”
`for plasma ammonia.
`
`Related proceedings
`B.
`The challenged ’559 patent is part of a family of patents involved in
`litigations and other inter partes reviews. The parent of the application that
`became the ’559 patent issued as patent 8,404,215. A continuation
`application filed from the application that became the ’559 patent was issued
`as patent 9,254,278. Furthermore, a continuation of the application that
`became the ’278 patent issued as patent 9,326,966. Each of these patents
`claims methods regarding dosing of GPB by comparison of plasma ammonia
`levels with the upper limit of normal. Each of these patents is or was the
`subject of a petition for inter partes reviews filed by either Par, the
`Petitioner in this case, or Lupin Ltd. and Lupin Pharmaceuticals Inc.
`(“Lupin”). A summary of these proceedings follows.
`Patent
`Proceeding
`Petitioner
`Status
`Final Decision – all claims
`Lupin
`9,095,559
`IPR2016-00829
`unpatentable (September
`
`
`26, 2017, Paper 42); Notice
`
`
`of appeal to Federal Circuit
`
`
`filed (November 22, 2017,
`
`
`Paper 43)
`
`
`
`IPR2017-01159
`
`
`IPR2017-01767
`
`9,254,278
`
`Lupin
`
`
`Par
`
`Trial instituted (September
`28, 2017, Paper 10)
`
`
` 
`
`3
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`8,404,215
`
`9,326,966
`
`IPR2015-01127
`
`
`
`IPR2016-00284
`
`IPR2017-01160
`
`
`IPR2017-01769
`
`Par
`
`
`
`Lupin
`
`Lupin
`
`
`Par
`
`Trial instituted (January 30,
`2018, Paper 10)
`
`Final Decision – all claims
`unpatentable (September
`29, 2016, Paper 49)
`
`Joined with IPR2015-01127
`
`Trial instituted (September
`28, 2017, Paper 10)
`
`Trial instituted (January 30,
`2018, Paper 10)
`
`
`
`We note that patent 8,642,012 is not related by lineage to the currently
`challenged ’278 patent, but the publication of the application from which it
`issued (publication 2010/0008859 (Ex. 1004)) 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. See IPR2015-01117
`(PTAB November 3, 2016) (Paper 53). That decision has been appealed to
`the Court of Appeals for the Federal Circuit (App. No.
`2017-1451).1
`In addition, the following infringement suits in the District of New
`Jersey have been reported as related to this proceeding (see Pet. 11):
`
`                                                            
`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 was
`reportedly stayed pending the resolution Appeal No. 2017-1451 to the
`Federal Circuit. See IPR2017-01159, Paper 5 at 4.  
`4
`
` 
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`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
`Oct. 19, 2015, asserting 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,
`asserting infringement of the ’278 patent and the ’966 patent is also related.
`In addition, patent application 15/457,643, filed March 13, 2017, is
`related as a continuation of the application that issued as the ’559 patent.
`C. Asserted Grounds of Unpatentability
`Petitioner challenges all of the claims of the ’559 patent under four
`grounds as follows:
`Ground
`1
`
`References
`Fernandes (Ex. 1015)2 in view of the
`’859 Publication (Ex. 1004)3 optionally
`in view of Blau (Ex. 1006)4, Simell (Ex.
`1007)5 and/or Lee (Ex. 1010)6
`
`Claims
`1, 2, 4, 7–10, 12,
`and 13
`
`                                                            
`2 INBORN METABOLIC DISEASES DIAGNOSIS AND TREATMENT, 214–22 (John
`Fernandes et al., eds., 3d ed. 2002) (Ex. 1015). 
`3 U.S. Patent Publication 2010/0008859 A1, filed January 7, 2009, published
`January 14, 2010 (Ex. 1004). 
`4 PHYSICIAN’S GUIDE TO THE LABORATORY DIAGNOSIS OF METABOLIC
`DISEASES, 261–76 (Nenad Blau et al. eds., 2d ed. 1996) (Ex. 1006). 
`5 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. 1007). 
`6 Brendan Lee et al., Phase 2 comparison of a novel ammonia scavenging
`agent with sodium phenylbutyrate in patients with urea cycle disorders:
`Safety, pharmacokinetics and ammonia control, 100 MOLECULAR GENETICS
`AND METABOLISM, 221–228 (2010) (Ex. 1010).
`5
`
` 
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`2
`
`3
`
`4
`
`
`
`Fernandes (Ex. 1015) in view of the ’859
`publication (Ex. 1004) and Lee (Ex.
`1010) or Lichter-Konecki (Ex. 1017)7,
`optionally in further view of Blau (Ex.
`1006) or Simell (Ex. 1007)
`The ’859 publication (Ex. 1004)
`optionally in view of Pandya (Ex. 1018)8
`and/or Lee (Ex. 1010)
`The ’859 publication (Ex. 1004) in view
`of Fernandes (Ex. 1015), optionally in
`further view of Pandya (Ex. 1018), Blau
`(Ex. 1006), Simell (Ex. 1007), and/or
`Lee (Ex. 1010)
`
`5
`
`3, 7–9, 11, 14
`
`6, 15
`
`II.
`Analysis
`Under 35 U.S.C. § 103(a), 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.
`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 Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007).
`
`
`                                                            
`7 Uta Lichter-Konecki et al., Ammonia Control in Children with Urea Cycle
`Disorders (UCDs): Phase 2 Comparison of Sodium Phenylbutyrate and
`Glycerol Phenylbutyrate, 103 MOLECULAR GENETICS AND METABOLISM,
`323–329 (2011) (Ex. 1017).
`8 A.L. Pandya et al., N-Acetylglutamate Synthetase Deficiency: Clinical and
`Laboratory Observations,”14 J. INHER. METAB. DIS. 685 (1991) (Ex. 1018).
`6
`
` 
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`A. Ground 1
`Petitioner argues that claim 1 is obvious under 35 U.S.C. § 103 over
`Fernandes (Ex. 1015) in view of the ’859 Publication (Ex. 1004) optionally
`in view of Blau (Ex. 1006), Simell (Ex. 1007), and/or Lee (Ex. 1010). See
`Pet. 27–46.
`Claim 1 of the ’559 patent 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, 24:21-35 (emphases added).
`Petitioner cites to Fernandes for its teaching that one of ordinary skill
`in the art would have known to measure plasma ammonia to determine how
`to adjust drug dosage because Fernandes teaches that “[t]he most important
`diagnostic test in urea cycle disorder is measurement of plasma ammonia
`concentration” (Ex. 1015, 217) and that “[a]ll treatment must be monitored
`with regular quantitative estimation of plasma ammonia and amino acids,
`paying particular attention to the concentration of glutamine and essential
`amino acids” (Ex. 1015, 219). See Pet. 30–31.
`Petitioner cites to Fernandes to demonstrate that it was known to
`increase drug dosage in patients with a plasma ammonia level below the
`
` 
`
`7
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`upper limit of normal. See Pet. 28, citing Ex. 1015, Fig. 17.2. Figure 17.2
`provides a flowchart with guidelines for the management of patients with
`UCDs. See Ex. 1015, 220. Under the guidance of Figure 17.2, medicine9
`can be increased when plasma ammonia levels are either above or below 80
`µmol/L, and if the glutamine level is above 1000 µmol/L. Because Figure
`17.2 does not set a limit below which one should not increase medicine, at
`this point in the proceeding, we understand that Figure to provide guidance
`for increasing medicine at potentially any level of plasma ammonia, even
`levels below the upper limit of normal.
`Petitioner also cites to Figure 2 of Lee as teaching the administration
`of GPB when a subject’s fasting plasma ammonia level is greater than half
`the upper limit of normal. See Pet. 35–37. The graph in Figure 2 of Lee
`shows that when GPB was administered at time 0 a mean plasma ammonia
`level was approximately 25 µmol/L – below the upper limit of normal of
`26–35 µmol/L reported in Lee, but above half that limit. See Ex. 1010, Fig.
`2 and 224); see Pet. 36.
`Petitioner cites to the ’859 publication for its teaching that GPB
`dosing can be increased to cover an increase in dietary protein. See Pet. 39,
`citing Ex. 1004 ¶ 234. The ’859 publication states that this adjustment
`would be based on urinary PAGN excretion, but elsewhere the ’859
`publication teaches that after a patient is judged to be adequately controlled
`
`                                                            
`9 Fernandes teaches adjusting dosages of sodium benzoate and sodium
`phenylbutyrate to treat UCD patients. Pet. 28, citing Ex. 1015, 219, Fig.
`17.2; Ex. 1002 ¶ 82. Petitioner relies on the ’859 publication for its teaching
`that GPB was a known and predictable substitute for sodium
`phenylbutryrate, with predictable dose adjustment. Pet. 28–29, Ex. 1004,
`¶ 23, Ex. 1002 ¶ 83.
` 
`
` 
`
`8
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`on sodium PBA and the amount of starting HPN-100 is determined,
`“[s]ubsequent dose adjustment would be based on repeated measurement of
`urinary PAGN as well as assessment of dietary protein and ammonia.” Ex.
`1004 ¶ 231(emphasis added). Pet. 39.
`Petitioner argues that one of ordinary skill in the art would have
`known to measure fasting plasma ammonia by citing to Blau, Simell, and
`Lee because these references demonstrate that blood ammonia levels were
`known to be affected by various factors including dietary protein. Pet. 29,
`citing Ex. 1006, 273, Table 11.9; Ex. 1007, 1118, Fig. 1; Ex. 1010, Fig. 2;
`Ex. 1004 ¶ 3; see also Pet. 31.
`Petitioner cites to Lee for reasons why one of ordinary skill in the art
`would have increased GPB at lower plasma ammonia levels as claimed. See
`Pet. 37. Lee teaches that some patients were receiving a lower than
`recommended dose of drug (PBA) and that increasing the dose to its labeled
`range “might improve ammonia control and, considering the high proportion
`of UCD patients with self-reported neurological disability, potentially
`improve neurological outcome.” See Ex. 1010, 226; see Pet. 37.
`Lee teaches that a higher percentage of subjects on NaPBA, a
`different drug, were above the upper limit of normal for ammonia compared
`with subjects taking GPB. See Pet. 37, citing Ex. 1010, 224. Although the
`difference was not significant, Lee reports that the lower incidence of
`exceeding the upper limit of normal with GPB was “attributable [] to lower
`‘overnight’ ammonia levels (12–24 h) . . . .” Pet. 37, citing Ex. 1010, 224.
`Petitioner’s witness, Dr. Sondheimer,10 testifies that one of ordinary skill in
`
`                                                            
`10 Dr. Neal Sondheimer testifies that he has Ph.D. and M.D. degrees and has
`completed a post-doctoral fellowship in Genetics, with certifications in the
`9
`
` 
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`the art would seek to lower plasma ammonia levels to improve neurological
`outcomes based on the teaching in Lee. See Ex. 1002 ¶ 98.
`Petitioner also relies on Figure 3 of Lee to argue that there would have
`been a reasonable expectation that plasma ammonia levels could be lowered
`to below one half the upper limit of normal by administering GPB. See Pet.
`37–38. Figure 3 reports ammonia levels in subjects after one week of dosing
`with NaPBA first and then with GPB. In one subject, ammonia levels were
`above the upper limit of normal with NaPBA and then fell to below 10
`µmol/L after GPB. Petitioner asserts the data show that at least one subject
`likely had a level after GPB treatment below half the upper limit of normal.
`See Pet. 38. At this point in the proceeding, we consider Petitioner’s reading
`of Figure 3 to be reasonable because the average upper limit of plasma
`ammonia is shown to be just below 30 µmol/L in Figure 3.
`
`                                                            
`American Academy of Pediatrics, the American Board of Medical Genetics
`– Clinical Genetics, and the American Board of Medical Genetics – Clinical
`Biochemical Genetics. See Ex. 1002 ¶¶ 8 and 10. Dr. Sondheimer also
`testifies that he has treated patients with nitrogen scavenging drugs,
`including glyceryl tri- Inter [4-phenylbutyrate] and sodium benzoate and that
`he continues to use those medications. See id. at ¶ 13. He also testifies that
`he has
`compared fasted and non-fasted plasma ammonia levels to the upper
`limit of normal (“ULN”) [and has] adjusted the dosage of these
`medications in response to elevated plasma ammonia values, both
`fasted and non-fasted, and did so prior to 2011 [as well as adjusting]
`PAA prodrug dosages for various reasons including ammonia control,
`alterations in diet and weight gain.
`
`Id. At this point in the proceeding, we find Dr. Sondheimer qualified to
`testify about the subject matter of the proceeding.
` 
`
` 
`
`10
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`In responding to Petitioner’s challenge, Patent Owner argues that the
`prior art does not recognize a normal plasma ammonia level as a cause for
`concern warranting GPB dosage adjustment. Prelim Resp. 18–19.
`According to Patent Owner, the prior art only discussed increasing a
`patient’s drug dosage when plasma ammonia levels were above the upper
`limit of normal. Prelim. Resp. 18. At this point in the proceeding, we
`determine that Figure 17.2 of Fernandes demonstrates that increasing
`medicine, even when plasma ammonia levels were below the upper limit of
`normal, was a known treatment choice.
`Patent Owner argues that Fernandes teaches increasing medicine
`using glutamine levels as the deciding factor, not plasma ammonia levels,
`and teaches away from the claimed method. See Prelim. Resp. 22–23.
`Fernandes teaches increasing medicine when ammonia levels are below 80
`µmol/L, which would include levels below the upper limit of normal even if
`that upper limit was 50 µmol/L or lower. See Ex. 1015, Fig. 17.2. Thus, at
`this point in the proceeding, we do not find that Fernandes would have
`discouraged one of ordinary skill in the art from carrying out the method of
`claim 1. “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 Fulton, 391 F.3d 1195, 1201
`(Fed.Cir. 2004). Disclosure of other pathways or factors indicating medicine
`should be increased does not mean that Fernandes criticizes, discredits, or
`otherwise discourages the claimed method. See id.
`Patent Owner argues that merely because some subjects falling with
`the treatment paradigm of Figure 17.2 could receive an increased dosage of
`
` 
`
`11
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`medication when their plasma ammonia levels are below the upper limit of
`normal is not sufficient to render the claimed method obvious because
`Fernandes fails to teach that one should administer an increased dosage of
`medication. Prelim. Resp. 21. We are not persuaded by Patent Owner’s
`argument at this point in the proceeding because claim 1 does not recite any
`result of adjusting the dosage as recited. Instead, claim 1 merely recites the
`steps that would be taken. If it would have been obvious for one of ordinary
`skill in the art to have taken these steps, the claimed method would have
`been obvious. Petitioner cites to the flowchart in Fernandes showing that it
`was known to increase medicine when plasma ammonia levels were below
`the upper limit of normal and cites to the teachings of Lee that increasing
`drug dosage could lead to improved neurological outcomes and that fewer
`incidences of exceeding the upper limit of normal were attributable to lower
`overnight ammonia levels. See Pet. 33-37; Ex. 1015, Fig. 17.2.
`Accordingly, we are persuaded at this point in the proceeding, that Petitioner
`has demonstrated a reasonable likelihood it would have been obvious to one
`of ordinary skill in the art to have administered more GPB even when
`plasma ammonia levels were below the upper limit of normal.
`Similarly, we are not persuaded by Patent Owner’s arguments that the
`teachings in Fernandes, the ’859 publication, and other references of plasma
`ammonia levels within the normal range as satisfactory indicate that the
`claimed method would not have been obvious. See Prelim. Resp. 19–20 and
`24–30, citing Ex. 2006 ¶¶ 96–105; Ex. 2012 (’157 publication) ¶¶ 90, 98;
`Ex. 1017; Ex. 2019 (Häberle); Ex. 2009 (Batshaw). Because of the
`teachings adjusting the dosage of GPB in a patient with a plasma ammonia
`level between the upper limit of normal and half the upper limit of normal in
`
` 
`
`12
`
`

`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`Fernandes (see Ex. 1015 Fig. 17.2) and the teaching that increased dosages
`of medicine might improve neurological outcomes (Ex. 1010, 226; Ex. 1002
`¶ 98), we are not persuaded that Petitioner has failed to demonstrate a
`reasonable likelihood the claimed methods would have been obvious.
`Patent Owner argues further that one of ordinary skill in the art would
`have aimed to use the lowest dosage of medication possible due to concerns
`of adverse side effects. See Prelim. Resp. 30–32. In support, Patent Owner
`cites the testimony of Dr. Enns11 that “massive overdose[s]” of nitrogen
`scavenging drugs can lead to toxicity and severe liver damage or failure.
`See Ex. 2006 ¶ 104. Dr. Enns also testifies that “even small increases in
`dosage” can lead to unpleasant side effects. According to Dr. Enns, “[s]uch
`side effects are typically not the subject of academic reports, but certainly
`are common in clinical practice in patients taking nitrogen scavenging
`medications.” Id. Dr. Enns concludes that clinicians typically aimed to use
`the lowest possible dosage of any medication in order to avoid such negative
`side effects and that, therefore, one of ordinary skill in the art would not
`have had a motivation to increase drug dosage of a patient presenting normal
`plasma ammonia levels. See id.
`                                                            
`11 Dr. Gregory Enns testifies that he has a U.K. Medical Degree, has
`completed a fellowship in Medical Genetics, and is Board Certified in
`Clinical Genetics and Clinical Biochemical Genetics by the American Board
`of Medical Genetics and Genomics. See Ex. 2006 ¶¶ 7–9. Dr. Enns testifies
`that he has cared for roughly 70 to 100 urea cycle disorder patients over the
`course of his career and sees approximately 600 to 700 patients with inborn
`errors of metabolism, or who are suspected of having a biochemical genetic
`or neurogenetic disorder, annually. See id. ¶ 13. He also testifies that he
`manages and prescribes nitrogen scavenging medications for his patients.
`See id. At this point in the proceeding, we find Dr. Enns qualified to testify
`about the subject matter of the proceeding.
` 
`
` 
`
`13
`
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`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`
`At this point in the proceeding, before Dr. Enns has been cross
`examined, his testimony about the dangers of increasing the dosage of
`nitrogen scavenging drugs in general does not persuade us that Petitioner is
`not likely to prevail. We note that at this point in the proceeding, we
`construe claim 1 of the ’559 patent to include adjusting the dosage of GPB
`in a patient who has a fasting plasma ammonia level that is only slightly
`below the upper level of normal, perhaps requiring only a minimal increase
`in drug.
`In addition, under 37 C.F.R. § 42.208(c) “[t]he Board’s decision will
`take into account a patent owner preliminary response where such a response
`is filed, including any testimonial evidence, but a genuine issue of material
`fact created by such testimonial evidence will be viewed in the light most
`favorable to the petitioner solely for purposes of deciding whether to
`institute an inter partes review.” Patent Owner argues that we need not
`comply with this rule because Dr. Sondheimer’s testimony is conclusory and
`unsupported and therefore does not rise to the level of creating a genuine
`issue of material fact. Prelim. Resp. 46. Patent Owner’s argument is
`directed to the weight we will ultimately accord to each witness’s testimony,
`not to whether the testimony creates a genuine issue of material fact.
`Accordingly, we are not persuaded by Patent Owner’s argument and apply
`the requirement of 37 C.F.R. § 42.208(c).
`Patent Owner also argues, citing various prior art references, that one
`of ordinary skill in the art would not have relied on plasma ammonia levels
`to increase drug dosage because they were known to be too variable. See
`Prelim. Resp. 32–37. According to Patent Owner, the prior art cited
`emphasizes the variability of plasma ammonia levels (see, e.g., Ex. 1015,
`
` 
`
`14
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`

`IPR2017-01768
`Patent 9,095,559 B2
` 
`217), the difficulty in predicting such levels (see, e.g., Ex. 1004 ¶¶ 39, 195–
`209), and the use of other markers to select dosages (see, e.g., Ex. 1017,
`328). See id.
`At this point in the proceeding, because Fernandes teaches that “[t]he
`most important diagnostic test in urea cycle disorder is measurement of
`plasma ammonia concentration” (Ex. 1015, 217) and that “[a]ll treatment
`must be monitored with regular quantitative estimation of plasma ammonia
`and amino acids, paying particular attention to the concentration of
`glutamine and essential amino acids” (Ex. 1015, 219; see also Ex. 1004,
`¶ 231), we consider it reasonably likely that Petitioner will prevail in its
`argument that one of ordinary skill in the art would have known to use
`plasma ammonia levels to determine how to adjust drug dosage. See Pet.
`30–31.
`Patent Owner also argues that one of ordinary skill in the art would
`not have understood the significance of using fasting plasma ammonia levels
`to make dosage adjustments before disclosure of the inventor’s discovery in
`the ’559 patent. See Prelim. Resp. 37–41. Patent Owner cites the lack of a
`specific teaching in the prior art to rely on fasting or fed plasma ammonia
`levels to make dosage adjustments for UCD patients. See id. At this point
`in the proceeding, we are persuaded by Dr. Sondheimer’s testimony that
`because Fernandes teaches plasma ammonia concentrations “may be slightly
`raised as a result of high protein intake . . . ,” (see Ex. 1015, 217), Petitioner
`has established sufficiently that one of ordinary skill in the art would have
`understood that measuring plasma ammonia levels in proximity to a meal
`would likely result in an inaccurate assessment of the patient’s plasma
`ammonia level and that fasting plasma ammonia levels should be measured.
`
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`See Ex. 1002 ¶ 89. Although Patent Owner argues that fasting plasma levels
`were known to not always be the lowest values (see Prelim. Resp. 38, citing
`Ex. 1010, 226), Dr. Sondheimer’s testimony was not based on an
`understanding that fasting plasma levels would be the lowest, only that they
`would be raised as a result of high protein intake. See Ex. 1002 ¶ 89.
`Furthermore, Patent Owner argues that Simell and Blau fail to cure
`the asserted deficiencies of the Fernandes, the ’859 publication, and Lee
`because they do not provide guidance for drug dosage adjustments in UCD
`patients. See Prelim. Resp. 39–40. Petitioner cites Simell and Blau only to
`show that it was known in the art to measure plasma ammonia levels in a
`fasted state. See Pet. 29–30. Thus, at this point in the proceeding, Patent
`Owner’s arguments do not persuade us that Petitioner is not likely to prevail
`on this challenge to claim 1.
`Patent Owner argues further that one of ordinary skill in the art would
`not have had a reasonable expectation that the claimed method would confer
`a treatment benefit, the asserted purpose of the methods, based on the
`claimed combination of steps. Prelim. Resp. 41. Patent Owner discusses the
`“relationship between a specific fasting plasma ammonia level and daily
`average ammonia and maximum plasma ammonia levels” (Prelim. Resp.
`42), which according to Dr. Enns, provide “an advance in treatment of urea
`cycle disorders and a new way of thinking about treating patients with this
`disorder” (Ex. 2006 ¶ 128). We note that claim 1 of the ’559 patent does not
`recite any treatment benefit, such as the lowering of plasma ammonia to any
`specific level. Thus, at this point in the proceeding, we are not persuaded
`that Petitioner is not reasonably likely to prevail because of a lack of a
`reasonable expectation of success of the claimed method.
`
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`
`Patent Owner also argues that Dr. Sondheimer’s testimony should not
`be given any weight because his opinions about what a person of ordinary
`skill in the art would have understood are conclusory. Prelim. Resp. 43–46.
`At this point in the proceeding, in light of Dr. Sondheimer’s background and
`experience (see above) and the support that he cites for his opinions, we
`decline to give his testimony no weight. We note that our decision is not a
`decision on the ultimate patentability of the claims of the ’559 patent.
`Before rendering a final decision on patentability, we will weigh
`Dr. Sondheimer’s opinions against the evidence cited by Patent Owner
`during the trial.
`Because it is reasonably likely that Petitioner will prevail in regard to
`the challenge to claim 1 in Ground 1, we institute review based on this
`ground.
`
`B. Ground 3
`Petitioner argues that independent claim 3 and claims 7–9, 11, and 14,
`which depend from claim 3, are obvious under 35 U.S.C. § 103 over the
`’859 publication, optionally in view of Pandya and/or Lee. Pet. 53–62.
`Claim 3 recites:
`A method of administering glyceryl tri-[4-phenylbu-tyrate] 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, 24:49–60. Like claim 1, claim 3 requires administering a dosage
`of GPB to a subject if the fasting plasma ammonia level is greater than half,
`but less than the upper limit of normal for plasma ammonia. Claim 3,
`though, requires administering an initial dosage of GPB, rather than an
`adjusted dosage.
`Petitioner relies on the ’859 publication for its teaching to administer
`GPB to a subject with a UCD after measurement of his or her plasma
`ammonia level. See Pet. 53, citing Ex. 1004 ¶¶ 2 and 195–197.
`Petitioner relies on Pandya (Ex. 1018) as teaching measurement of
`fasting levels of plasma ammonia and comparison of those levels with the
`upper limit of normal. See Pet. 54–55. Pandya reports on two patients with
`urea cycle disorders. One patient was described as having an “elevated”
`plasma ammonia level of 185 µmol/L, with the normal range described as
`18–47 µmol/L. See Ex. 1018, 687. The patient’s plasma ammonia level
`decreased to 28 µmol/L after treatment with intravenous fluids, sodium
`benzoate, and arginine. Two days later, the patient was started on the
`nitrogen scavenging drug “Ucephan,” with oral feeding of increasing
`amounts of protein beginning after three days. See Ex. 1018, 687–88; see
`Ex. 1002 ¶ 132. Thus, according to Petitioner, the patient was started on
`Ucephan when his plasma ammonia level was below the upper limit of
`normal (47 µmol/L) and above one half the upper limit of normal (23.5
`µmol/L). See Pet. 55–56, citing Ex. 1002 ¶ 137.
`According to Dr. Sondheimer, Ucephan was discontinued in 1997 and
`one of ordinary skill in the art woul