throbber

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner
`
`v.
`
`HORIZON THERAPEUTICS, LLC,
`Patent Owner
`__________
`
`Case IPR2017-01767
`Patent 9,254,278
`__________
`
`HORIZON THERAPEUTICS, LLC’S RESPONSE TO PETITION FOR
`INTER PARTES REVIEW
`
`
`

`

`I.
`II.
`
`TABLE OF CONTENTS
`INTRODUCTION ........................................................................................... 1
`BACKGROUND AND STATE OF THE ART .............................................. 6
`A.
`Prior Art at Issue .................................................................................... 6
`B.
`Technical Background on Treatment of UCDs ..................................... 6
`III. THE ’278 PATENT CLAIMS .......................................................................10
`IV. PAR’S DEFINITION OF ONE OF ORDINARY SKILL IN THE
`ART IS OVERLY BROAD ..........................................................................12
`CLAIM INTERPRETATION .......................................................................15
`V.
`VI. CLAIMS 1-15 WOULD NOT HAVE BEEN OBVIOUS IN VIEW
`OF THE ASSERTED PRIOR ART ..............................................................17
`A.
`The Board’s Finding of Unpatentability of the ’215 Patent is
`Inapplicable .........................................................................................17
`Ground 3 Fails .....................................................................................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 .............................................................19
`(a)
`The Cited Prior Art Provides No Motivation to
`Increase the Dosage for a Patient With a Normal
`Plasma Ammonia Level ................................................. 20
`The Prior Art as a Whole Refutes Par’s Assertion
`that a POSA Would Have Been Motivated to
`Perform the Claimed Methods ....................................... 29
`The Variability in Plasma Ammonia Levels Discouraged
`Reliance on Normal Plasma Ammonia Levels in Making
`Dosage Adjustments .................................................................35
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`i
`
`
`B.
`
`(b)
`
`2.
`
`

`

`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`3.
`
`4.
`
`5.
`
`C.
`
`The Prior Art Does Not Suggest Reliance on Fasting
`Plasma Ammonia Measurements For Dosage Adjustment ......40
`Par Fails to Demonstrate a Reasonable Expectation of
`Success ......................................................................................43
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given No Weight ...................................47
`Grounds 2 and 4 Fail ...........................................................................50
`1.
`The Prior Art Does Not Suggest Targeting a Fasting
`Plasma Ammonia Level at or Below Half the ULN .................50
`Dr. Sondheimer’s Unsupported and Hindsight-Driven
`Testimony Should be Given No Weight ...................................52
`Par Fails to Demonstrate a Reasonable Expectation of
`Success ......................................................................................57
`D. Ground 1 Fails .....................................................................................60
`VII. CONCLUSION ..............................................................................................63
`
`
`
`2.
`
`3.
`
`ii
`
`
`

`

`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`TABLE OF AUTHORITIES
`
`Cases
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) ..................................................................... 56, 57
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) ....................................................................... 34, 47
`Belden Inc. v. Berk-Tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) ............................................................................22
`DePuy Spine Inc. v. Medtronic Sofamor Danek, Inc.,
`567 F.3d 1314 (Fed. Cir. 2009) ............................................................................44
`Disney Enter., Inc. v. Kappos,
`923 F. Supp. 2d 788 (E.D. Va. 2013) ...................................................................31
`DSS Tech. Mgmt., Inc. v. Apple Inc.,
`885 F.3d. 1367 (Fed. Cir. 2018) .................................................................... 56, 57
`Envtl. Designs, Inc. v. Union Oil Co.,
`713 F.2d 693 (Fed. Cir. 1983) ..............................................................................15
`Hospitality Core Services LLC v. Nomadix, Inc.,
`IPR2016-00052, Paper 8 (PTAB Apr. 27, 2016) .................................................15
`In re Cyclobenzaprine Extended-Release Patent Litigation,
`676 F.3d 1063 (Fed. Cir. 2012) ............................................................................44
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) ..............................................................................47
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) ............................................................................26
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) ..............................................................................16
`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) ......................................................................... 22, 23
`
`iii
`
`
`

`

`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`Institut Pasteur & Universite Pierre Et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) ..................................................................... 45, 58
`K/S HIMPP v. Hear-Wear Techs., LLC,
`751 F.3d 1362 (Fed. Cir. 2014) ............................................................................56
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) .............................................................................................56
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................................20
`Perfect Web Techs., Inc. v. InfoUSA, Inc.,
`587 F.3d 1324 (Fed. Cir. 2009) ............................................................................57
`Tissue Transplant Tech. Ltd. et al. v. Mimedx Group, Inc.,
`IPR2015-00320, Paper 13 (PTAB June 29, 2015) ...............................................47
`W.L. Gore & Assocs. Inc. v. Garlock, Inc.,
`721 F.2d 1540 (Fed. Cir. 1983) ............................................................................54
`Statutes
`35 U.S.C. § 102(b) ..................................................................................................... 6
`35 U.S.C. § 103(a) ..................................................................................................... 6
`35 U.S.C. § 316(e) ...................................................................................................26
`Regulations
`37 C.F.R. § 42.65(a) .......................................................................................... 34, 47
`
`
`
`iv
`
`
`

`

`INTRODUCTION
`Par Pharmaceutical, Inc. (“Par” or “Petitioner”) has failed to meet its burden
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`I.
`
`of establishing that claims 1-15 of U.S. Patent No. 9,254,278 (“the ’278 patent”)
`
`are not patentable. Thus, Horizon Therapeutics, LLC (“Horizon” or “Patent
`
`Owner”) respectfully requests that the Patent Trial and Appeal Board (“Board”)
`
`affirm the patentability of these claims.
`
`The Board instituted inter partes review (“IPR”) proceedings on four
`
`grounds based on Par’s mischaracterizations of the prior art. See Decision -
`
`Institution of Inter Partes Review (Paper No. 10, herein “Institution Decision”).
`
`As demonstrated herein, one of ordinary skill in the art would not have been led to
`
`the claimed treatment methods based on the prior art that Par has identified.
`
`Indeed, Par’s obviousness position is nothing but a hindsight analysis of the prior
`
`art. The Supreme Court and the Federal Circuit have repeatedly stated that this
`
`type of hindsight approach to obviousness is improper.
`
`The ’278 patent claims are directed to innovative methods of treating a
`
`patient suffering from a urea cycle disorder (“UCD”) and of 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),
`
`
`
`1
`
`

`

`difficult to diagnose and to treat, and, most alarmingly, have an extremely low
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`survival rate (an estimated 65% mortality rate in newborns presenting with UCD).
`
`UCDs are characterized by the accumulation of toxic and potentially fatal levels of
`
`ammonia 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 ’278 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 ’278 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 ’278 patent analyzed extensive plasma ammonia
`
`
`
`2
`
`

`

`data and discovered that certain UCD patients with normal fasting plasma
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`ammonia levels were at risk and should be administered an increased dosage of
`
`medication.
`
`To address this previously unrecognized problem, the inventors developed
`
`treatment methods that counterintuitively direct physicians to increase the dosage
`
`of glycerol phenylbutyrate for certain UCD patients previously considered to have
`
`satisfactory normal ammonia levels. For example, representative independent
`
`claim 4 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
`
`24:31-45.) 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.
`
`Par’s assertion that the claimed methods would have been obvious is
`
`unfounded and hindsight-fueled. Par fails to demonstrate even a prima facie case
`
`of obviousness because Par 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
`
`
`
`3
`
`

`

`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`the risk associated with a plasma ammonia level below the ULN and above half the
`
`ULN was in U.S. Patent No. 9,095,559 (“the ’559 patent”), of which the ’278
`
`patent is a continuation. And the prior art, including Par’s primary references—
`
`Fernandes and the ’859 Publication—refutes Par’s obviousness 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-
`
`221.) 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 likewise provide no support for Par because
`
`they suggest that ammonia levels anywhere within or near the normal range
`
`indicate satisfactory ammonia control. And none of these references, nor the
`
`additionally cited Simell or Blau, suggests dosage adjustment based on normal
`
`fasting plasma ammonia levels.
`
`
`
`4
`
`

`

`Aside from the prior art’s failure to recognize any risk or disadvantage
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`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
`
`dosing adjustments in stabilized patients due to the recognized potential for
`
`unpredictable fluctuations in daily plasma ammonia levels.
`
`Finding no prior art support for its theory, Par 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 as it is
`
`unsupported and impermissibly interprets the prior art through the lens of the ’278
`
`patent claims. Dr. Sondheimer also ignores decades of prior art concerning the use
`
`of nitrogen scavenging drugs 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 repeatedly administering more drug to a
`
`patient who already has satisfactory normal ammonia levels when there was no
`
`known benefit in doing so. Thus, on this basis alone, Par has failed as a matter of
`
`law to establish that the challenged claims are obvious.
`
`
`
`5
`
`

`

`For the reasons herein, Par fails to establish that claims 1-15 of the ’278
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`patent are not patentable. Thus, Horizon respectfully requests that the Board
`
`affirm the patentability of these claims.
`
`II. BACKGROUND AND STATE OF THE ART
`Prior Art at Issue
`A.
`The Board instituted this IPR as to claims 1-15 of the ’278 patent based on
`
`the following four grounds:
`
`References
`Ground Basis
`’859 Publication
`1
`35 U.S.C. § 102(b)
`2
`35 U.S.C. § 103(a) Fernandes in view of the ’859
`Publication and Lee or Lichter-Konecki,
`optionally in further view of Blau or
`Simell
`35 U.S.C. § 103(a) Fernandes in view of the ’859
`Publication, and optionally in view of
`Blau, Simell, and/or Lee
`35 U.S.C. § 103(a) Fernandes in view of the ’859
`Publication and Lee or Lichter-Konecki,
`and optionally further in view of Blau or
`Simell
`
`3
`
`4
`
`Claims
`1-3
`1-3
`
`4, 6-8,
`10-12,
`14-15
`5, 9, 13
`
`
`(Institution Decision at 20).
`Technical Background on Treatment of UCDs
`B.
`In conducting an obviousness analysis, one must consider the state of the art
`
`at the time of the claimed inventions. As noted, UCD patients cannot remove
`
`
`
`6
`
`

`

`excess nitrogen due to a defect in the operation of the urea cycle, resulting in
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`elevated plasma ammonia levels. (Ex. 1001 at 1:19-24; Ex. 2006 at ¶¶ 36-37.)
`
`This genetic metabolic disorder is extremely rare and difficult to diagnose and to
`
`treat. (Ex. 2006 at ¶¶ 31-34, 38-41.) It is estimated 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 UCD patients 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-
`
`68.)
`
`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 ¶¶ 30-34, 41; Ex. 2017 at S66-67, S69; Ex. 2034 at S33; Ex. 2037 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, 41; Ex. 2016 at
`
`1605S-1606S; Ex. 2017 at S68 (reporting that only 21% of patients ages 12-74
`
`
`
`7
`
`

`

`months had an IQ over 70); Ex. 2019 at 1-2; Ex. 1011 at 3; Ex. 2039 at 133.) A
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`UCD diagnosis therefore presents a patient and the patient’s family with a lifetime
`
`of coordinating a complex therapeutic regimen aimed at promoting growth and
`
`development while concurrently trying to avoid the potentially devastating
`
`consequences of a hyperammonemic crisis. (Ex. 2006 at ¶¶ 40-41, 46; Ex. 2017 at
`
`S67; Ex. 2019 at 12-13.)
`
`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 ¶¶ 43-45;
`
`Ex. 1001 at 1:55-2:60.) Glycerol phenylbutyrate is a pre-prodrug of phenylacetic
`
`acid (“PAA”) and undergoes the fatty acid oxidation cycle to produce PAA, which
`
`converts in vivo to phenylacetylglutamine (“PAGN”). (Ex. 2006 at ¶¶ 43-44; Ex.
`
`1001 at 1:65-2:44.) PAGN is then excreted in the urine, bypassing the urea cycle.
`
`
`
`8
`
`

`

`(Id.) Each molecule of glutamine contains two nitrogen atoms, allowing the body
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`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
`
`levels that have undermined its usefulness as a diagnostic tool. (Ex. 2006 at ¶¶ 47-
`
`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. (Id.;
`
`Ex. 2013 at 101; 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 ’278 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. (Id. at ¶¶ 48, 96-105; 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”).)
`
`
`
`9
`
`

`

`III. THE ’278 PATENT CLAIMS
`The ’278 patent addresses the limitations in the art noted above. For
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`example, the ’278 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 4:34-41; Ex. 2006 at ¶ 49.) The inventors of the ’278 patent
`
`identified a need for improved methods of determining the appropriate dosage of
`
`nitrogen scavenging drugs such as glycerol phenylbutyrate to use in subjects
`
`having UCDs. (Ex. 1001 at 2:56-60; 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 4:62-5:15, 14:60-19:4 (Example 1); Ex. 2006 at ¶¶ 50-51.) 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 ULN is a clinically useful target that is predictive of average daily ammonia
`
`
`
`10
`
`

`

`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`values over twenty-four hours. (Ex. 1001 at 4:64-5:15, 5:51-6:1; 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
`
`2:64-3:10; 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 adjustment of
`
`glycerol phenylbutyrate dosages. (Ex. 1001 at 5:10-15, 15:10-14; Ex. 2006 at
`
`¶ 50.)
`
`Example 1 of the ’278 patent details the inventors’ investigation of the
`
`relationship between fasting ammonia levels and the profile of ammonia levels
`
`over twenty-four hours using plasma ammonia data from sixty-five UCD patients.
`
`(Ex. 1001 at 14:60-15:15; Ex. 2006 at ¶ 51.) From their statistical analysis, the
`
`inventors concluded with 95% confidence that the true probability of having an
`
`ammonia value (measured as “area under the curve” or “AUC”) in the desired
`
`normal range when a fasting ammonia level is less than or equal to half the ULN is
`
`on average 84% and as high as 93%. (Ex. 1001 at 17:56-19:4; Ex. 2006 at ¶¶ 51-
`
`52.) Conversely, the inventors determined that a patient with a fasting ammonia
`
`level above half the ULN but below the ULN had only a 58% likelihood of having
`
`
`
`11
`
`

`

`an average daily ammonia level in the normal range. (Ex. 1001 at 17:1-54 (Table
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`2); Ex. 2006 at ¶ 52.)
`
`Thus, the ’278 patent inventors were the first to recognize that a normal
`
`fasting plasma ammonia level (i.e., below the ULN but above half the ULN)
`
`carries an increased risk of having elevated ammonia levels. (Id.) The inventors
`
`translated this discovery into treatment methods that eliminated prior art confusion
`
`over plasma ammonia levels. (Ex. 1001 at 5:10-15.) As Dr. Enns explains, the
`
`information reported in the ’278 patent represented “an advance in the treatment of
`
`urea cycle disorders and a new way of thinking about treating patients with this
`
`disorder.” (Ex. 2006 at ¶ 128.) Without this, a POSA would not have had any
`
`expectation that an increased dosage of nitrogen scavenging drug when the
`
`patient’s fasting plasma level was already within normal limits would confer a
`
`treatment benefit, i.e., ensure that the patient stayed within the normal limits over
`
`the course of the day and reduce the likelihood of hyperammonemic crises. (Id.)
`
`Rather, the POSA was content with plasma ammonia values within the normal
`
`range. (Id. at ¶¶ 96-105.)
`
`IV. PAR’S DEFINITION OF ONE OF ORDINARY SKILL IN THE ART
`IS OVERLY BROAD
`Based on the subject matter of the ’278 patent claims, a POSA would have
`
`had the following qualifications: (a) an M.D. or equivalent degree, (b) at least three
`
`
`
`12
`
`

`

`years of residency/fellowship training in Medical Genetics, including Biochemical
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`Genetics, followed by certification in Clinical Genetics and Clinical or Medical
`
`Biochemical Genetics by the American Board of Medical Genetics and Genomics,
`
`and (c) at least five years of experience treating patients with nitrogen retention
`
`disorders, including UCDs (urea cycle disorders). (Ex. 2006 at ¶ 30.)
`
`Horizon’s expert Dr. Enns meets this definition. (Id. at ¶¶ 6-17.) He is a
`
`Professor of Pediatrics-Medical Genetics at the Lucile Salter Packard Children’s
`
`Hospital of Stanford University and an internationally recognized expert in UCD
`
`treatment. (Id. at ¶¶ 9-12; Ex. 2007 at 1.) He completed a three-year residency in
`
`medical genetics at the University of California, San Francisco, and is board
`
`certified in Clinical Genetics and Clinical Biochemical Genetics. (Ex. 2006 at ¶¶
`
`6-8; Ex. 2007 at 2.) These certifications demonstrate that he possesses, broad
`
`knowledge in, inter alia, “the etiology, pathogenesis, clinical manifestations, and
`
`management of human inherited biochemical disorders,” including UCDs. (Ex.
`
`2026; Ex. 2006 at ¶¶ 8, 32.) Dr. Enns testifies that Horizon’s POSA definition is
`
`appropriate for the claimed subject matter and that he meets (and exceeds) this
`
`definition. (Ex. 2006 at ¶¶ 18, 30.)
`
`Par proposes that a POSA would have been a “physician or scientist with a
`
`Ph.D. or M.D. degree and specialized training in the diagnosis or treatment of
`
`
`
`13
`
`

`

`inherited metabolic disorders, such as UCD and other nitrogen retention
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`disorders.” (Pet. at 18-19; Ex. 1002 at ¶ 40). Par also provides that “such a person
`
`may also have post-graduate training to fulfill the requirements of the American
`
`Board of Medical Genetics and Genomics in Clinical Genetics, Clinical
`
`Biochemical Genetics, or Medical Biochemical Genetics.” (Pet. at 18-19
`
`(emphasis added).) Par’s definition should not be adopted because it does not
`
`require any experience treating UCDs or specify the amount of specialized training
`
`needed in the treatment or diagnosis of patients with nitrogen retention disorders,
`
`such as UCDs. Indeed, the Board in IPR2016-00829, concerning the ’559 patent
`
`(the parent of the ’278 patent), specifically found that it “agree[d] with Patent
`
`Owner that one of ordinary skill in the art would have experience treating patients
`
`with nitrogen retention disorders, including UCDs.” (IPR2016-00829, Final
`
`Written Decision, Paper No. 42 at 15.)1
`
`
`1 The ’559 patent is also the subject of IPR2016-00829, filed by Lupin on April 1,
`
`2016. On September 26, 2017, the Board issued a Final Written Decision holding
`
`that all of the claims of the ’559 patent are unpatentable. Horizon strongly
`
`disagrees with the Board and filed an appeal of its Decision to the Federal Circuit
`
`on November 22, 2017.
`
`
`
`
`
`14
`
`

`

`Accordingly, Par’s definition is too broad to ensure that a POSA possesses
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`the expertise necessary to navigate the complex treatment of UCD patients. And
`
`Par’s definition does not align with the prior art’s emphasis that the complexity of
`
`UCD treatment requires experienced personnel with specific and extensive
`
`expertise in genetic metabolic disorders. (Ex. 2017 at S66, S69; Ex. 2034 at S33;
`
`Ex. 2037 at S86-87; Ex. 2006 at ¶¶ 31-34; Envtl. Designs, Inc. v. Union Oil Co.,
`
`713 F.2d 693, 696 (Fed. Cir. 1983) (listing the prior art, the sophistication of the
`
`technology, and the education of workers in the field as factors to consider when
`
`determining the level of ordinary skill).) Thus, as an initial matter, because Par’s
`
`expert Dr. Sondheimer employed a diluted conception of a POSA without any
`
`required experience treating UCD patients as found necessary in IPR2016-00829,
`
`he did not testify as to the motivations or understandings of the proper POSA.
`
`Par’s obviousness analysis, which relies on Dr. Sondheimer’s unsupported
`
`testimony to assert the unpatentability of claims 1-15, should therefore be rejected.
`
`V. CLAIM INTERPRETATION
`Under the broadest reasonable interpretation standard, claim terms are given
`
`their ordinary and customary meaning, as would be understood by a POSA at the
`
`time of the invention, in light of the specification. Hospitality Core Servs. LLC v.
`
`Nomadix, Inc., IPR2016-00052, Paper 8 at 7 (Apr. 27, 2016).
`
`
`
`15
`
`

`

`Horizon proposes an interpretation of the term “upper limit of normal”
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`(“ULN”) that mirrors the definition set forth in the ’278 patent specification. The
`
`’278 patent provides the following definition for ULN: “The ULN for blood
`
`ammonia typically represents the highest level in the range of normal values . . .”
`
`(Ex. 1001 at 12:7-8.) The ’278 patent repeatedly recognizes that normal blood
`
`ammonia values are in a range, with the ULN as the highest level within that range.
`
`(See, e.g., Ex. 1001 at 4:29-30 (“Control of blood ammonia level generally refers
`
`to ammonia values within the normal range . . .”); 3:9-10, 3:35-36, 3:65-66; 12:46-
`
`49 (“In certain of these embodiments, the ULN for blood ammonia may be in the
`
`range of . . .”).) Horizon’s interpretation of the term “upper limit of normal” as
`
`representing “the highest value in the range of normal values” is thus described in
`
`the specification “with reasonable clarity, deliberateness, and precision.” In re
`
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994); (Ex. 2006 at ¶¶ 60-63.)
`
`Accordingly, the Board should adopt Horizon’s proposed construction of “upper
`
`limit of normal.”
`
`Horizon proposes that the remaining claim terms in the ’278 patent claims
`
`should be assigned their ordinary meaning.
`
`
`
`16
`
`

`

`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`VI. CLAIMS 1-15 WOULD NOT HAVE BEEN OBVIOUS IN VIEW OF
`THE ASSERTED PRIOR ART
`A. The Board’s Finding of Unpatentability of the ’215 Patent is
`Inapplicable
`The Petition asserts that the “challenged claims are nearly identical” to the
`
`claims of U.S Patent No. 8,404,215 (“the ’215 patent”), held unpatentable in
`
`IPR2015-01127, and thus, should also be found unpatentable. (Pet. at 2-3.) But
`
`the Board’s finding of unpatentability for the ’215 patent has no bearing here
`
`because the ’278 patent’s methods of treatment differ from those of the ’215
`
`patent.
`
`Significantly, the Board construed the ’215 patent claims to include dosage
`
`adjustment for patients who have any plasma ammonia level greater than half the
`
`ULN. (IPR2015-01127, Paper No. 49 at 14-15.) Par asserted (and the Board was
`
`persuaded) that the prior art taught increasing the dosage of nitrogen scavenging
`
`medication where plasma ammonia levels were greater than the ULN, but did not
`
`suggest that the prior art suggested increasing the dosage for ammonia levels
`
`below the ULN. (IPR2015-01127, Paper No. 2 at 19-22, citing Ex. 1002 at ¶¶ 53,
`
`57; Paper No. 49 at 17.) In contrast, as depicted below, the ’278 patent claims
`
`address increasing the dosage for fasting ammonia levels within the normal range
`
`i.e., between half the ULN and the ULN. Thus, the reason the Board found the
`
`claims of the ’215 patent unpatentable is not present for the ’278 patent. And, as
`
`
`
`17
`
`

`

`explained herein, the prior art raised in the ’215 patent IPR, including Fernandes,
`
`Case No. IPR2017-01767
`U.S. Patent No. 9,254,278
`
`
`does not render the ’278 patent claims obvious.
`
`
`
`B. Ground 3 Fails
`Par asserts that independent claims 4, 8 and 12 and dependent claims 6, 7,
`
`10, 11, 14 and 15 are obvious over Fer

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket