`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`PAR PHARMACEUTICAL, INC.,
`Petitioner,
`
`v.
`
`HORIZON THERAPEUTICS, INC.,
`Patent Owner.
`
`_____________________
`
`Case IPR: Unassigned
`Patent 9,326,966
`_____________________
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT
`NO. 9,326,966 PURSUANT TO 35 U.S.C. § 311–319 AND 37 C.F.R. § 42
`
`
`
`
`
`
`
`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`
`
`

`

`
`I. 
`
`II. 
`
`IPR Petition of U.S. Patent No. 9,326,966
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1 
`
`BACKGROUND REGARDING THE UREA CYCLE,
`UCDS, AND NITROGEN SCAVENGING DRUGS. .................................... 4 
`
`A. 
`
`B. 
`
`C. 
`
`The Urea Cycle ....................................................................................... 4 
`
`Urea Cycle Disorders. ............................................................................ 5 
`
`Nitrogen Scavenging Drugs ................................................................... 6 
`
`D.  GPB ........................................................................................................ 9 
`
`E. 
`
`The Standard Of Care For Administering Nitrogen
`Scavenging Drugs................................................................................. 11 
`
`III.  GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ............................... 12 
`
`IV.  PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................. 13 
`
`V.  MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................. 13 
`
`A. 
`
`B. 
`
`C. 
`
`Real-Parties-In-Interest ........................................................................ 13 
`
`Related Matters ..................................................................................... 14 
`
`Lead And Backup Counsel (37 C.F.R. § 42.8(b)(3))
`And Service Information (37 C.F.R. § 42.8(b)(4)) .............................. 15 
`
`VI.  SUMMARY OF THE ’966 PATENT ........................................................... 15 
`
`VII.  PERSON OF ORDINARY SKILL IN THE ART. ....................................... 20 
`
`VIII.  STATEMENT OF THE PRECISE RELIEF REQUESTED
`AND THE REASONS THEREFORE (37 C.F.R. §§ 42.22(a)
`AND 42.104(b)). ............................................................................................ 21 
`
`A. 
`
`Claim Construction .............................................................................. 24 
`
`
`
`i
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`1. 
`
`“Plasma Ammonia Level” Means “The Level
`Of Ammonia Found In Blood Or Plasma”. .............................. 25 
`
`B. 
`
`Brief Overview Of Prior Art Underlying The Grounds. ...................... 26 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`6. 
`
`Fernandes (Ex. 1015) ................................................................ 26 
`
`The ’859 Publication (Ex. 1004) ............................................... 27 
`
`Blau (Ex. 1006) ......................................................................... 29 
`
`Simell (Ex. 1007) ...................................................................... 29 
`
`Lee (Ex. 1010) ........................................................................... 30 
`
`Lichter-Konecki (Ex. 1017) ...................................................... 30 
`
`C. 
`
`Ground 1: Claims 1-3, 5, 6, 8, 9 And 11 Of The
`’966 Patent Are Obvious Under 35 U.S.C. § 103(a)
`Over Fernandes In View Of The ’859 Publication,
`Optionally In View Of Blau, Simell And/Or Lee. ............................... 31 
`
`1. 
`
`Independent Claims 1, 6 And 9 Are Obvious. .......................... 32 
`
`Preambles Of Independent Claims 1, 6 And 9 ............... 32 
`a. 
`Step (a) Of Independent Claims 1, 6, And 9 .................. 35 
`b. 
`Step (b) Of Independent Claims 1, 6, And 9 .................. 37 
`c. 
`Step (c) Of Independent Claims 1, 6, And 9 .................. 38 
`d. 
`The Additional Limitation In Challenged Claim 1 ........ 44 
`e. 
`Dependent Claims 2, 3, 5, 8, And 11 ........................................ 45 
`
`2. 
`
`Dependent Claims 2 And 3 ............................................. 45 
`a. 
`Dependent Claims 5, 8, And 11 ...................................... 46 
`b. 
`3.  Motivation To Combine Prior Art Applied In
`Ground 1 ................................................................................... 46 
`
`D.  Ground 2: Dependent Claims 4, 7, And 10 Are
`Obvious Under 35 U.S.C. § 103(a) Over Fernandes In
`View Of The ’859 Publication And Lee Or Lichter-
`
`
`
`ii
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`Konecki, Optionally In Further View Of Blau Or
`Simell. ................................................................................................... 48 
`
`E. 
`
`Ground 3: Dependent Claim 13 Is Obvious Under 35
`U.S.C. § 103(a) Over The ’859 Publication In View Of
`Lee Or Lichter-Konecki, Optionally In Further View
`Of Blau. ................................................................................................ 56 
`
`1. 
`
`All Steps Of Independent Claim 12 Are Taught
`Or Suggested By The ’859 Publication
`Optionally In View Of Blau. ..................................................... 56 
`
`The Preamble Of Independent Claim 12 ........................ 56 
`a. 
`Step (a) Of Independent Claim 12 .................................. 56 
`b. 
`Step (b) Of Independent Claim 12 .................................. 57 
`c. 
`Step (c) Of Independent Claim 12 .................................. 61 
`d. 
`The Additional Steps Of Claim 13 Are Taught
`Or Suggested By One Or More Of Lee, Lichter-
`Konecki And Blau. .................................................................... 61 
`
`2. 
`
`F. 
`
`Secondary Considerations .................................................................... 62 
`
`IX.  CONCLUSION .............................................................................................. 62 
`
`
`
`
`
`iii
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`Par Pharmaceutical, Inc. (“Petitioner” or “Par”) petitions for Inter Partes
`
`Review (“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. Part 42 of claims 1-11
`
`and 131 (“Challenged Claims”) of U.S. Patent No. 9,326,966 (“’966 Patent”). (Ex.
`
`1001.)
`
`I.
`
`INTRODUCTION
`
`The Challenged Claims cover methods of selecting an initial dose and
`
`adjusting a dose of a known prior art drug in accordance with prior art standard-of-
`
`care methods for treating urea cycle disorders (“UCD”) to achieve a known result–
`
`reducing and maintaining low levels of toxic ammonia in the subject’s blood.
`
`At the time of filing of the ’966 Patent, it was already known in the prior art
`
`that the standard of care for managing urea cycle disorders in all patients, including
`
`pediatric and adult patients, was to use nitrogen scavenging drugs, which react
`
`with chemical precursors to ammonia, including the amino acid glutamine, before
`
`it can be metabolized into ammonia. (Ex. 1015, 216-219; Ex. 1004, [0005, 0015];
`
`
`1 On June 28, 2017, Horizon filed a statutory disclaimer pursuant to under 35
`
`U.S.C. § 253(a) disclaiming claims 12, 14 and 15 of the ’966 patent.
`
`
`
`1
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`Ex. 1009, 1.) Glyceryl tri-[4-phenylbutyrate]2 (“GPB”), the drug in the Challenged
`
`Claims, was a well-known nitrogen scavenging drug in the art prior to the filing of
`
`the ’966 Patent. (See e.g., Ex. 1004, [0020].)
`
`Most of the Challenged Claims are directed to the purported discovery of a
`
`method in which GPB is administered to pediatric and adult subjects having
`
`plasma ammonia levels greater than one-half of the “upper limit of normal”
`
`(“ULN”). Although the Challenged Claims further state that the subjects also have
`
`a plasma ammonia level that is less than ULN, the administration of nitrogen
`
`scavenging drugs to subjects having plasma ammonia in the claimed “normal” and
`
`higher range of ammonia levels was already part of the standard of care and well-
`
`known in the art prior to the filing of the ’966 Patent. (See e.g., Ex. 1015, Fig.
`
`17.2.) Furthermore, it was well-known in the prior art to the ’966 Patent to
`
`regularly monitor a patient’s plasma ammonia levels and to adjust the dose of
`
`nitrogen scavenging drug to optimize the patient’s treatment to avoid
`
`hyperammonemic events (i.e., periods of dangerously elevated plasma ammonia).
`
`(Id., 217, 219, Fig. 17.2.)
`
`
`2 GPB is also known in the prior art as HPN-100, glycerol PBA, glycerol
`
`phenylbutyrate and GT4P. (Ex. 1004, [0020]; Ex. 1020, 2077; Ex. 1021, 276; Ex.
`
`1001, 1:66-2:2; Ex. 1002 ¶13 fn. 1.)
`
`
`
`2
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`Other Challenged Claims are directed to a method of treating UCDs with
`
`GPB when the initial dose is calculated based on body surface area and a
`
`subsequent dose is calculated based on the patient’s urinary PAGN and/or fasting
`
`plasma ammonia level. It was well-known in the art that an initial dose of nitrogen
`
`scavenging drugs could be calculated based on a patient’s body surface area and a
`
`subsequent adjusted dose could be calculated based on the patient’s urinary PAGN
`
`and/or fasting plasma ammonia level. (See e.g., Ex. 1004, [0084, 0091].)
`
`The Challenged Claims are nearly identical to those that the Patent Trial and
`
`Appeal Board (“the Board”) already found invalid in IPR2015-01127, which
`
`involved the ’215 Parent Patent (“the ’215 IPR”) that is in the same continuity
`
`family as the ’966 Patent. In the ’215 IPR, the Board concluded that the prior art
`
`disclosed initial and adjusted doses of nitrogen scavenging drugs to treat urea cycle
`
`disorders, including several prior art references that are raised herein. (See e.g.,
`
`IPR2015-01127, Paper 49, 8-12 (Sept. 29, 2016).) The instant Challenged Claims
`
`differ from those claims found invalid in the ’215 IPR by merely limiting the target
`
`patients to those whose plasma ammonia is less than the upper limit of normal.
`
`Because the prior art disclosed this limitation, however, this additional limitation
`
`provides no basis to distinguish the Board’s reasoning that the claims of the
`
`’215 Parent Patent are invalid.
`
`
`
`3
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`II.
`
`BACKGROUND REGARDING THE UREA
`CYCLE, UCDS, AND NITROGEN SCAVENGING DRUGS.
`
`A.
`
`The Urea Cycle
`
`Protein is an essential part of everybody’s diet. Most people can consume a
`
`reasonable excess of protein without any adverse health problems. Dietary protein
`
`is metabolized into amino acids. In normal people, excess3 amino acids (such as
`
`glutamine) are metabolized into, among other things, waste nitrogen in the form of
`
`ammonia. This ammonia is processed in the urea cycle into urea through the
`
`action of enzymes. (Ex. 1008, 101.) Urea is readily eliminated from the body in
`
`urine. (Id., Fig. 1.) The following schematic figure illustrates the above and how
`
`the urea cycle contributes to the elimination of ammonia, following the unshaded
`
`pathway:
`
`
`3 Excess amino acids refer to amino acids beyond those necessary for ordinary
`
`bodily functions. (Ex. 1002 ¶36.)
`
`
`
`4
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`
`
`(Ex. 1002 ¶36.)
`
`B. Urea Cycle Disorders.
`
`The urea cycle is the major pathway for the metabolism and excretion of
`
`waste nitrogen. (Ex. 1008, 101.) Urea cycle disorders occur in newborn, child and
`
`adult patients due to deficient enzymes or transporters in the urea cycle, often due
`
`to genetic conditions. (Id., 101–103; Ex. 1004, [0005]; Ex. 1015, 215-16.) A
`
`breakdown in the urea cycle significantly reduces the body’s ability to process
`
`excess ammonia, leading to elevated plasma ammonia levels and
`
`hyperammonemia. (Ex. 1009, 1.) The following figure illustrates the above and
`
`how a disorder in the urea cycle causes toxic ammonia to build-up in the unshaded
`
`pathway:
`
`
`
`5
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`(Ex. 1002 ¶37.) Ammonia is toxic to the nerve cells. Thus, prolonged or severe
`
`hyperammonemia can cause lethargy, coma, irreversible brain defects and death.
`
`
`
`(Ex. 1009, 1.)
`
`Applicants admitted during prosecution of its ’215 Parent Patent that it was
`
`“well known in the art that nitrogen retention disorders are associated with
`
`elevated blood ammonia levels, and that these disorders can be treated by
`
`administering nitrogen scavenging drugs.” (Ex. 1012, 169; see also Ex. 1004,
`
`[0015].)
`
`C. Nitrogen Scavenging Drugs
`
`In addition to diet modifications, the prior art standard of care was to
`
`administer nitrogen scavenging drugs to adult and pediatric patients having UCDs.
`
`(Ex. 1015, 219.) As admitted in the ’966 Patent specification, such drugs were
`
`
`
`6
`
`

`

`known, and were primarily based on the archetypical nitrogen scavenging drug,
`
`IPR Petition of U.S. Patent No. 9,326,966
`
`
`phenylacetic acid (“PAA”). (Ex. 1001, 1:57–2:6.)
`
`In the body, PAA is conjugated to glutamine to form phenylacetylglutamine
`
`(“PAGN”), which can be easily eliminated through urine. (Ex. 1004, [0022]; Ex.
`
`1011, 1.) Each molecule of glutamine converted to PAGN removes two nitrogen
`
`atoms that would form two molecules of toxic ammonia. (Ex. 1004, [0022-23].)
`
`Horizon developed two different prodrugs of PAA, both of which were
`
`known before the earliest possible filing date of the ’966 Patent. In 1996, Horizon
`
`began marketing sodium phenylbutyrate (“PBA”), under the brand name
`
`Buphenyl, which was indicated for use in oral tablet form in adult patients and
`
`children having a body weight greater than 20 kg, and for use in oral powder form
`
`in infant, children and adult patients. (Ex. 1011, 5.) PBA is rapidly metabolized to
`
`PAA after administration. (Id., 1.) A few years later, Horizon developed the pre-
`
`prodrug GPB–the drug recited in the Challenged Claims–which is made up of three
`
`PBA molecules esterified to one glycerol molecule. (Ex. 1004, [0023]; Ex. 1019,
`
`4:66-5:2; Ex. 1017, 324.) After administration, the PBA from GPB is metabolized
`
`by pancreatic lipases, and PBA is then metabolized into PAA. (Ex. 1010, 224.)
`
`Both GPB and PBA provide their therapeutic efficacy through the PAA that is
`
`formed after administration. (Ex. 1004, [0022].)
`
`
`
`7
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`The following figure illustrates this process and how it was known in the
`
`prior art that PAA and PAA prodrugs remove free glutamine and thereby reduce
`
`the risk of toxic ammonia build-up in a UCD patient:
`
`
`
`(Ex. 1002 ¶38.)
`
`Thus, nitrogen scavenging drugs PAA and its prodrugs (GPB and PBA)
`
`were well-known in the prior art to the ’966 Patent, as well as the way in which the
`
`prodrugs are converted to PAA as the following scheme illustrates.
`
`
`References:
`
`GPB
` the ’859 Publication
` the ’979 Patent
` Lichter-Konecki
` Lee
`
`PBA
` Fernandes
` Blau
` Buphenyl Label
`
`PAA
` Pandya
`
`
`
`8
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`D. GPB
`
`As explained above, the PAA pre-prodrug GPB–the drug recited in the
`
`Challenged Claims–was already well-known in the prior art. (Ex. 1004, [0023];
`
`Ex. 1019.) GPB was known to overcome the limitations of PBA and PAA by
`
`providing the same amount of active ingredient in a smaller dose (four
`
`teaspoonfuls instead of forty tablets), decreasing the amount of sodium intake for
`
`patients, avoiding the unpleasant taste, and providing the active component of the
`
`drug at a more constant level. (Ex. 1004, [0065]; Ex. 1019, 3:48-55.)
`
`Furthermore, effective doses of GPB were published by Patent Owner before
`
`September 30, 2011. For example, the ’859 Publication, also assigned to the
`
`Patent Owner (Ex. 1013), states that “[f]or a subject weighing more than 20 kg, a
`
`dosage range for HPN-100 would be between 8.6 and 11.2 mL/m2.” (Ex. 1004,
`
`[0084].) One of ordinary skill in the art would understand that both pediatric and
`
`adults fall within the range of “subject[s] weighing more than 20 kg” described in
`
`the ’859 Publication. (Ex. 1002 ¶72.) The examples of the ’859 Publication
`
`further describe treating healthy adult volunteers with GPB “at a dosage of
`
`3 g/m2.” (Ex. 1004, [0186].) For adult subjects, the ’859 Publication states that the
`
`selected dosage of GPB is “[c]ommonly” around 19 grams per day. (Id., [0179-
`
`80].)
`
`
`
`9
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`The ’859 Publication also states that GPB dosage adjustments could be
`
`“based on the observed urinary excretion of PAGN and/or total urinary nitrogen
`
`(TUN), the difference between the two reflecting the patient’s endogenous capacity
`
`for waste nitrogen excretion.” (Id., [0020, 0039, 0041, 0219].) In this regard, the
`
`’859 Publication further explains that “the dosage of the ammonia scavenging drug
`
`can be adjusted or calculated to compensate for an estimated protein intake,” and
`
`such calculation can be based on GPB being converted into “urinary PAGN at an
`
`overall efficiency of about 60% to about 75% on average….” (Id., [0040, 0043,
`
`0072, 0082, 0143-0155, 0223].)
`
`The ’859 Publication further states that “[t]he subject’s plasma ammonia
`
`level may also be determined; this is a critical parameter for tracking the overall
`
`effectiveness of an overall treatment program….” (Id., [0039]; see also Id.,
`
`[0092].) The ’859 Publication further discloses a method which includes the step
`
`of “monitoring plasma level of ammonia in the patient to assess the effectiveness
`
`of the replacement amount of the prodrug” and that “if the [GPB] is significantly
`
`more effective than predicted when the estimated amount [is] used…in a first step,
`
`the replacement amount used in a subsequent step” can be adjusted. (Id., [0119,
`
`0121].) A person of ordinary skill in the art (“POSA”) would further understand if
`
`the GPB dose was less effective, then the dose could also be appropriately
`
`adjusted. (Ex. 1002 ¶40.) In particular, according to the ’859 Publication, “the
`
`
`
`10
`
`

`

`subject will typically achieve and maintain normal plasma ammonia levels.” (Id.,
`
`IPR Petition of U.S. Patent No. 9,326,966
`
`
`[0182].)
`
`E.
`
`The Standard Of Care For
`Administering Nitrogen Scavenging Drugs.
`
`During treatment of UCDs, physicians routinely and continuously monitor a
`
`number of different biochemical parameters, including fasting plasma ammonia
`
`levels and free blood amino acids. (Ex. 1005, 9, 16-17; Ex. 1006, 273 (Table
`
`11.9); Ex. 1007, 1117-18; Ex. 1010, 222, 226, Fig. 2.) For example, doctors
`
`routinely measure plasma ammonia to ensure that the patients did not have unduly
`
`elevated plasma ammonia levels. (Ex. 1015, 217, 219.) Measuring fasting plasma
`
`ammonia levels was preferred because plasma ammonia levels are elevated
`
`throughout the day in a variable manner, especially after dietary protein from
`
`meals. (See Ex. 1005, 9, 16-17; Ex. 1006, Table 11.9; Ex. 1010, 226, Fig. 2; Ex.
`
`1015, 217-18; Ex. 1017, 324.) If fasting plasma ammonia values were determined
`
`to be too high for the patient, then physicians would often adjust the dose of
`
`nitrogen scavenging drug by increasing its dose, recommend a reduction in dietary
`
`protein or both. (Ex. 1015, Fig. 17.2; Ex. 1004, [0083].)
`
`Determining whether plasma ammonia levels were being adequately
`
`controlled required comparing the patient’s plasma ammonia levels with the
`
`patient’s, hospital’s or clinic’s range of normal plasma ammonia values, as well as
`
`assessing the patient for symptomology suggesting ammonia toxicity. (Ex. 1015,
`11
`
`
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`219-20.) It was also known that target ammonia levels for patients was age
`
`dependent, with adult patients having different target ammonia values than
`
`pediatric patients. (See, e.g., Ex. 1006, 268.) Even if a patient’s plasma ammonia
`
`was normal, elevated levels of amino acids could signal an impending
`
`hyperammonemic crisis. (Ex. 1015, 219-20, Fig. 17.2.) Thus, elevated free amino
`
`acid in the blood would signal to physicians that the dose of nitrogen scavenging
`
`drugs should be increased to preempt a hyperammonemic crisis. (Id., Fig. 17.2.)
`
`Because there is no physiological consequence to low plasma ammonia
`
`levels, physicians were generally disposed to providing therapeutically acceptable
`
`doses of nitrogen scavenging drugs to reduce the risk of a hyperammonemic event.
`
`(Ex. 1002 ¶40.) The ’859 Publication explains that “[i]n some patients or clinical
`
`settings, [GPB] doses well above the approved PBA dosages are expected to be
`
`beneficial; for example in UCD patients who exhibit recurrent hyperammonemia
`
`even on maximal doses of sodium PBA, in UCD patients who need increased
`
`dietary protein to support body requirements or in patients with other nitrogen
`
`retaining states.” (Ex. 1004, [0086].)
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`
`Petitioner certifies that (1) the ’966 Patent, issued on May 3, 2016, is
`
`available for IPR; (2) Petitioner is not barred or estopped from requesting an IPR
`
`on the grounds identified in this Petition; and (3) Petitioner has not filed any
`
`
`
`12
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`complaint relating to the ’966 Patent. Petitioner was served with a complaint
`
`alleging infringement of the ’966 Patent on July 15, 2016 (Ex. 1014), and therefore
`
`this petition is timely filed within the one-year limitation of 35 U.S.C. § 315(b).
`
`IV. PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`Petitioner authorizes required fees to be charged to Deposit Account
`
`No. 013050.
`
`V. MANDATORY NOTICES (37 C.F.R. § 42.8)
`
`A. Real-Parties-In-Interest
`
`Petitioner Par Pharmaceutical, Inc. (“Par”) is the real-party-in-interest for
`
`this proceeding. Out of an abundance of caution, and as a result of ongoing
`
`integration and reorganization activities, Petitioner identifies the following
`
`additional entities as actual or potential real-parties-in-interest who, going forward,
`
`may have control over this proceeding: Endo International PLC; Endo DAC; Endo
`
`Luxembourg Holding Company S.a.r.l.; Par Pharmaceutical Holdings, Inc.;
`
`Luxembourg Endo Specialty Pharmaceuticals Holding II S.a.r.l.; Luxembourg
`
`Endo Specialty Pharmaceuticals Holding I S.a.r.l.; and Par Pharmaceutical
`
`Companies, Inc. No other parties exercised or could have exercised control over
`
`this petition; no other parties funded or directed this petition. See Office Patent
`
`Trial Practice Guide, 77 Fed. Reg. 48759-60.
`
`
`
`13
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`B.
`
`Related Matters
`
`The following litigation matters would affect or be affected by a decision in
`
`this proceeding: (1) Horizon Therapeutics, Inc. v. Lupin Ltd., No. 1:16-cv-04438-
`
`RBK-JS (D.N.J.) (“the Lupin Action”) and (2) Horizon Therapeutics, Inc. v. Par
`
`Pharmaceutical, Inc., No. 1:16-cv-03910-RBK-JS (D.N.J.) (“the Par Action”).
`
`Both the Par and Lupin Actions involve, among other things, allegations that Par
`
`and Lupin, respectively, infringe the ’966 Patent.
`
`The following matters pending before the Board would affect or be affected
`
`by a decision in this proceeding: Lupin Ltd. v. Horizon Therapeutics, Inc.,
`
`IPR2017-01160 (“the Lupin IPR”). In the Lupin IPR, the petitioner argued that
`
`claims 12, 14 and 15 of the ’966 Patent are anticipated by the ’859 Publication and
`
`claims 1-15 were argued to be obvious over Blau, Simell and the ’859 Publication,
`
`in view of the POSA’s knowledge. Petitioner is not a party or real party-in-interest
`
`to the Lupin IPR, and has not sought and does not seek joinder with the Lupin IPR.
`
`On April 29, 2015, Petitioner filed a petition (IPR2015-01127) for inter
`
`partes review for the ’215 Parent Patent. On September 29, 2016, the Board issued
`
`the Final Written Decision in IPR2015-01127 (“the ’215 Final Written Decision”)
`
`and determined that all the claims of the ’215 Parent Patent are unpatentable. The
`
`time to appeal the ’215 Final Written Decision has expired without appeal, and
`
`Horizon has thus waived its right to appeal the ’215 Final Written Decision.
`
`
`
`14
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`C.
`
`Lead And Backup Counsel (37 C.F.R. § 42.8(b)(3))
`And Service Information (37 C.F.R. § 42.8(b)(4))
`
`Lead Counsel
`David H. Silverstein
`Reg. No. 61,948
`Axinn, Veltrop & Harkrider LLP
`114 West 47th Street
`New York, NY 10036
`Tel: 212-261-5651
`dsilverstein@axinn.com
`
`Backup Counsel
`Dan Feng Mei
`Reg. No. 71,518
`Axinn, Veltrop & Harkrider LLP
`114 West 47th Street, 22nd Floor
`New York, NY 10036
`Tel: 212-728-2216
`Fax: 212-728-2201
`dmei@axinn.com
`Ravicti@axinn.com
`
`Please address all correspondence and service to counsel listed above.
`
`Petitioner consents to service by email, provided copies are simultaneously sent to
`
`dsilverstein@axinn.com, dmei@axinn.com, and ravicti@axinn.com.
`
`VI. SUMMARY OF THE ’966 PATENT
`
`The ’966 Patent was filed on December 3, 2015 and is a continuation of
`
`U.S. Application No. 14/816,674, filed on August 3, 2015, now U.S. Patent
`
`No. 9,254,278, which is a continuation of U.S. Application No. 13/775,000, filed
`
`on February 22, 2013, now U.S. Patent No. 9,095,559, which is a continuation U.S.
`
`Application No. 13/417,137, filed on March 9, 2012, now U.S. Patent
`
`No. 8,404,215 (“the ’215 Parent Patent”). The ’966 Patent claims benefit to U.S.
`
`Provisional Application No. 61/564,668, filed on November 29, 2011, and U.S.
`
`Provisional Application No. 61/542,100, filed September 30, 2011. It is currently
`
`assigned to Horizon Therapeutics, Inc. (“Horizon” or “Patent Owner”).
`
`
`
`15
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`The ’966 Patent claims priority to and has the same specification as the
`
`unpatentable ’215 Parent Patent. The earliest effective filing date of the
`
`’966 Patent is September 30, 2011.4 The ’966 Patent is set to expire on March 9,
`
`2032. On June 28, 2017, Horizon filed a statutory disclaimer pursuant to under 35
`
`U.S.C. § 253(a) disclaiming claims 12, 14 and 15 of the ’966 patent.
`
`The ’215 Parent Patent was found unpatentable by the Board in IPR
`
`No. IPR2015-01127. The Challenged Claims are substantially the same as the
`
`unpatentable ’215 Parent Patent claims. The following chart is a side-by-side
`
`comparison of an exemplary, representative claim from the unpatentable
`
`’215 Parent Patent and the ’966 Patent.
`
`
`
`Unpatentable
`’215 Patent,
`Exemplary Claim
`1
`
`’966 Patent,
`Exemplary Claim
`1
`
`’966 Patent,
`Exemplary Claim
`6
`
`’966 Patent,
`Exemplary Claim
`9
`
`A method for
`adjusting the
`dosage of a
`nitrogen
`
`A method of
`treating a subject
`with a urea cycle
`disorder who has
`
`A method of
`treating a
`pediatric subject
`with a urea cycle
`
`A method of
`treating an adult
`subject with a
`urea cycle
`
`
`4 Petitioner does not challenge the claims of priority or of the benefit of an earlier
`
`filing date for the purposes of this IPR petition only and reserves the right to
`
`challenge such claims in future proceedings.
`
`
`
`16
`
`

`

`Unpatentable
`’215 Patent,
`Exemplary Claim
`1
`scavenging
`drug in a subject
`who has
`previously been
`administered an
`initial dosage of
`the nitrogen
`scavenging drug,
`comprising:
`
`IPR Petition of U.S. Patent No. 9,326,966
`
`
`’966 Patent,
`Exemplary Claim
`1
`
`’966 Patent,
`Exemplary Claim
`6
`
`’966 Patent,
`Exemplary Claim
`9
`
`previously been
`administered an
`initial dose of
`[GPB] and who
`has a fasting
`plasma ammonia
`level less than
`the upper limit
`of normal for
`plasma ammonia
`level, the method
`comprising:
`
`disorder who has
`previously been
`administered an
`initial dosage of
`[GPB] and who
`has a fasting
`plasma ammonia
`level less than the
`upper limit of
`normal for
`plasma ammonia
`level, the method
`comprising:
`
`disorder who has
`previously been
`administered an
`initial dosage of
`[GPB] 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 blood
`ammonia level
`for the subject;
`
`a) measuring a
`fasting plasma
`ammonia level
`for the subject;
`
`a) measuring a
`fasting plasma
`ammonia level for
`the pediatric
`subject;
`
`a) measuring a
`fasting plasma
`ammonia level
`for the adult
`subject;
`
`b) comparing
`the fasting blood
`ammonia level to
`the upper limit
`of normal for
`blood ammonia
`level; and
`
`b) comparing
`the fasting
`plasma ammonia
`level to the upper
`limit of normal
`for plasma
`ammonia level;
`and
`
`b)
`comparing
`the fasting plasma
`ammonia level to
`the upper limit of
`normal for plasma
`ammonia level;
`and
`
`b) comparing
`the fasting
`plasma ammonia
`level to the upper
`limit of normal
`for plasma
`ammonia level;
`and
`
`c) administering
`an adjusted
`dosage of the
`nitrogen
`scavenging
`
`c) administering
`an adjusted
`dosage of [GPB]
`that is greater
`than the initial
`
`c)
`administering
`an adjusted dosage
`of [GPB] that is
`greater than the
`initial dosage if
`
`c) administering
`an adjusted
`dosage of [GPB]
`that is greater
`than the initial
`
`17
`
`

`

`Unpatentable
`’215 Patent,
`Exemplary Claim
`1
`drug, wherein
`the adjusted
`dosage is greater
`than the initial
`dosage if the
`fasting blood
`ammonia level is
`greater than half
`the upper limit of
`normal for blood
`ammonia level.
`
`IPR Petition of U.S. Patent No. 9,326,966
`
`
`’966 Patent,
`Exemplary Claim
`1
`
`’966 Patent,
`Exemplary Claim
`6
`
`’966 Patent,
`Exemplary Claim
`9
`
`the fasting plasma
`ammonia level is
`greater than half
`the upper limit of
`normal for plasma
`ammonia level.
`
`
`dosage if the
`fasting plasma
`ammonia level is
`greater than half
`the upper limit of
`normal for
`plasma ammonia
`level.
`
`
`dosage if the
`fasting plasma
`ammonia level is
`greater than half
`the upper limit of
`normal for
`plasma ammonia
`level,
`wherein the
`upper limit of
`normal for
`plasma
`ammonia level is
`in the range of
`26-64 µmol/L.
`
`
`The above chart illustrates that there are very few differences, identified by the
`
`bolded text between the unpatentable ’215 Parent Patent claims and the Challenged
`
`Claims.
`
`- First, although the Challenged Claims more narrowly recite GPB instead of
`
`“nitrogen scavenging drugs,” the Board found claim 6 of the ’215 Parent
`
`Patent, which recites PAA prodrugs including GPB, invalid. (IPR2015-
`
`01127, Paper 49, 6, 24 (Sept. 29, 2016).) In any event, the same prior art
`
`that invalidated the ’215 Parent Patent claims also discloses GPB as a PAA
`
`prodrug for treating UCD.
`
`
`
`18
`
`

`

`- Second, although the Challenged Claims require that the subject have “a
`
`IPR Petition of U.S. Patent No. 9,326,966
`
`
`fasting plasma ammonia level less than the upper limit of normal” and the
`
`’215 Parent Patent claims do not, the same prior art that invalidated the ’215
`
`Parent Patent claims disclose initial and adjusted doses of nitrogen
`
`scavenging drugs in UCD patients having fasted plasma ammonia levels less
`
`than the upper limit of normal.
`
`- Third, although the Challenged Claims recite “plasma” ammonia levels and
`
`the unpatentable ’215 Parent Patent claims recite “blood” ammonia levels,
`
`the Board and the parties have treated the two as being interchangeable.
`
`(Id., 8 n.2.)
`
`- Fourth, although claims 6 and 9 of the Challenged Claims recite “pediatric”
`
`and “adult” subjects, respectively, treatment of each of these groups of
`
`patients with nitrogen scavenging drugs, including GPB, is disclosed in the
`
`’215 IPR prior art, e.g., Fernandes, the ’859 Publication, Lee and Blau.
`
`- Fifth, while claim 1 of the Challenged Claims require that the upper limit of
`
`normal for plasma ammonia level be in the range of 26-64 µmol/L, the
`
`Board found in the ’215 Final Written Decision that the prior art disclosed
`
`upper limits of normal that substantially overlap with the claimed ULN
`
`range of 26-64 umol/L. (Id., 10, 11.)
`
`
`
`19
`
`

`

`IPR Petition of U.S. Patent No. 9,326,966
`
`
`Further to these reasons discussed below, none of the differences between the
`
`unpatentable ’215 Parent Patent claims and the Challenged Claims are patentable
`
`differences and the Board’s rationale in finding the ’215 Parent Patent claims
`
`unpatentable is consistent herewith.
`
`VII. PERSON OF ORDINARY SKILL IN THE ART.
`
`A person of ordinary skill in the art is a hypothetical person who is
`
`presumed to know all of the relevant prior art,