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 IPR2017-01767
`Patent 9,254,278 B2
`____________
`
`
`
`Before DEBORAH KATZ, GRACE KARAFFA OBERMANN, and
`RAMA G. ELLURU, Administrative Patent Judges.
`
`KATZ, Administrative Patent Judge.
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`
`I.
`BACKGROUND
`Par Pharmaceutical, Inc. (“Petitioner” or “Par”) filed a request for an
`inter partes review (“IPR”) of claims 1–15 of U.S. Patent No. 9,254,278 B2
`(Ex. 1001 (“the ’278 patent”) (Paper 3 (“Pet.”)). Horizon Therapeutics,
`
`

`

`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`LLC. (“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 for at least claim 1. We institute review of 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 ’278 Patent (Ex. 1001)
`The claims of the ’278 patent are directed to methods of using a drug,
`glyceryl tri-[4-phenylbutryate] (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. Ex. 1002 ¶ 28. When the body functions
`normally, dietary amino acids are converted to ammonia and then to urea in
`the urea cycle and, finally, excreted in urine. Id. ¶ 29.
`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. Id. ¶ 30; Ex. 2006 ¶¶ 37–38. GPB and other
`so-called “nitrogen scavenging drugs” are used to treat UCDs because these
`drugs are converted in the body to a compound that binds nitrogen and
`
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`allows nitrogen to be excreted. Ex. 1002 ¶¶ 31–32; Ex. 2006 ¶ 43–44.
`Patent Owner does not dispute that GPB was a known nitrogen scavenging
`drug before 2011, when the applications cited as priority for the ’278 patent
`were filed. See Ex. 1004.
`The ’278 patent claims methods of treating a subject with urea cycle
`disorders by administering GPB. In claim 1 of the ’278 patent, the amount
`of GPB administered is sufficient to produce an amount of ammonia in the
`plasma, called a “plasma ammonia level,” that is within a recited target
`range. In the other claims of the ’278 patent, GPB is administered on the
`condition that the plasma ammonia level is within a certain range.
`B.
`Related proceedings
`The challenged ’278 patent is part of a family of patents involved in
`litigations and other inter partes reviews. The grandparent of the application
`that became the ’278 patent issued as patent 8,404,215. The parent of the
`application that became the ’278 patent issued as patent 9,095,559. The
`application that became the ’278 patent is the parent of the application that
`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.
`Petitioner
`Patent
`Proceeding
`9,254,278
`IPR2017-01159 Lupin
`
`Status
`Trial instituted (September
`28, 2017, Paper 10)
`
`
` 
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`3
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`
`8,404,215
`
`IPR2015-01127
`
`
`
`IPR2016-00284
`
`9,095,559
`
`9,326,966
`
`IPR2016-00829
`
`
`
`
`
`
`IPR2016-01768
`
`IPR2017-01160
`
`
`IPR2017-01769
`
`Par
`
`
`
`Lupin
`
`Lupin
`
`
`
`
`
`
`Par
`
`
`Lupin
`
`
`Par
`
`Final Decision – all claims
`unpatentable (September
`29, 2016, Paper 49)
`
`Joined with IPR2015-01127
`
`Final Decision – all claims
`unpatentable (September
`26, 2017, Paper 42); Notice
`of appeal to Federal Circuit
`filed (November 22, 2017,
`Paper 43)
`
`Trial instituted (January 30,
`2018, Paper 10)
`
`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, and 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.
`
` 
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`2017-1451).1
`The following infringement suits in the District of New Jersey have
`been reported as related to this proceeding because they involved the ’278
`patent or the patents related to it:
`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;
`and
`
`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.
`
`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, 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 ’278 patent.
`C.
`Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of ’278 patent claims 1–15
`under the following grounds:
`
`
`Ground
`1
`
`Basis
`35 U.S.C. § 102(b)
`
`References
`’859 Publication (Ex. 1004)2
`
`Claims
`1–3
`
`                                                            
`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.  
`2 U.S. Patent Publication 2010/0008859 A1, was filed on January 7, 2009,
`and published on January 14, 2010 (Ex. 1004).
`5
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`
`2
`
`3
`
`4
`
`
`
`35 U.S.C. § 103(a) Fernandes (Ex. 1015)3 in
`view of the ’859 publication
`(Ex. 1004) and Lee (Ex.
`1010)4 or Lichter-Konecki
`(Ex. 1017)5, optionally
`further in view of Blau (Ex.
`1006)6 or Simell (Ex. 1007)7
`35 U.S.C. § 103(a) Fernandes (Ex. 1015) in view
`of the ’859 publication (Ex.
`1004), and optionally in view
`of Blau (Ex. 1006), Simell
`(Ex. 1007) and/or Lee (Ex.
`1010)
`35 U.S.C. § 103(a) Fernandes (Ex. 1015) in view
`of the ’859 publication (Ex.
`1004) and Lee (Ex. 1010) or
`Lichter-Konecki (Ex. 1017),
`and optionally further in view
`of Blau (Ex. 1006) or Simell
`(Ex. 1007)
`
`1–3
`
`4, 6, 7, 8,
`10–12,
`14, 15
`
`5, 9, 13
`
`                                                            
`3 INBORN METABOLIC DISEASES DIAGNOSIS AND TREATMENT, 214–22 (John
`Fernandes et al., eds., 3d ed. 2002) (Ex. 1015).
`4 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 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).
`6 PHYSICIAN’S GUIDE TO THE LABORATORY DIAGNOSIS OF METABOLIC
`DISEASES, 261–76 (Nenad Blau et al. eds., 2d ed. 1996) (Ex. 1006). 
`7 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
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`Case IPR2017-01767
`Patent 9,254,278 B2
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`
`Analysis
`II.
`Petitioner argues that claim 1 is anticipated under 35 U.S.C. § 102 in
`the first ground of challenge and rendered obvious under 35 U.S.C. § 103 by
`the prior art in the second ground of challenge. Pet. 28–39.
`Claim 1 recites:
`A method of treating a subject with a urea cycle disorder, the
`method comprising:
`administering to the subject in need thereof glyceryl tri-[4-
`phenylbutyrate] in an amount sufficient to produce a fasting plasma
`ammonia level that is less than half the upper limit of normal for
`plasma ammonia level.
`
`Ex. 1001, 24:21–26.
`
`Anticipation
`A.
`Petitioner’s first ground of challenge asserts that claim 1 is anticipated
`by the ’859 publication under 35 U.S.C. § 102(b). Pet. 28–30.
`“Anticipation requires a showing that each limitation of a claim is
`found in a single reference, either expressly or inherently.” Atofina v. Great
`Lakes Chem. Corp., 441 F.3d 991, 999 (Fed. Cir. 2006). “The identical
`invention must be shown in as complete detail as is contained in the patent
`claim.” Richardson v. Suzuki Motor Co., Ltd., 868 F.2d 1226, 1236 (Fed.
`Cir. 1989).
`The ’859 publication teaches oral administration of nitrogen
`scavenging drugs, including glyceryl tri-[4-phenylbutyrate] (GPB), to treat
`urea cycle disorders. See Ex. 1004 ¶¶ 20 and 195–97, Fig. 13; see Pet. 28.
`The ’859 publication also teaches methods of adjusting drug dosage,
`
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`Case IPR2017-01767
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`including GPB, based in part on plasma ammonia levels. See Ex. 1004
`¶¶ 88–92, 95–99, 107–108, 226, 232; see Pet. 14–15.
`The ’859 publication teaches comparing a patient’s plasma ammonia
`level to the upper limit of normal plasma ammonia level, which is reported
`to be from 26 to 35 µmol/L. Ex. 1004 ¶ 201 see Pet. 29. Petitioner argues
`that given the range of upper limit of normal plasma ammonia level reported
`in the ’859 publication, one of ordinary skill in the art would have known
`that half the upper limit of normal in that reference would range from 13 to
`17.5 µmol/L. Pet. 29, citing Ex. 1002 ¶ 61.
`Petitioner argues further that the ’859 publication provides an
`example wherein a subject, labeled number “1006,” demonstrates a “time-
`normalized area under the curve” (abbreviated “TN-AUC”) for plasma
`ammonia concentration of 8.30 µmol/L after treatment with sodium PBA
`and HPN-100. Pet. 29, citing Ex. 1004 ¶ 201. Dr. Neal Sondheimer,
`Petitioner’s witness,8 explains that the TN-AUC measures the plasma
`
`                                                            
`8 Dr. Sondtheimer testifies that he has a Ph.D. and M.D. degrees and has
`completed a post-doctoral fellowship in Genetics, with certifications in the
`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. Sondtheimer 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
`8
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`ammonia level over the course of the day, including fasted and fed plasma
`ammonia levels. Ex. 1002 ¶ 61. According to Dr. Sondheimer, “[b]ecause
`the fasted ammonia level would be the lowest measured ammonia level
`during the course of the day, a [person of ordinary skill in the art] would
`understand that a subject with a TN-AUC value of 8.30 μmol/L would have
`a fasting plasma ammonia level lower than 8.30 μmol/L and therefore less
`than half the upper limit of normal according to the ’859 Publication.” Ex.
`Id. Thus, Petitioner argues that subject 1006 in the ’859 publication would
`have received an amount of glyceryl tri-[4-phenylbutyrate] sufficient to
`produce a fasting ammonia level less than one-half the upper limit of
`normal, as required in claim 1 of the ’278 patent.
`Patent Owner disputes Petitioner’s challenge by relying on the
`testimony of its witness, Dr. Gregory Enns.9 Prelim. Resp. 54. Dr. Enns
`disagrees that the reported average plasma ammonia value reported for
`subject 1006 “inevitably means that during that 24 hour period, there existed
`
`                                                            
`well as adjusting] PAA prodrug dosages for various reasons
`including ammonia control, alterations in diet and weight gain.
`
`See id. At this point in the proceeding, we find Dr. Sondheimer qualified to
`testify about the subject matter of the proceeding.  
`9 Dr. 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 ¶¶ 6–8. 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. at ¶ 12. 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. 
`9
`
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`a fasting plasma ammonia level for this patient that was below 8.3 μm/L and
`therefore less than half the ULN[10], as required by claim 1.” Ex. 2006
`¶ 141. According to Dr. Enns, because it was known that plasma ammonia
`levels vary widely over the course of a day, a person of ordinary skill in the
`art would not assume a specific fasting ammonia level based on the TN-
`AUC reported for patient 1006. See id.
`Dr. Enns testifies further that even though a fasting level may, in some
`instances, be the lowest measured ammonia value for a patient over the
`course of a day, a person of ordinary skill in the art would not assume it was
`necessarily the lowest. See id. at ¶ 142. Dr. Enns cites, for example, to
`Figure 2 of Lee, which reportedly presents the same data as the study
`provided in the ’859 publication, to show that the lowest mean plasma
`ammonia level occurred 30 minutes after a fasting measurement. See id.,
`citing Ex. 1010, 226. Dr. Enns also testifies that it was well-known that
`fasting levels of plasma ammonia could be artificially high. See Ex. 2006
`¶ 142, citing Ex. 1023, Ex. 2015.
`Patent Owner’s argument is based on testimony by Dr. Enns that
`contradicts Dr. Sondheimer’s testimony. In the absence of cross-
`examination of either witness, it is reasonably likely that one of ordinary
`skill in the art would have understood the data provided for subject 1006
`indicated a fasting plasma ammonia level that is half the upper limit of
`normal in light of Dr. Sondheimer’s testimony (see Ex. 1002 ¶ 61). At this
`point in the proceeding, it seems to us that patient 1006’s average plasma
`ammonia level of 8.30 µmol/L is reasonably likely to include plasma
`ammonia levels below and above that level. Thus, it is reasonably likely that
`
`                                                            
`10 The parties use the abbreviation “ULN” for the “upper limit of normal.”
`10
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`an average of 8.30 µmol/L represents plasma ammonia levels below one half
`the upper limit of normal. Accordingly, as this point in the proceeding, it is
`reasonably likely that Petitioner will prevail with respect to claim 1 as
`anticipated by the ’859 publication.
`In addition, under 37 C.F.R. § 42.208(c) we view the testimony
`regarding how one of ordinary skill in the art would have understood the
`data presented for subject 1006 in the light most favorable to the Petitioner.
`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. 53. 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).
`Because it is reasonably likely that Petitioner will prevail in regard to
`the challenge to claim 1 in Ground 1, we institute a trial based on this
`ground.
`
`B. Obviousness
`Petitioner argues that claim 1 is obvious under 35 U.S.C. § 102 over
`Fernandes, the ’859 publication, Lee or Lichter-Konecki, and optionally
`Blau or Simell. Pet. 31–39.
`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
`
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`which said subject matter pertains.” The Supreme Court has explained that
`if the person of ordinary skill could have arrived at the claimed subject
`matter using common sense to combine different teachings of the prior art,
`that subject matter is likely obvious, not innovative. See KSR Int’l Co. v.
`Teleflex Inc., 550 U.S. 398, 421 (2007).
`Petitioner cites Fernandes and the ’859 publication for their teachings
`of the variability of plasma ammonia levels, which according to Petitioner
`would have motivated a person of ordinary skill in the art to use fasted
`plasma ammonia levels when treating UCD patients. See Pet. 31–32.
`Specifically, the ’859 publication teaches: “The subject's plasma ammonia
`level may also be determined; this is a critical parameter for tracking
`effectiveness of an overall treatment program, but reflects a variety of
`factors such as dietary protein and physiological stress, as well as the effect
`of a drug used to promote nitrogen excretion.” Ex. 1004 ¶ 39. Similarly,
`Fernandes teaches: “The most important diagnostic test in urea cycle
`disorders is measurement of plasma ammonia concentration. Normally, this
`is less than 50 µmol/L, but may be slightly raised as a result of a high
`protein intake, exercise, struggling or a haemolysed blood sample.” Ex.
`1015, 217. Both the ’859 publication and Fernandes demonstrate that it was
`known that eating protein could affect plasma ammonia levels.
`Petitioner also cites Blau, Lee, and Lichter-Konecki for their
`teachings of the degrees to which plasma ammonia levels can vary over the
`course of a day. Pet. 32–33. Blau teaches that plasma ammonia levels can
`vary 30–60 µmol/L after eating, depending on the time of day and nitrogen
`load. Ex. 1006, 268. Lee provides data from the plasma ammonia levels of
`patients tracked over the course of one day, showing a range of from about
`
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`Case IPR2017-01767
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` 
`16 µmol/L to about 45 µmol/L, which Petitioners calculate to be a 2.8-fold
`increase. Ex. 1010, 226; see Pet. 33. Lichter-Konecki teaches that ammonia
`levels varied on average more than 10-fold over the course of a day. Ex.
`1017, 328. Petitioner argues that one of ordinary skill in the art would have
`targeted a fasting ammonia level less than half the upper limit of normal in
`light of these reported variations in plasma ammonia levels in order to keep
`the patient’s levels at or below the upper limit of normal. Pet. 34–35.
`Petitioner relies on the testimony of Dr. Sondheimer in support of this
`assertion. See id., citing Ex. 1002, ¶ 89. Dr. Sondheimer explains that one
`of ordinary skill in the art would have targeted a fasting plasma ammonia
`level that accounts for increases throughout the day so as not to exceed the
`upper limit of normal. Id. According to Dr. Sondheimer, it would have
`been common sense to a person of ordinary skill in the art in September
`2011 to reduce fasting plasma ammonia levels to below half the upper limit
`of normal in order to account for plasma ammonia variability over the
`course of the day. See id. at ¶ 92.
`Dr. Sondheimer exemplifies his opinion by testifying to calculations
`one of ordinary skill in the art could do to determine a target fasting plasma
`ammonia level that would account for daily activities such as eating and
`avoid exceeding the upper limit of normal. See id. at ¶ 89. According to Dr.
`Sondheimer, given the potential 30 µmol/L increase in plasma ammonia due
`to daily activities reported in Blau and the upper limit of normal reported in
`the ’859 publication (35 µmol/L,) one of ordinary skill in the art would have
`targeted a fasting plasma ammonia level of at or below 5 µmol/L to account
`for daily fluctuation of plasma ammonia and avoid exceeding the upper limit
`of normal. See id. Similarly, Dr. Sondheimer testifies that given the
`
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`Case IPR2017-01767
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` 
`potential for a 2.8-fold increase in plasma ammonia as reported in Lee, one
`of ordinary skill in the art would have targeted a fasting plasma ammonia
`level of at or below 12.5 µmol/L to account for daily fluctuation in plasma
`ammonia and avoid exceeding the upper limit of normal. See id. Dr.
`Sondheimer testifies further that given the potential for a 10-fold increase in
`plasma ammonia as reported in Licher-Konecki, one of ordinary skill in the
`art would have targeted a fasting plasma ammonia level of at or below 3.5
`µmol/L. See id.
`Each of these target fasting plasma ammonia levels is less than half
`the upper limit of 35 µmol/L (17.5 µmol/L) reported in the ’859 publication.
`Thus, Dr. Sondheimer concludes that either one of Blau, Lee, or Lichter-
`Konecki would have motivated a person or ordinary skill in the art to
`decrease a subject’s fasting plasma ammonia level to less than one-half the
`upper limit of normal. See Ex. 1002 ¶ 90.
`Dr. Sondheimer also testifies that because treatment of Subject 1006
`in Example 3 of the ’859 publication demonstrated a normalized TN-AUC
`for plasma ammonia of 8.3 µmol/L (see Ex. 1004 Table 2), one of ordinary
`skill in the art would have had a reasonable expectation of success in treating
`other patients with HPN-100 to achieve a fasting plasma ammonia level of
`less than half the upper limit of normal. See id. at ¶ 91.
`Patent Owner opposes this challenge by arguing that the prior art is
`completely silent about an alleged goal of targeting a particular ammonia
`level within the normal range. See Prelim Resp. 48. According to Patent
`Owner, there was no suggestion that achieving a lower ammonia level
`within the normal range would prevent exceeding upper limit of normal at
`any time. Prelim. Resp. 48. Patent Owner argues that the examples of the
`
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`Case IPR2017-01767
`Patent 9,254,278 B2
` 
`’859 publication and the data provided for subject 1006 are not teachings of
`what a physician should have done. See id. 48–50.
`Despite Patent Owner’s arguments, we are persuaded that Petitioner is
`reasonably likely to prevail with respect to at least claim 1 because
`Petitioner presents the testimony of Dr. Sondheimer that a person of
`ordinary skill in the art in September 2011 would reduce fasting plasma
`ammonia levels to below half the upper limit of normal in order to account
`for plasma ammonia variability over the course of the day. See Ex. 1002
`¶ 92. Even though the prior art does not expressly teach the limitations of
`the challenged claims, an obviousness 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.” KSR , 550 U.S. at 418. As the
`Supreme Court recognized,
`[w]hen there is a design need or market pressure to solve a
`problem and there are a finite number of identified, predictable
`solutions, a person of ordinary skill has good reason to pursue
`the known options within his or her technical grasp. If this leads
`to the anticipated success, it is likely the product not of
`innovation but of ordinary skill and common sense. In that
`instance the fact that a combination was obvious to try might
`show that it was obvious under § 103.
`
`
`Id. at 421.
`Patent Owner argues that Dr. Sondheimer’s testimony is unsupported
`and should not be accorded any weight. Prelim. Resp. 49. Nevertheless, at
`this point in the proceeding, we consider the references cited by Dr.
`Sondheimer teaching the daily variability in plasma ammonia levels (see Ex.
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`1002 ¶ 89, citing Ex. Blau, Ex. Lee, Ex. Lichter-Konecki) to support his
`arguments.
`Patent Owner argues further that one of ordinary skill in the art would
`not have considered it necessary to account for daily fluctuations in plasma
`ammonia levels and that plasma ammonia levels anywhere within the
`normal range were acceptable. See Prelim. Resp. 50. Patent Owner also
`argues that Dr. Sondheimer’s calculations are merely hindsight. See id. 50–
`51. Nevertheless, we are persuaded at this time that Petitioner is reasonably
`likely to prevail because even if normal plasma ammonia levels were
`considered to be acceptable, Dr. Sondheimer testifies that one of ordinary
`skill in the art would have wanted to prevent a subject’s plasma ammonia
`levels from exceeding the normal range. See Ex. 1002 ¶ 92.
` Patent Owner argues further that “basic math belies” Dr.
`Sondheimer’s theory regarding determination of a target plasma ammonia
`level. Prelim. Resp. 51–52. As an example, Patent Owner asserts that if 40
`µmol/L is half the upper limit of normal, a plasma ammonia level of 34
`µmol/L would be below half the upper limit of normal, but would not
`account for the 2.8-fold, 10-fold, or 60 µmol/L increase in ammonia levels
`reported in the prior art and would not be low enough to ensure that the
`subject would not exceed the upper limit of normal of 80 µmol/L. See id.
`We do not consider this argument to be persuasive at this time because Dr.
`Sondheimer does not testify that one of ordinary skill in the art would
`consider every value below one half the upper limit of normal to be
`appropriate. Given Dr. Sondheimer’s testimony that some values below one
`half that level would be targeted because of the concerns of exceeding the
`upper limit of normal and the reported degree of fluctuation in daily plasma
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`ammonia levels reported in the prior art, it is reasonably likely that Petitioner
`will prevail in regard to claim 1 of the ’278 patent.
`Patent Owner also argues that Petitioner has not cited to evidence
`showing that an increased dosage of medication would prevent excursions
`above the upper limit of normal and that the approach taken by Petitioner
`and Dr. Sondheimer “vastly over-simplifies” the complexities of UCD
`treatment. See Prelim. Resp. 51. According to Patent Owner, only the
`disclosures of the challenged ’278 patent provide a rational basis for
`lowering plasma ammonia levels below the upper limit of normal. See id. at
`53. Patent Owner argues that Figure 2 of Lee (Ex. 1010) refutes Dr.
`Sondheimer’s theory and shows this complexity because it suggests that a
`fasting ammonia level below half the upper limit of normal will not ensure
`that a subject’s maximum daily ammonia level would not exceed the upper
`limit of normal. See id. at 52.
`We are not persuaded by these arguments at this time. Claim 1 of the
`’278 patent requires only administering GPB in a sufficient amount to
`produce a fasting plasma ammonia level less than the upper limit of normal.
`Claim 1 does not require preventing the subject’s plasma ammonia from
`ever exceeding the upper limit of normal. Thus, while Dr. Sondheimer
`testifies to the general desire of ordinarily skilled artisans to prevent such
`high, abnormal levels, at this point in the proceeding, we do not consider it
`necessary for Petitioner to prove that reducing plasma ammonia levels
`would never allow a level above the upper limit of normal.
`C.
`35 U.S.C. § 325(d)
`Patent Owner argues that a trial should not be instituted on
`Petitioner’s challenges because the art cited in Grounds 1–4 was previously
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`cited during prosecution of the application that became the ’278 patent.
`Prelim. Resp. 57–58. In addition, Patent Owner argues that invalidity
`contentions put forth by Petitioner in a related district court litigation over a
`different, but related patent 8,404,215 patent were considered by the
`Examiner. See id. at 58.
`As is our delegated discretion (see 35 U.S.C. § 325(d) (“In
`determining whether to institute or order a proceeding under this chapter,
`chapter 30 . . . the Director may take into account whether, and reject the
`petition or request because, the same or substantially the same prior art or
`arguments previously were presented to the Office.”) (emphasis added)), we
`decline to reject Petitioner’s challenges. Even if the Examiner of the
`application that became the ’278 patent considered the prior art cited in the
`challenges, it is not clear that the teachings were supported by the testimony
`of a qualified witness regarding what one of ordinary skill in the art would
`have understood about these teachings. Accordingly, we do not consider the
`same challenges to have been considered by the Examiner.
`D.
`35 U.S.C. § 312(A)(3)
`Patent Owner also argues that the Petition fails to comply with the
`particularity requirement of 35 U.S.C. § 312(a)(3), which requires that a
`petition must identify “in writing and with particularity” each challenged
`claim, the grounds on which the challenge to each claim is based, and the
`evidence that support the grounds of challenge. See Prelim. Resp. 59.
`According to Patent Owner, the assertion of multiple grounds, presumably
`due to citing references in the alternative, in Grounds 2–4 is a violation of
`this requirement. See id.
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`We disagree under the facts of this proceeding. Petitioner stated
`which claims were challenged and identified the relevant teachings in each
`cited reference and other evidence that supports the challenges.
`Accordingly, even though alternate references were cited, they were done so
`with particularity.
`
`III. Conclusion
`We are persuaded that there is a reasonable likelihood that Petitioner
`will prevail as to the unpatentability of claim 1 of Patent Owner’s ’278
`patent under 35 U.S.C. § 102 over the ’859 publication and under 35 U.S.C.
`§ 103(a) over Fernandes in view of the ’859 publication and Lee or Lichter-
`Konecki, optionally further in view of Blau or Simell. Accordingly, we
`institute inter partes review based on Grounds 1 and 2 of the Petition.
`The issues raised by Grounds 3 and 4 are closely related to the issues
`discussed above regarding Grounds 1 and 2 because the challenged claims
`are similar to claim 1 and the references cited