Paper No. 13
`
`
`
`
`
`Trials@uspto.gov
`571.272.7822 Filed: September 30, 2016
`
`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 TONI R. SCHEINER, DEBORAH KATZ, and
`GRACE KARAFFA OBERMANN, Administrative Patent Judges.
`
`KATZ, Administrative Patent Judge.
`
`
`
`
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`I.
`
`BACKGROUND
`
`Lupin Ltd. and Lupin Pharmaceuticals, Inc. (“Petitioners”) 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.”)), which
`
`was accorded a filing date of April 1, 2016 (Paper 4). Horizon
`
`

`

`IPR2016-00829
`Patent 9,095,559 B2
`
`Therapeutics, Inc. (“Patent Owner”) timely filed a Preliminary Response
`
`(Paper 9 (“Prelim. Resp.”)).
`
`Under 35 U.S.C. § 314(a), an inter partes review may not be instituted
`
`unless Petitioners show that there is “a reasonable likelihood that the
`
`petitioner would prevail with respect to at least 1 of the claims challenged in
`
`the petition.” Petitioners make that showing with respect to the grounds for
`
`unpatentability of claims 1–15. Therefore, we institute review as to
`
`claims 1–15.
`
`Our findings of fact and conclusions of law are based on the record
`
`developed thus far, prior to Patent Owner’s Response. This is not a final
`
`decision as to the patentability of any challenged claim. If a final decision is
`
`issued in this case, it will be based on the full record developed during trial.
`
`A.
`
`Related proceedings
`
`Petitioners and Patent Owner report that Patent Owner served
`
`Petitioners with a complaint in the District Court for the District of New
`
`Jersey (Case No. 1:15-cv-07624) alleging that Petitioners infringed the ʼ559
`
`patent, as well other related patents. Pet. 7; Prelim. Resp. 2.
`
`Petitioners also report that patent 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, which was instituted
`
`and joined with the IPR2015-01127 proceeding.
`
`
`
`2
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`

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`IPR2016-00829
`Patent 9,095,559 B2
`
`
`Petitioners report further that PR2015-01117 and IPR2016-00283
`
`were instituted and joined, both involving Horizon’s U.S. Patent 8,642,012,1
`
`although that patent is not related by lineage to the ʼ559 patent.
`
`B.
`
`The ’559 Patent (Ex. 1001)
`
`The ’559 patent issued from an application filed February 22, 2013.
`
`Ex. 1001. It cites two provisional applications filed November 29, 2011 and
`
`September 30, 2011, for priority. Ex. 1001, at [60].
`
`C.
`
`Applied Prior Art
`
`Petitioner relies on the following prior art references:
`
`
`Abbreviation
`
`Citation
`
`Blau
`
`Simell
`
`’859 Publication
`
`Brusilow ’84
`
`PHYSICIAN’S GUIDE TO THE LABORATORY
`DIAGNOSIS OF METABOLIC DISEASES, 261–
`76 (Nenad Blau et al. eds., 2d ed. 1996).
`Olli Simell et al., Waste Nitrogen Excretion
`Via Amino Acid Acylation: Benzoate and
`Phenylacetate in Lysinuric Protein
`Intolerance, 20 PEDIATRIC RESEARCH
`1117–21 (1986).
`U.S. Patent Publication 2010/0008859 A1,
`filed January 7, 2009, published January
`14, 2010.
`Saul W. Brusilow et al., Treatment of
`Episodic Hyperammonia in Children with
`Inborn Errors of Urea Synthesis, 310 THE
`NEW ENGLAND JOURNAL OF MEDICINE
`1630–34 (1984).
`
`Exhibit
`Number
`1006
`
`1005
`
`1007
`
`1004
`
`
`
`
`
`
`
`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.
`
`
`
`3
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`

`

`IPR2016-00829
`Patent 9,095,559 B2
`
`
`D.
`
`Asserted Grounds of Unpatentability
`
`Petitioner challenges the patentability of ’559 patent claims 1–15
`
`under 35 U.S.C. § 103 over the following groups of references:
`
`
`
`
`
`Ground
`1
`
`References
`Blau, Simell, and the ’859 Publication
`
`2
`
`Blau, Simell, the ’859 publication, and
`Brusilow ’84
`
`Claims
`1, 2, 4, 5, 7–10,
`12, and 13
`3, 6, 11, 14, and
`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.” In KSR Int’l Co. v. Teleflex Inc., 550
`
`U.S. 398, 421 (2007), the Supreme Court explained that, where there is a
`
`design need or market pressure to solve a problem and there are a finite
`
`number of identified, predictable solutions, 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, then that subject matter is likely
`
`obvious, not innovative.
`
`A. Ground 1
`
`The claims of the ’559 patent are directed to methods of using a drug,
`
`glyceryl tri-[4-phenylbutryate], to treat subjects with urea cycle disorders.
`
`Petitioner’s witness, Keith Vaux, M.D., Ph.D.2, testifies that subjects
`
`
`2 Petitioner relies on the testimony of Keith Vaux, M.D. Ex. 1002.
`Dr. Vaux testifies that he is Professor and Clinical Chief of the Division of
`
`
`
`4
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`IPR2016-00829
`Patent 9,095,559 B2
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`suffering from urea cycle disorders (“UCDs”) are unable to remove excess
`
`nitrogen waste, which is normally excreted in the urine. Id. ¶ 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 the urine. Id. ¶ 31.
`
`In those with UCDs, the enzymes controlling the urea cycle are deficient,
`
`leading to high levels of ammonia in the blood and toxicity. Id. ¶ 32.
`
`Claim 1 of the ’559 patent is representative of the claims challenged
`
`in Petitioners’ 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, 24:20–35. Independent claim 2, the only other independent claim
`
`challenged in Ground 1, is similar to claim 1, differing mostly in the
`
`
`Medical Genetics in the Department of Medicine at UC San Diego. Ex.1002
`¶ 1. Dr. Vaux testifies that he regularly prescribes nitrogen scavenging
`drugs and treats patients who are maintained on therapy with nitrogen
`scavenging drugs. Id. ¶ 2. Dr. Vaux testifies that he has published articles
`in peer reviewed journals on metabolic disorders and speaks at national and
`international conferences on genetics and metabolic and genomic medicine.
`Id. ¶ 4. At this stage of the proceeding, we find Dr. Vaux to be qualified to
`provide opinions on the subject matter at issue.
`
`
`
`5
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`IPR2016-00829
`Patent 9,095,559 B2
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`preamble.3 Patent Owner does not argue separately for the patentability of
`
`claim 2.
`
`Petitioners argue that claim 1 would have been obvious because
`
`the ’859 publication teaches using nitrogen scavenging drugs, including
`
`glyceryl tri-[4-phenylbutyrate], which is also called “HPN-100,” to treat urea
`
`cycle disorders. Pet. 22–23, citing Ex. 1007 ¶¶ 88–91, 95–99, 107–108, 226,
`
`and 232; also citing Ex. 1002 ¶ 53. For example, the ’859 publication states:
`
`“In some embodiments, HPN-100 is the PBA prodrug of choice for these
`
`methods” of starting or adjusting doses of nitrogen scavenging drugs in
`
`patients with UCDs. Ex. 1007 ¶¶ 88 and 108.
`
`Petitioners also argue that the ’859 publication teaches adjusting the
`
`dosage of nitrogen scavenging drugs such as HPN-100 on the basis of
`
`plasma ammonia values, wherein if plasma levels are too high, drug dosages
`
`can be increased. Pet. 23, citing Ex. 1007 ¶ 83 (“If the ammonia control is
`
`inadequate, the dosage of the nitrogen scavenging drug may need to be
`
`
`3 Claim 2 recites:
`A method of treating a subject with a urea cycle disorder who
`has previously been administered an initial dosage of glyceryl tri-[4-
`phenylbutyrate] and who has a fasting plasma ammonia level less than
`the upper limit of normal for plasma ammonia level, the method
`comprising:
`(a) measuring a fasting plasma ammonia level for the subject;
`(b) comparing the fasting plasma ammonia level to the upper
`limit of normal for plasma ammonia level; and
`(c) administering an adjusted dosage of glyceryl tri-[4-
`phenylbutyrate] that is greater than the initial dosage if the fasting
`plasma ammonia level is greater than half the upper limit of normal
`for plasma ammonia level.
`Ex. 1001, 24:36–48.
`
`
`
`6
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`IPR2016-00829
`Patent 9,095,559 B2
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`increased if that can be done . . .”); Ex. 1007 ¶¶ 88–91, 95–99, 226, and 232;
`
`and Ex. 1002 ¶ 53.
`
`Petitioners argue further that the ’859 publication demonstrates it was
`
`known to compare measured plasma ammonia levels to normal levels.
`
`Pet. 26–27, citing Ex. 1007 ¶ 94 (“As used herein, plasma levels are
`
`acceptable when they are at or below a level considered normal for the
`
`subject, and commonly this would mean a plasma ammonia level is below
`
`about 40 µmol/L.”). The ’859 publication also teaches that it was known
`
`that normal levels vary depending on the way they are measured. Ex. 1007
`
`¶ 94; see Pet. 26–27.
`
`Petitioners argue that it would have been known to those in the art to
`
`carry out the steps of the method of claim 1 on a subject “who has a fasting
`
`plasma ammonia level less than the upper limit of normal for plasma
`
`ammonia level,” as recited in claim 1, because it was known that
`
`maintenance of ammonia levels within normal limits is the objective of
`
`therapy with nitrogen scavenging drugs and because ammonia levels were
`
`also known to vary during the day, for example after eating. Pet. 24–25,
`
`citing Ex. 2007 ¶ 83; Ex. 1020; Ex. 1016 at S58; and Ex. 1002 ¶ 54.
`
`Petitioners rely on Dr. Vaux’s testimony to show that one of skill in the art
`
`would have considered it obvious to administer more drug to reduce
`
`ammonia levels in patients whose fasting plasma ammonia level is
`
`approaching the upper limit of normal, but still below it. Pet. 24–25, citing
`
`Ex. 1002 ¶¶ 51 and 55.
`
`Petitioners rely further on the testimony of Dr. Vaux to show that
`
`because of the goal to maintain a patient at normal ammonia levels, one of
`
`skill in the art would have also known to increase drug doses when fasting
`
`
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`7
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`IPR2016-00829
`Patent 9,095,559 B2
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`ammonia levels approach the upper limit of normal and, thus, are above half
`
`of the upper limit of normal. Pet. 28–29, citing Ex. 1002 ¶ 65; Ex. 1006, at
`
`268 (Table 11.5); Ex. 1012 at 213; Ex. 1017, at 164 (Table II).
`
`Dr. Vaux also testifies that those of ordinary skill in the art would
`
`have had reason to combine these references because they each contribute
`
`knowledge about dosing nitrogen scavenging drugs when treating UCDs.
`
`Ex. 1002 ¶¶ 47–50; Pet. 19–20.
`
`In regard to the claim limitation of measuring a fasting ammonia
`
`level, Petitioners cite to Blau and Simell for their teachings of collecting
`
`blood from UCD patients for measuring plasma ammonia levels after a fast.
`
`Pet. 25–26, citing Ex. 1006, at 273 (Table 11.9). Petitioners rely on the
`
`testimony of Dr. Vaux to argue that these teachings would have indicated to
`
`those in the art that blood for plasma ammonia measurement should be
`
`collected after a fast. Pet. 25–26, citing Ex. 1002 ¶¶ 58 and 59; see also
`
`Ex. 1002 ¶ 46, n.2., citing Ex. 1015.
`
`Petitioners’ arguments regarding claims 1 and 2 are supported by
`
`evidence. At this point in the proceeding, Patent Owner’s arguments do not
`
`persuade us that Petitioners do not have a reasonable likelihood of
`
`prevailing.
`
`Specifically, we are not persuaded at this time by Patent Owner’s
`
`argument that the ’859 publication teaches away from reliance on plasma
`
`ammonia levels because it discusses why such measurements are
`
`inconvenient and unreliable. See Prelim. Resp. 13–14, citing Ex. 1007 ¶ 73.
`
`We are also not persuaded that the ’859 publication teaches away from
`
`reliance on plasma ammonia levels because it teaches using other indicators,
`
`
`
`8
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`IPR2016-00829
`Patent 9,095,559 B2
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`such as excreted PAGN4, to determine the effectiveness of treatment.
`
`Prelim. Resp. 14, citing Ex. 1007 ¶ 135.
`
`“A reference may be said to teach away when a person of ordinary
`
`skill, upon reading the reference, would be discouraged from following the
`
`path set out in the reference, or would be led in a direction divergent from
`
`the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553
`
`(Fed. Cir. 2004). Even though the ’859 publication teaches alternatives to
`
`evaluating treatment with plasma ammonia levels, it also teaches relying on
`
`these levels. See Ex. 1007 ¶ 83 (“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.”). Mere disclosure of an alternative does not indicate that
`
`a reference teaches away from what is claimed. See In re Fulton, 391 F.3d
`
`1195, 1201 (Fed. Cir. 2004).
`
`We are also not persuaded at this time by Patent Owner’s argument
`
`that the ’859 publication “teaches away from reliance on a single plasma
`
`ammonia measurement (under fed or fasted conditions) in assessing the
`
`dosage of nitrogen scavenging drugs.” Prelim. Resp. 14–15. The
`
`challenged claims are not shown to be limited to a single measurement.
`
`Patent Owner argues further that the ’859 teaches away from
`
`increasing the dosage of nitrogen scavenging medication when a patient’s
`
`plasma ammonia level is below the upper limit of normal but above half the
`
`upper limit of normal. Prelim. Resp. 15–18. Patent Owner cites to two
`
`
`4 Dr. Vaux explains that drugs such as HPN-100 provide an alternative
`mechanism for the clearance of glutamine from proteins, wherein “PAGN”
`acts like urea to carry nitrogen out of the body. (Ex. 1002, ¶ 32.)
`
`
`
`9
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`IPR2016-00829
`Patent 9,095,559 B2
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`apparently conflicting reports of “normal” plasma ammonia levels in the
`
`’859 publication: (1) at paragraph 85, where a level of “less than about
`
`40 μmol/L, or of not greater than 35 μmol/L” is considered to be normal, and
`
`(2) at paragraph 94 where a plasma level of between 26 and 35 μmol/L is
`
`considered to be the “upper limit of normal.” Patent Owner suggests that
`
`because 40 µmol/L, or 44 µmol/L when the term “about” is considered, is
`
`considered to be normal, the ’859 publication contemplates normal plasma
`
`ammonia levels as being above the upper limit of normal (26–35 μmol/L).
`
`Thus, according to Patent Owner, the ’859 publication teaches that plasma
`
`ammonia levels above one half the upper limit, or even above the upper limit
`
`of normal, are adequately controlled. Prelim. Resp. 16–17.
`
`At this point in the proceeding, Patent Owner’s argument does not
`
`persuade us that Petitioner is reasonably likely to fail in its challenges.
`
`Patent Owner’s argument appears to be based on specific plasma ammonia
`
`levels that have not yet been shown to be accepted by those of skill in the art
`
`as the only levels considered to be “normal” or the “upper limit of normal.”
`
`In addition, at this point in the proceeding, we credit the testimony of
`
`Dr. Vaux that the goal of maintaining a patient at normal ammonia levels
`
`would have lead one of ordinary skill in the art to increase drug doses when
`
`fasting ammonia levels approach the upper limit of normal and, thus, are
`
`above half of the upper limit of normal. See, e.g. Pet. 28–29, citing Ex. 1002
`
`¶ 65; Ex. 1006, at 268 (Table 11.5); Ex. 1012 at 213; Ex. 1017 at 164 (Table
`
`II). Patent Owner’s bare argument regarding a teaching away from
`
`increasing the dosage of nitrogen scavenging medication when a patient’s
`
`plasma ammonia level is below the upper limit of normal but above half the
`
`
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`10
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`IPR2016-00829
`Patent 9,095,559 B2
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`upper limit of normal does not outweigh Dr. Vaux’s testimony at this point
`
`in the proceeding.
`
`Patent Owner argues that Petitioners fail to provide sufficient
`
`explanation or evidence to support its argument about the goals of treatment
`
`and the knowledge in the art to administer drug when fasting ammonia
`
`levels approach the upper limit of normal. Prelim. Resp. 17–18. At this
`
`point in the proceeding we disagree. Dr. Vaux’s testimony and the evidence
`
`on which he relies is reasonable, wherein a goal of treatment would be to
`
`avoid having a patient exceed the upper limit of normal during the day.
`
`Dr. Vaux’s testimony is also supported by the evidence he cites, for
`
`example, that plasma ammonia levels vary a different times of the day
`
`(Ex. 1012) or after eating (Ex. 1006, 268 (Table 11.5) and Ex. 1017). See,
`
`e.g., Ex. 1002, ¶ 55.
`
`Patent Owner’s argument that the ’859 publication does not teach
`
`comparison of fasting plasma ammonia levels (Prelim. Resp. 19–20) is not
`
`persuasive either because, at this point in the proceeding, we are persuaded
`
`that Blau and Simell teach this element of the challenged claims. Patent
`
`Owner argues that Simell does not render the challenged claims obvious
`
`because it reports only an experimental study on patients who are not usually
`
`treated with nitrogen scavenging medication. Prelim. Resp. 21–23. Patent
`
`Owner also argues that Blau teaches only diagnosis, not treatment. Id. at 23.
`
`We are not persuaded by these arguments at this time because Dr. Vaux
`
`testifies that those of ordinary skill in the art would have looked to the
`
`references. Ex. 1002 ¶ 46, n.2. Furthermore, Dr. Vaux testifies that it was
`
`known to use fasting levels when measuring plasma ammonia levels because
`
`
`
`11
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`IPR2016-00829
`Patent 9,095,559 B2
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`it was known that plasma ammonia levels vary after eating. See Ex. 1007
`
`¶ 49.
`
`Patent Owner argues further that Blau cautions against “over-reliance”
`
`on plasma ammonia levels in making treatment decisions because it can lead
`
`to over-restriction of amino acids. Prelim. Resp. 23, citing Ex. 1006, at 275.
`
`At this point in the proceeding, we are not persuaded that this caution would
`
`discourage those of skill in the art from ever using plasma ammonia levels to
`
`determine drug dosage, particularly in light of the specific teachings in the
`
`’859 publication and other references to do so.
`
`Patent Owner does not provide arguments against Petitioners’
`
`challenge to the dependent claims recited in Ground 1 at this point in the
`
`proceeding. We determine that Petitioners are reasonably likely to prevail in
`
`these challenges based on the evidence and arguments presented in the
`
`Petition. See Pet. 31–35.
`
`For example, Petitioners argue that dependent claim 4, which recites
`
`the method of claim 1 or 2 and requires that “administering the adjusted
`
`dosage of glycerol tri[4-phenylbutyrate] produces a normal average daily
`
`ammonia level in the subject” (Ex. 1001, 24:61–63), would have been
`
`obvious because maintenance of plasma ammonia levels within normal
`
`limits was an objective of therapy with nitrogen scavenging drugs. Pet. 30,
`
`citing Ex. 1007, ¶ 83, Ex. 1002, ¶ 67.
`
`After considering Petitioners’ evidence and arguments and the
`
`specific arguments in Patent Owner’s Preliminary Response, we are
`
`persuaded that it is reasonably likely Petitioners will prevail in the
`
`challenges of the claims recited in Ground 1.
`
`
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`IPR2016-00829
`Patent 9,095,559 B2
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`
`B. Ground 2
`
`Claim 3 of the ’559 patent 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.
`
`
`Ex. 1001, 24:49–60. Claim 3 is similar to claim 1 of the ’559 patent but
`
`does not have the limitation of a subject “who has a fasting plasma ammonia
`
`level less than the upper limit of normal for plasma ammonia level” in the
`
`preamble and recites measuring a “first” fasting plasma ammonia level in
`
`step (a). Claim 3 also includes the limitation of administering an “initial”
`
`dosage of drug in step (c).
`
`Petitioners cite to Brusilow ’84 in addition to the ’859 publication,
`
`Blau, and Simell, to argue that claim 3 would have been obvious to those of
`
`skill in the art. Brusilow ’84 teaches measuring a patient’s fasting plasma
`
`ammonia level upon admission and determining that it was 111 µmol/L and
`
`145 µmol/L one hour later. Ex. 1004, 1631. Sodium benzoate and
`
`phenylacetate and another drug were administered intravenously, causing the
`
`patient’s plasma ammonia level to drop to 79 µmol/L after three hours. Id.
`
`Maintenance therapy of sodium benzoate plus another drug was
`
`administered orally over the next six hours, resulting in a plasma ammonia
`
`
`
`13
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`IPR2016-00829
`Patent 9,095,559 B2
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`level of 33 µmol/L, which was determined to be within normal limits, after
`
`19 hours. Id.
`
`As in Ground 1, Petitioners rely on the testimony of Dr. Vaux to show
`
`that the limitation of administering an initial dosage of HPN-100 “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” would have been obvious to those in the art. Pet. 42–43,
`
`citing Ex. 1002, ¶ 93. Dr. Vaux testifies that the goal of nitrogen scavenging
`
`therapy for UCD patients was known to be to maintain a stable, normal
`
`plasma ammonia level. Ex. 1002 ¶ 93, citing Ex. 1007 ¶¶ 83, 226, and 232,
`
`and Ex. 1020. Dr. Vaux testifies further that claim 3 recites the known
`
`premise that administering a nitrogen scavenging drug will decrease plasma
`
`ammonia levels and that it was known that variation of these levels due to
`
`the time of day or ingestion of food would potentially take a patient outside
`
`of the normal levels. Id. ¶ 93, citing Ex. 1006, 268, Table 11.5; Ex. 1012;
`
`Ex. 1017; and Ex. 1016. According to Dr. Vaux, those of skill in the art
`
`would have increased the dose of a nitrogen scavenging drug in a patient
`
`with a fasting plasma ammonia level approaching the upper limit of normal.
`
`Ex. 1002 ¶ 93.
`
`Dr. Vaux testifies that those of ordinary skill would have had reason
`
`to combine the references because they all contribute knowledge of dosing
`
`with nitrogen scavenging drugs. Ex. 1002 ¶¶ 78–80; Pet. 38.
`
`Patent Owner argues that Petitioners have failed to show that claim 3
`
`would have been obvious for the same reasons argued against Ground 1.
`
`Prelim. Resp. 25. As explained above, these arguments are not persuasive at
`
`this point in the proceeding.
`
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`14
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`
`Patent Owner argues further that claim 3 requires administration of an
`
`“initial” dose of drug in step (c), but that Petitioners have failed to address
`
`this limitation and address only increasing the dose of drug. Prelim.
`
`Resp. 25–26 and 28–30. We are not persuaded by this argument at this time.
`
`Dr. Vaux’s testimony about the knowledge of those of skill in the art to treat
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`patients whose plasma ammonia levels approach the upper limit of normal is
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`persuasive regarding increasing the dosage of drug or an initial treatment.
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`At this point in the proceeding, we do not discern a meaningful difference in
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`the goal of treating a patient as he or she approaches the upper limit of
`
`normal whether increasing drug dosages or providing an initial
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`administration of a drug.
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`While acknowledging that Brusilow ’84 teaches measuring fasting
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`plasma ammonia levels, Patent Owner argues that it does not place any
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`significance on measurement in a fasting state. Prelim. Resp. 27. Because
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`at this time we find that other references teach measurement of plasma
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`ammonia levels in a fasting state (see Ex. 1005 and 1006), we are not
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`persuaded by this argument.
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`Patent Owner also argues that Brusilow ’84 does not teach comparing
`
`the measured fasting plasma ammonia level to the upper limit of normal.
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`Prelim. Resp. 28. Because at this point in the proceeding we are persuaded,
`
`as discussed above, that the ’859 publication teaches this comparison, Patent
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`Owner’s argument is not persuasive.
`
`Ground 2 includes challenges to dependent claims 6, 11, 14, and 15.
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`Pet. 44–46. Claim 6 recites the method of claim 3, further comprising steps
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`of measuring a second fasting plasma ammonia level for the subject,
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`comparing it to the upper limit of normal for plasma ammonia levels, and
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`administering an adjusted dosage of drug that is greater than the initial
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`dosage if the second fasting ammonia level is greater than half the upper
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`limit of normal and less than the upper limit of normal. Ex. 1001, 25:1–10.
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`Petitioners argue, relying on the testimony of Dr. Vaux, that it would have
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`been obvious to take a second measurement of a patient’s fasting plasma
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`ammonia level to determine whether the dosage of nitrogen scavenging drug
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`should be readjusted to maintain a level below the upper limit of normal
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`because of the known variation in plasma ammonia levels throughout the
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`date and after eating. Pet. 44, citing Ex. 1002 at ¶ 95.
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`Patent Owner responds to Petitioners’ argument, asserting that
`
`Petitioners merely refer to their argument regarding claim 3 and fail to
`
`address the specific method of claim 6 or provide an articulated reason for
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`its challenge. Prelim. Resp. 31–32. Patent Owner also argues that claim 6 is
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`not obvious because the ’859 publication teaches away from increasing drug
`
`dosages when the plasma ammonia level falls below 44 µmol/L, as that level
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`is above the upper limit of normal recited in the ’859 publication. Prelim.
`
`Resp. 32. Patent Owner argues further that Brusilow ’84 teaches that plasma
`
`ammonia levels falling with the normal or near normal limits are
`
`satisfactory. Prelim. Resp. 32. In light of Dr. Vaux’s testimony regarding
`
`treatment of patients as they approach the upper limit of normal, we are not
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`persuaded by these arguments at this time.
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`Patent Owner does not provide arguments against Petitioners’
`
`challenge to the other dependent claims (claims 11, 14, and 15) recited in
`
`Ground 2 at this point in the proceeding. We determine that Petitioners are
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`reasonably likely to prevail in these challenges based on the evidence and
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`arguments presented in the Petition. See Pet. 44–46.
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`After considering Petitioners’ evidence and arguments and the
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`specific arguments in Patent Owner’s Preliminary Response, we are
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`persuaded that it is reasonably likely Petitioners will prevail in the
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`challenges of the claims recited in Ground 2.
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`C.
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`Patent Owner’s Other Arguments
`
`In addition to Patent Owner’s specific arguments against Grounds 1
`
`and 2, Patent Owner also argues we should deny the Petition under
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`35 U.S.C. § 325(d) because the Examiner previously considered the art cited
`
`in Grounds 1 and 2 during prosecution and Petitioners add nothing new.
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`Prelim. Resp. 33–34. Under that section of the statute, “the Director may
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`take into account whether, and reject the petition or request because, the
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`same or substantially the same prior art or arguments previously were
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`presented to the Office.” 35 U.S.C. § 325(d). We exercise the discretion
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`delegated to us to institute review on the basis of Grounds 1 and 2 because
`
`Petitioner has presented new evidence, such as Dr. Vaux’s testimony, and
`
`therefore new arguments that were not before the Examiner.
`
`Patent Owner also argues that the Petition should be denied under
`
`37 C.F.R. § 42.104(b)(4) and 42.22(a)(2) because it hinges on conclusory
`
`statements, citing to Dr. Vaux’s testimony, which according to Patent
`
`Owner, “parrots the same assertions without citation or explanation of how
`
`his conclusions are supported by the prior art of record.” Prelim. Resp. 34–
`
`41. As discussed above, we disagree with Patent Owner’s characterization
`
`of Dr. Vaux’s testimony because he cites evidence to support it. As the
`
`Supreme Court noted, “[i]n many fields it may be that there is little
`
`discussion of obvious techniques or combinations, and it often may be the
`
`case that market demand, rather than scientific literature, will drive design
`
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`trends.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007). At this
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`time, we are not persuaded by Patent Owner’s arguments.
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`III. CONCLUSION
`
`We are persuaded that there is a reasonable likelihood that Petitioner
`
`will prevail as to the unpatentability of claims 1, 2, 4, 5, 7–10, 12, and 13 of
`
`the ’559 patent under 35 U.S.C. § 103(a) over Blau, Simell, and the ’859
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`publication.
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`We are also persuaded there is a reasonable likelihood that Petitioner
`
`will prevail as to the unpatentability of claims 3, 6, 11, 14, and 15 of the
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`’559 patent under 35 U.S.C. § 103 over Blau, Simell, the ’859 publication,
`
`and Brusilow ’84.
`
`Our findings of fact and conclusions of law are based on the record
`
`developed thus far, prior to Patent Owner’s Response. This is not a final
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`decision as to the patentability of any challenged claim. If a final decision is
`
`issued in this case, it will be based on the full record developed during trial.
`
`For the reasons given, it is
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`IV. ORDER
`
`ORDERED that an inter partes review is instituted as to claims 1, 2,
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`4, 5, 7–10, 12, and 13 under 35 U.S.C. § 103 over Blau, Simell, and the
`
`’859 Publication;
`
`FURTHER ORDERED that an inter partes review is instituted as to
`
`claims 3, 6, 11, 14, and 15 under 35 U.S.C. § 103 over Blau, Simell, the
`
`’859 publication, and Brusilow ’84;
`
`FURTHER ORDERED that no inter partes review is instituted on any
`
`other grounds;
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`FURTHER ORDERED that pursuant to 35 U.S.C. § 314(a), inter
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`partes review of the ’559 Patent is hereby instituted commencing on the
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`entry date of this Order, and pursuant to 35 U.S.C. § 314(c) and 37 C.F.R.
`
`§ 42.4, notice is hereby given of the institution of a trial.
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`
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`Petitioner:
`
`
`Elizabeth J. Holland
`Cynthia Lambert Hardman
`Goodwin Procter, LLP
`eholland@goodwinprocter.com
`chardman@goodwinprocter.com
`
`Patent Owner:
`
`
`Robert Green
`Matthew Phillips
`Lauren Stevens
`Dennis Bennett
`Emer Simic
`Jessica Tyrus
`rgreen@greengriffith.com
`matthew.phillips@renaissanceiplaw.com
`lstevens@horizonpharma.com
`dennissbennett@globalpatentgroup.com
`esimic@greengriffith.com
`jtyrus@greengfiffith.com
`
`
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