UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner
`__________
`
`Case IPR2017-01769
`Patent 9,326,966
`__________
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`LUPIN EX. 1023
`Page 1 of 64
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`RELATED PROCEEDINGS .......................................................................... 6
`
`
`
`I.
`
`II.
`
`III. BACKGROUND AND STATE OF THE ART .............................................. 6
`
`IV. THE ’966 PATENT CLAIMS ......................................................................... 9
`
`V.
`
`CLAIM INTERPRETATION .......................................................................12
`
`VI. PERSON OF ORDINARY SKILL IN THE ART ........................................13
`
`VII. THE PETITION FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD THAT ANY CHALLENGED CLAIM IS
`UNPATENTABLE ........................................................................................15
`
`A.
`
`The Board’s Finding of Unpatentability of the ’215 Patent is
`Inapplicable to the ’966 Patent Claims ...............................................16
`
`B. Ground 1 Should be Denied ................................................................18
`
`1.
`
`The Prior Art Did Not Recognize that UCD Patients
`Having a Plasma Ammonia Level Within the Normal
`Range Required an Increased Dosage of Nitrogen
`Scavenging Medication .............................................................18
`
`(a) The Prior Art in the Petition Provides no
`Motivation to Increase the Dosage of Nitrogen
`Scavenging Medication for a Patient with a
`Normal Plasma Ammonia Level ....................................20
`
`(b) The Prior Art as a Whole Refutes Petitioner’s
`Assertion that a POSA Would Have Been
`Motivated to Perform the Claimed Methods ..................27
`
`The Variability in Plasma Ammonia Levels Discouraged
`Reliance on Normal Plasma Ammonia Levels in Making
`Dosage Adjustments .................................................................32
`
`The Prior Art Does Not Suggest Reliance on Fasting
`Plasma Ammonia Measurements for Dosage Adjustment .......37
`
`2.
`
`3.
`
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
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`4.
`
`5.
`
`6.
`
`The Petition Fails to Demonstrate a Reasonable
`Expectation of Success .............................................................41
`
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given no Weight ....................................43
`
`Dependent Claims 2, 3, 5, 8 and 11 are Not Obvious
`Over the Prior Art .....................................................................47
`
`C. Grounds 2 and 3 Should be Denied .....................................................47
`
`1.
`
`2.
`
`The Prior Art Does Not Suggest Targeting a Fasting
`Plasma Ammonia Level at or Below Half the ULN .................47
`
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given no Weight ....................................50
`
`VIII. THE PETITION SHOULD BE REJECTED UNDER 35 U.S.C. §
`325(D) ............................................................................................................54
`
`IX. THE PETITION SHOULD BE REJECTED UNDER
`35 U.S.C. § 312(A)(3) ...................................................................................55
`
`IV. CONCLUSION ..............................................................................................56
`
`
`
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
`
`TABLE OF AUTHORITIES
`
`Cases
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ................................................................. 32, 44, 54
`
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) ............................................................................22
`
`Broadcom Corp. v. Emulex Corp.,
`732 F.3d 1325 (Fed. Cir. 2013) ............................................................................42
`
`Cultec, Inc. v. Stormtech LLC,
`IPR2017-00777, Paper 7 (Aug. 22, 2017) ............................................................56
`
`Disney Entm't., Inc. v. Kappos,
`923 F. Supp. 2d 788 (E.D. Va. 2013) ...................................................................30
`
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ..............................................................................15
`
`Hospira, Inc. v. Genentech, Inc.,
`IPR2017-00739, Paper 16 (July 27, 2017) ...........................................................56
`
`Hospitality Core Services LLC v. Nomadix, Inc.,
`IPR2016-0052, Paper 8 (Apr. 27, 2016) ..............................................................12
`
`In re Am. Acad. of Sci. Tech. Ctr.,
`367 F.3d 1359 (Fed. Cir. 2004) ............................................................................44
`
`In re Cyclobenzaprine Extended-Release Capsule Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) ............................................................................42
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ..............................................................................44
`
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) ..............................................................................13
`
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) ................................................................................22
`
`iii
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`In re Smith Int’l, Inc.,
`No. 2016-2303, slip op. at 12-13 (Fed. Cir. Sept. 26, 2017) ................................12
`
`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
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`In re Zurko,
`258 F.3d 1379 (Fed. Cir. 2001) ............................................................................50
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`821 F.3d 1359, 1369 (Fed. Cir. 2016). ................................................................. 33
`
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................................19
`
`Oil States Energy Servs., LLC v Greene’s Energy Group, LLC,
`No. 16-712 (cert. granted June 12, 2017) .............................................................57
`
`Tissue Transplant Tech. Ltd. et al. v. Mimedx Group, Inc.,
`IPR2015-00320, Paper 13 (June 29, 2015) ..........................................................45
`
`Unified Patents Inc. v. Berman,
`IPR2016-01571, Paper 10 (Dec.14, 2016) ...........................................................56
`
`W.L. Gore & Assocs. Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ..................................................................... 52, 55
`
`Statutes
`
`35 U.S.C. § 103(a) ............................................................................................ 18, 48
`
`35 U.S.C. § 253(a) ..................................................................................................... 1
`
`35 U.S.C. § 312(a)(3) ........................................................................................ 56, 57
`
`35 U.S.C. § 313 .......................................................................................................... 1
`
`35 U.S.C. § 314(a) ............................................................................................ 15, 16
`
`35 U.S.C. § 325(d) ........................................................................................ 5, 55, 56
`
`Regulations
`
`37 C.F.R. § 42 ..........................................................................................................57
`
`37 C.F.R. § 42.22(a)(2) .............................................................................................. 5
`
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`37 C.F.R. § 42.65(a) .............................................................................. 33, 44, 47, 55
`37 COLR. § 42.65(a).cssecccssssssssssscsssecesssneessssssecessueesssnsesssssvesssnessssseseesse 33, 44, 47, 55
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`Case No. IPR2017-01769
`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
`U.S. Patent No. 9,326,966
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`37 C.F.R. § 42.104(b)(4) ............................................................................................ 5
`37 CAFAR. § 42.104(b)(4)..cccccccssesscsssescsssseecsssucecssssesessssecessusesssssscsssneesessssesssseeesssneessen5
`
`37 C.F.R. § 42.107 ..................................................................................................... 1
`BT CAFAR. § 42.107 cccccsccccsssscsssssecssssneesessssecsssucesssssessssssecessusessssscessnsesessuessssseesssneessen 1
`
`37 C.F.R. § 42.108(c) ........................................................................................ 47, 55
`37 COFLR. § 42.108(C)scccccsssesccssseccssssesssssscsssssscesssnsesessusecsssucesssssessssueesssneesssssesess 47, 55
`
`
`
`
`Vv
`
`v
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`I.
`
`INTRODUCTION
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
`
`Horizon Therapeutics, LLC (“Horizon” or “Patent Owner”) submits this
`
`Preliminary Response pursuant to 35 U.S.C. § 313 and 37 C.F.R. § 42.107, in
`
`response to the Petition for inter partes review (“IPR”) of U.S. Patent No.
`
`9,326,966 (Paper 1, herein “Petition”) filed by Par Pharmaceutical, Inc. (“Par” or
`
`“Petitioner”). Par has failed to meet its burden of demonstrating a reasonable
`
`likelihood of unpatentability of claims 1-11 and 13 of the ’966 patent (“the
`
`challenged claims”).1 Thus, Horizon respectfully requests that the Petition be
`
`rejected.
`
`The ’966 patent claims are directed to innovative methods of treating a
`
`patient suffering from a urea cycle disorder (“UCD”) by adjusting the dosage of
`
`glyceryl tri-[4-phenylbutyrate] (also known as “glycerol phenylbutyrate,” “HPN-
`
`100” or “GPB”) in subjects being treated for UCD. UCDs are genetic metabolic
`
`disorders that are extremely rare (only 113 new U.S. patients per year), difficult to
`
`diagnose and to treat, and, most alarmingly, have an extremely low survival rate
`
`(an estimated 65% mortality rate in newborns presenting with UCD). UCDs are
`
`1 On June 28, 2017, Horizon filed a statutory disclaimer under 35 U.S.C. § 253(a)
`
`disclaiming claims 12, 14, and 15 of the ’966 patent. (Ex. 2001.) Accordingly,
`
`only claims 1-11 and 13 of the ’966 patent remain at issue in this proceeding. See
`
`37 C.F.R. § 42.107.
`
`1
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`characterized by the accumulation of toxic and potentially fatal levels of ammonia
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`in the plasma and brain arising from the body’s inability to remove excess
`
`ammonia. UCD treatment involves a complex regimen of dietary protein
`
`restriction, nitrogen scavenging medication and/or amino acid supplementation.
`
`Prior to the ’966 patent, the prior art consensus was that UCD treatment was
`
`effective when a patient presented with a plasma ammonia level falling within the
`
`normal or near normal range. And, as confirmed by internationally recognized
`
`UCD expert, Dr. Gregory Enns (“Dr. Enns”), clinicians treating UCDs prior to the
`
`2011 priority date of the ’966 patent did not seek to reduce ammonia levels to any
`
`particular level within the normal range. But assessment of treatment effect based
`
`on ammonia levels was confounded by the fact that individual plasma ammonia
`
`levels were subject to unpredictable daily variation. And even with careful
`
`treatment and monitoring, UCD patient outcomes remained poor and previously
`
`stabilized patients could experience dangerously high plasma ammonia levels (i.e.,
`
`hyperammonemia) without warning, often causing irreversible brain damage, coma
`
`or death. Recognizing the need for improved UCD treatment methods and dosing
`
`guidance, the inventors of the ’966 patent analyzed extensive plasma ammonia
`
`data and discovered that certain UCD patients with normal fasting plasma
`
`ammonia levels were at risk and should be administered an increased dosage of
`
`medication.
`
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`To address this previously unrecognized problem, the inventors developed
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
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`
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`treatment methods that counterintuitively direct physicians to increase the dosage
`
`of nitrogen scavenging medication (glycerol phenylbutyrate) for certain UCD
`
`patients previously considered to have satisfactory normal ammonia levels. For
`
`example, representative independent claim 1 requires, inter alia, administration of
`
`an increased dosage of glycerol phenylbutyrate to a UCD patient whose fasting
`
`plasma ammonia level is less than the upper limit of normal (“ULN”) but greater
`
`than half the ULN. (Ex. 1001 at 24:11-25.) These methods provide significant
`
`advantages over the prior art by eliminating confusion over interpretation of
`
`ammonia levels, providing much needed dosing guidance and assuring improved
`
`ammonia control.
`
`Petitioner’s assertion that the claimed methods would have been obvious is
`
`unfounded and hindsight-fueled. The Petition fails to demonstrate even a prima
`
`facie case of obviousness because Petitioner has not identified any recognition in
`
`the prior art that a normal plasma ammonia level (i.e., below the ULN but above
`
`half the ULN) was of any concern or warranted dosage adjustment. The first
`
`indication that a normal plasma ammonia level should and could be relied on to
`
`adjust dosage because of the risk associated with a plasma ammonia level below
`
`the ULN and above half the ULN was in the ’559 patent, of which the ’966 patent
`
`is a continuation. And the prior art, including Petitioner’s primary prior art
`
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`references—Fernandes and the ’859 Publication—refutes Petitioner’s obviousness
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`theory by consistently expressing satisfaction with plasma ammonia levels
`
`anywhere within or even near normal levels (e.g., <80 µmol/L).
`
`Fernandes teaches that a plasma ammonia level less than 80 µmol/L, which
`
`includes levels above the ULN, are satisfactory and the goal of treatment. And
`
`Fernandes only suggests that very high plasma ammonia levels well above the
`
`normal range (e.g., >120 µmol/L) mandate a dosage increase. (Ex. 1015 at 220.)
`
`The ’859 Publication also teaches that ammonia levels within the normal range are
`
`indicative of an effective dosage and confines dosage increases to patients with
`
`inadequate (i.e., above normal) ammonia levels. Secondary references, Lee, and
`
`Lichter-Konecki provide no support for Petitioner because these references suggest
`
`that ammonia levels anywhere within or near the normal range indicate satisfactory
`
`ammonia control. And none of these references suggest dosage adjustment based
`
`on normal fasting plasma ammonia levels.
`
`Aside from the failure of the prior art to recognize any risk or disadvantage
`
`associated with plasma ammonia levels falling within the normal range (i.e., below
`
`the ULN but above half the ULN), the prior art as a whole taught away from the
`
`claimed methods. Fernandes, the ’859 Publication, Lee, Lichter-Konecki and
`
`others expressly discouraged reliance on normal plasma ammonia levels in making
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`dosing adjustments in stabilized patients due to the recognized potential for
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`unpredictable fluctuations in daily plasma ammonia levels.
`
`Finding no prior art support for its theory, Petitioner depends entirely on the
`
`testimony of its expert, Dr. Sondheimer, to supply a reason to pursue the claimed
`
`methods. But Dr. Sondheimer’s testimony should be given no weight. His
`
`testimony has no support and impermissibly interprets the prior art through the lens
`
`of the’966 patent claims. Dr. Sondheimer also ignores two decades of prior art that
`
`discourages performance of the claimed methods and refutes his over-simplistic
`
`theory that a person of ordinary skill in the art (“POSA”) would be singularly
`
`focused on administering more and more drug to a patient who already has
`
`satisfactory normal ammonia levels when there was no known benefit in doing so.
`
`On this basis alone, the Board should deny the Petition pursuant to 37 C.F.R. §
`
`42.104(b)(4) and/or 37 C.F.R. § 42.22(a)(2).
`
`Denial of review pursuant to 35 U.S.C. § 325(d) is also warranted because
`
`substantially the same prior art and arguments were previously considered and
`
`rejected by the Patent Examiner during prosecution of the ’966 patent. (Ex. 2002 at
`
`6-7.)
`
`For the reasons herein, Petitioner has failed to meet its burden to
`
`demonstrate a reasonable likelihood that challenged claims 1-11 and 13 are
`
`obvious and the Board should deny institution of the Petition.
`
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`II. RELATED PROCEEDINGS
`The ’966 patent is also the subject of IPR2017-01160, filed by Lupin Ltd.
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
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`and Lupin Pharmaceuticals Inc. (collectively, “Lupin”) on March 27, 2017, and
`
`instituted by the Board on September 28, 2017. The ’966 patent is a continuation
`
`of U.S. Patent Application No. 14/816,674, now U.S. Patent No. 9,254, 278 (“the
`
`’278 patent”), which is a continuation of U.S. Patent Application No. 13/775,000,
`
`now U.S. Patent No. 9,095,559 (“the ’559 patent.”) The ’559 patent is the subject
`
`of IPR2016-00829, filed by Lupin on April 1, 2016. On September 26, 2017, the
`
`Board issued a Final Written Decision in that IPR holding that all of the claims of
`
`the ’559 patent are unpatentable. Horizon strongly disagrees with the Board’s
`
`Decision and intends to appeal to the Federal Circuit.
`
`Par has separately filed petitions for IPR of the ’559 patent (IPR2017-01768)
`
`and ’278 patent (IPR2017-01767), which is also the subject of IPR2017-01159,
`
`filed by Lupin and instituted by the Board on September 28, 2017.
`
`III. BACKGROUND AND STATE OF THE ART
`In conducting an obviousness analysis, one must consider the state of the art
`
`at the time of the claimed inventions. As noted, a patient with a UCD cannot
`
`remove excess nitrogen from the plasma due to a defect in the operation of the urea
`
`cycle, and this results in elevated plasma ammonia levels. (Ex. 1001 at 1:21-23;
`
`Ex. 2006 at ¶¶ 36-37.) This genetic metabolic disorder is extremely rare and
`
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`difficult to diagnose and to treat. (Ex. 2006 at ¶¶ 33-34, 38-41.) It is estimated
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`that only one out of 35,000 live births have this disorder, resulting in only 113 new
`
`patients in the U.S. per year. (Ex. 2035 at 1-2; Ex. 2006 at ¶ 38; Ex. 2019 at 1-2.)
`
`Unfortunately, survival in patients with a UCD is extremely low because high
`
`levels of ammonia (hyperammonemia) are toxic to the brain. (Ex. 2006 at ¶¶ 38-
`
`40; Ex. 2008 at 1; Ex. 2020 at 21.) Between 1982 and 2003, patients presenting
`
`with hyperammonemia within the first 30 days of life had only a 35% survival rate
`
`(65% mortality rate). (Ex. 2006 at ¶¶ 34, 39; Ex. 2036 at 1423; Ex. 2017 at S66.)
`
`Because of the rarity and complexity of UCD, it requires the supervision of
`
`specialists in metabolic genetic disorders rather than general practitioners. (Ex.
`
`2006 at ¶¶ 33-34, 41; Ex. 2017 at S66-67, S69; Ex. 2034 at S33; Ex. 2044 at S87.)
`
`But even with frequent monitoring and specialized treatment, even well-controlled
`
`UCD patients remain at risk for life-threatening episodic hyperammonemia, which
`
`can lead to brain damage, coma and death. (Ex. 2006 at ¶¶ 38-39; Ex. 2016 at
`
`1605S-1606S; Ex. 2017 at S68 (reporting that only 21% of patients ages 12-74
`
`months had an IQ over 70); Ex. 2019 at 2 (reporting in 2012 that despite the
`
`existence of effective therapy outcomes remain poor); Ex. 1011 at 3; Ex. 2039 at
`
`133.) A UCD diagnosis therefore presents a patient and one’s family with a
`
`lifetime of coordinating a complex therapeutic regimen that involves promoting a
`
`child’s development while concurrently trying to avoid the potentially devastating
`
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`consequences of a hyperammonemic crisis. (Ex. 2006 at ¶¶ 40-41, 46; Ex. 2017 at
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
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`S67.)
`
`Dietary treatment is the “cornerstone of therapy” for UCD patients because
`
`minimizing protein intake will decrease the nitrogen load on the urea cycle. (Ex.
`
`2006 at ¶ 42; Ex. 2019 at 12-13.) But protein restriction decreases the nutrients
`
`needed for growth and normal development. Therefore, essential amino acid
`
`supplementation and/or the use of nitrogen scavenging drugs is often necessary to
`
`achieve good metabolic control. (Ex. 2006 at ¶ 42; Ex. 2021 at 32-33.) Nitrogen
`
`scavenging drugs, such as glycerol phenylbutyrate, use a different pathway than
`
`the urea cycle to remove excess nitrogen from the body. (Ex. 2006 at ¶ 43-44; Ex.
`
`1001 at 1:55-2:64.) Glycerol phenylbutyrate is a pre-prodrug of phenylacetic acid
`
`(“PAA”) and undergoes beta oxidation by the fatty acid oxidation cycle to produce
`
`PAA, which converts in vivo to phenylacetylglutamine (“PAGN”). (Ex. 2006 at ¶
`
`43; Ex. 1001 at 1:65-2:44.) PAGN is then excreted in the urine, bypassing the urea
`
`cycle. (Ex. 2006 at ¶ 43-44; Ex. 1001 at 1:65-2:46.) Each molecule of glutamine
`
`contains two nitrogen atoms, allowing the body to eliminate two waste nitrogen
`
`atoms for every molecule of PAGN excreted. (Id.)
`
`Although the prior art teaches that clinicians must monitor a patient’s
`
`clinical status and plasma ammonia level to track the effectiveness of UCD
`
`treatment, inherent difficulties exist with the interpretation of plasma ammonia
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`levels that have undermined its usefulness as a diagnostic tool. (Ex. 2006 at ¶¶ 47-
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`48.) With any given individual, ammonia values undergo a several-fold fluctuation
`
`throughout the day. Such factors as diet, infection, routine surgery, pregnancy,
`
`medication, and exercise can cause an increase in plasma ammonia levels. (Ex.
`
`2006 at ¶ 48; Ex. 2012 at [0090]; Ex. 2016 at 1608S; Ex. 2021 at 33; Ex. 2015 at
`
`75, Box 1.)
`
`Given the unpredictable fluctuations of ammonia values, clinicians did not
`
`rely on normal plasma ammonia levels prior to the ’966 patent as a basis to adjust a
`
`patient’s treatment. (Ex. 2006 at ¶ 48.) Clinicians only considered plasma
`
`ammonia levels well above the ULN as cause to act. (Ex. 2006 at ¶¶ 48, 95-104;
`
`Ex. 2019 at 9, Table 4; Ex. 2009 at S51 (“aim of long-term therapy has been to
`
`maintain metabolic control with plasma ammonia concentrations less than twice
`
`normal”).)
`
`IV. THE ’966 PATENT CLAIMS
`The ’966 patent addresses the limitations in the art noted above. For
`
`example, the ’966 patent explains that the dosing of nitrogen scavenging drugs is
`
`usually based upon the clinical assessment and measurement of ammonia, but such
`
`assessment and treatment are confounded by the fact that individual ammonia
`
`values vary over the course of a day and are impacted by the timing of the blood
`
`draw. (Ex. 1001 at 4:36-43; Ex. 2006 at ¶ 49.) The inventors of the ’966 patent
`
`9
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`identified a need for improved methods of determining the appropriate dosage of
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`Case No. IPR2017-01769
`U.S. Patent No. 9,326,966
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`nitrogen scavenging drugs such as glycerol phenylbutyrate to use in subjects
`
`having UCDs. (Ex. 1001 at 2:58-62; Ex. 2006 at ¶ 49.)
`
`In response to this need, the inventors investigated the previously unknown
`
`relationship between a fasting ammonia level and daily ammonia exposure. (Ex
`
`1001 at 4:64-5:53, 14:60-18:67, Example 1; Ex. 2006 at ¶ 50.) From their results,
`
`the inventors recognized for the first time that patients who were previously
`
`deemed to be well-controlled with a fasting ammonia level within the normal range
`
`carried an increased risk of having elevated ammonia levels compared to patients
`
`with ammonia levels at or below half the ULN. (Id.) The inventors also
`
`discovered that a fasting ammonia value that does not exceed half of the upper
`
`limit of normal is a clinically useful target that is predictive of average daily
`
`ammonia values over twenty-four hours. (Ex. 1001 at 4:64-5:18, 5:54-67; Ex.
`
`2006 at ¶ 50.) The inventors translated these discoveries into bright-line methods
`
`for adjusting the dosage of a nitrogen scavenging drug, glycerol phenylbutyrate.
`
`(Ex. 1001 at 2:65-3:12; Ex. 2006 at ¶ 50.) These methods provide significant
`
`advantages over the prior art by eliminating the confusion over conflicting
`
`ammonia levels, assuring ammonia control, and providing a statistical basis for the
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`adjustment of glycerol phenylbutyrate dosages. (Ex. 1001 at 5:13-18, 15:11-16;
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`Ex. 2006 at ¶ 50.)
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`Example 1 of the ’966 patent details the inventors’ investigation of the
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`relationship between fasting ammonia levels and the profile of ammonia levels
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`over twenty-four hours using plasma ammonia data from sixty-five UCD patients.
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`(Ex. 1001 at 14:60-15:15; Ex. 2006 at ¶ 51.) From their statistical analysis of this
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`data, the inventors concluded with 95% confidence that the true probability of
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`having an ammonia value AUC in the desired normal range when a fasting
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`ammonia level is less than or equal to half the upper limit of normal is on average
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`84% and as high as 93%. (Ex. 1001 at 17:54-18:67; Ex. 2006 at ¶ 51-52.)
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`Conversely, the inventors determined that a patient with a fasting ammonia level
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`above half the ULN but below the ULN had only a 58% likelihood of having an
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`average daily ammonia level in the normal range. (Ex. 1001 at 17:1-55 (Table 2);
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`Ex. 2006 at ¶ 52.)
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`Thus, the inventors of the ’966 patent were the first to recognize that a
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`normal fasting plasma ammonia level (i.e., below the ULN but above half the
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`ULN) carries an increased risk of having elevated ammonia levels. (Ex. 1001 at
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`17:1-55 (Table 2); Ex. 2006 at ¶ 52.) And the inventors translated this discovery
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`into treatment methods that eliminated prior art confusion over plasma ammonia
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`levels. (Ex. 1001 at 5:12-17.) As Dr. Enns explains, the information reported in
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`the ’966 patent represented “an advance in the treatment of urea cycle disorders
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`and a new way of thinking about treating patients with this disorder.” (Ex. 2006 at
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`¶ 127.) Without this, a POSA would not have had any expectation that an
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`increased dosage of nitrogen scavenging drug when the patient’s fasting plasma
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`level was already within normal limits would confer a treatment benefit, i.e.,
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`ensure that the patient stayed within the normal limits over the course of the day
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`and reduce the likelihood of hyperammonemic crises. (Ex. 2006 at ¶ 127.) Rather,
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`the POSA was content with plasma ammonia values within the normal range. (Ex.
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`2006 at ¶¶ 95-104.)
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`V. CLAIM INTERPRETATION
`Under the broadest reasonable interpretation standard, claim terms are given
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`their ordinary and customary meaning, as would be understood by one of ordinary
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`skill in the art at the time of the invention, in light of the specification. Hospitality
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`Core Servs. LLC v. Nomadix, Inc., IPR2016-0052, Paper 8 at 7 (Apr. 27, 2016); In
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`re Smith Int’l, Inc., No. 2016-2303, slip op. at 12-13 (Fed. Cir. Sept. 26, 2017).
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`The Patent Owner proposes an interpretation of the term “upper limit of
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`normal” that mirrors the definition of the term set forth in the specification of the
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`’966 patent. The ’966 patent provides the following definition for ULN (“upper
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`limit of normal”): “The ULN for blood ammonia typically represents the highest
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`level in the range of normal values . . .” (Ex. 1001 at 12:11-12.) Elsewhere, the
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`’966 patent repeatedly recognizes that normal blood ammonia values are in a
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`range, and that the ULN is the highest level within that range. (See, e.g., Ex. 1001
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`at 4:31-32 (“Control of blood ammonia level generally refers to ammonia values
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`within the normal range . . . ”); 3:11-12, 3:37-38, 3:67-4:1 (“In certain
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`embodiments, the ULN is around 35 μmol/L . . . ”); 12:46-49 (“In certain of these
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`embodiments, the ULN for blood ammonia may be in the range of . . . ”).) The
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`Patent Owner’s interpretation of the term “upper limit of normal” as representing
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`“the highest value in the range of normal values” is thus described in the
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`specification “with reasonable clarity, deliberateness, and precision.” In re
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`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994); (Ex. 2006 at ¶¶ 59-62.)
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`Accordingly, the Board should adopt the Patent Owner’s proposed construction of
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`“upper limit of normal.”
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`The Patent Owner proposes that the remaining claim terms in the ’966 patent
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`claims should be assigned their ordinary meaning.
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`VI. PERSON OF ORDINARY SKILL IN THE ART
`Based on the subject matter of the ’966 patent claims, a POSA would have
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`had the following qualifications: (a) an M.D. or equivalent degree, (b) at least three
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`years of residency/fellowship training in Medical Genetics, including Biochemical
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`Genetics, followed by certification in Clinical Genetics and Clinical or Medical
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`Biochemical Genetics by the American Board of Medical Genetics and Genomics,
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`and (c) at least five years of experience treating patients with nitrogen retention
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`disorders, including UCDs (urea cycle disorders). (Ex. 2006 at ¶ 30.)
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`Horizon’s expert Dr. Enns meets this definition. (Ex. 2006 at ¶¶ 6-17.) He
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`is a Professor of Pediatrics-Medical Genetics at the Lucile Salter Packard
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`Children’s Hospital of Stanford University and an internationally recognized
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`expert in UCD treatment. (Ex. 2006 at ¶¶ 9-12; Ex. 2007 at 1.) He completed a
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`three-year residency in medical genetics at the University of California, San
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`Francisco, and is board certified in Clinical Genetics and Clinical Biochemical
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`Genetics. (Ex. 2006 at ¶¶ 6-8; Ex. 2007 at 2.) These certifications demonstrate
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`that he possesses, inter alia, “the ability to integrate clinical and genetic
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`information and understand the uses, limitations, interpretation, and significance of
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`specialized laboratory and clinical procedures.” (Ex. 2026; Ex. 2006 at ¶ 8.) Dr.
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`Enns testifies that Horizon’s definition of a POSA is appropriate for the claimed
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`subject matter and that he meets (and exceeds) this definition. (Ex. 2006 at ¶¶ 18,
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`30.)
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`Petitioner proposes that a POSA would have been a “physician or scientist
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`with a Ph.D. or M.D. degree and specialized training in the diagnosis or treatment
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`of inherited metabolic disorders, such as UCD and other nitrogen retention
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`disorders.” (Pet. at 20; Ex. 1002 at ¶ 47). Petitioner also provides that “such a
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`person may also have post-graduate training to fulfill the requirements of the
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`American Board of Medical Genetics and Genomics in Clinical Genetics, Clinical
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`Biochemical Genetics, or Medical Biochemical Genetics.” (Pet. at 20.)
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`Petitioner’s POSA definition should not be adopted because it does not require any
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`experience in treating UCDs or specify the amount of specialized training needed
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`in the treatment or diagnosis of patients with nitrogen retention disorders, such as
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`UCDs, to qualify as a POSA. Accordingly, Petitioner’s definition of a POSA is
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`too broad to ensure that a person who meets its definition possesses the expertise
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`necessary to navigate the complex treatment of UCD patients. And Petitioner’s
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`definition does not align with the emphasis in the prior art that the complex
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`treatment of UCD requires experienced personnel with specific and extensive
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`expertise in genetic metabolic disorders. (Ex. 2017 at S66, S69; Ex. 2034 at S33;
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`Ex. 2037 at S86-87; Ex. 2006 at ¶¶ 31-34; Envtl. Designs, Inc. v. Union Oil Co.,
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`713 F.2d 693, 696 (Fed. Ci