`
`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 9,254,278
`_____________________
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT
`NO. 9,254,278 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. 9,254,278
`
`Table of Contents
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND REGARDING THE UREA CYCLE,
`UCDs, AND NITROGEN SCAVENGING DRUGS. .................................... 3
`
`A.
`
`B.
`
`C.
`
`The Urea Cycle ....................................................................................... 3
`
`Urea Cycle Disorders ............................................................................. 4
`
`Nitrogen Scavenging Drugs ................................................................... 6
`
`D. GPB ........................................................................................................ 8
`
`E.
`
`The Standard Of Care For Administering Nitrogen
`Scavenging Drugs................................................................................... 9
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ............................... 11
`
`IV. PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................. 11
`
`V. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................. 11
`
`A.
`
`B.
`
`C.
`
`Real-Parties-In-Interest ........................................................................ 11
`
`Related Matters ..................................................................................... 12
`
`Lead And Backup Counsel (37 C.F.R. § 42.8(b)(3))
`And Service Information (37 C.F.R. § 42.8(b)(4)) .............................. 13
`
`VI. SUMMARY OF THE ’278 PATENT ........................................................... 13
`
`VII. PERSON OF ORDINARY SKILL IN THE ART ........................................ 18
`
`VIII. STATEMENT OF THE PRECISE RELIEF REQUESTED
`AND THE REASONS THEREFORE (37 C.F.R. §§ 42.22(a)
`and 42.104(b)) ................................................................................................ 19
`
`A.
`
`Claim Construction .............................................................................. 22
`
`
`
`i
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`1.
`
`“Plasma Ammonia Level” Means “The Level
`Of Ammonia Found In Blood Or Plasma”. .............................. 23
`
`B.
`
`Brief Overview Of Prior Art Underlying The Grounds. ...................... 24
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Fernandes (Ex. 1015) ................................................................ 24
`
`The ’859 Publication (Ex. 1004) ............................................... 25
`
`Blau (Ex. 1006) ......................................................................... 26
`
`Simell (Ex. 1007) ...................................................................... 26
`
`Lee (Ex. 1010) .......................................................................... 27
`
`Lichter-Konecki (Ex.1017) ....................................................... 27
`
`C.
`
`Ground 1: Independent Claim 1 And Dependent
`Claims 2 And 3 Are Anticipated Under 35 U.S.C.
`§ 102 By The ’859 Publication. ........................................................... 28
`
`1.
`
`2.
`
`Independent Claim 1 ................................................................. 28
`
`Dependent Claims 2 and 3 ........................................................ 30
`
`D. Ground 2: Independent Claim 1 And Dependent
`Claims 2 And 3 Are Obvious Under 35 U.S.C.
`§ 103(a) Over Fernandes In View Of The
`’859 Publication And Lee Or Lichter-Konecki,
`Optionally In Further View Of Blau Or Simell. .................................. 31
`
`1.
`
`2.
`
`Independent Claim 1 ................................................................. 31
`
`Dependent Claims 2 and 3 ........................................................ 37
`
`3. Motivation To Combine Prior Art Applied In
`Ground 2 ................................................................................... 37
`
`
`
`ii
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`IPR Petition of U.S. Patent No. 9,254,278
`
`E.
`
`F.
`
`Ground 3: Independent Claims 4, 8 And 12 And
`Dependent Claims 6, 7, 10, 11, 14 And 15 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. ..................................................................... 39
`
`1.
`
`2.
`
`Independent Claims 4, 8 And 12 .............................................. 39
`
`Dependent Claims 6, 7, 10, 11, 14 And 15 ............................... 53
`
`3. Motivation To Combine Prior Art Applied In
`Ground 3 ................................................................................... 54
`
`Ground 4: Dependent Claims 5, 9 And 13 Are
`Obvious Under 35 U.S.C. § 103(a) Over Fernandes In
`View Of The ’859 Publication And Lee Or Lichter-
`Konecki, Optionally In Further View Of Blau Or
`Simell. ................................................................................................... 56
`
`G.
`
`Secondary Considerations .................................................................... 63
`
`IX. CONCLUSION. ............................................................................................. 63
`
`
`
`
`
`
`
`
`
`iii
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`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
`
`to 15 (“Challenged Claims”) of U.S. Patent No. 9,254,278 (“’278 Patent”). (Ex.
`
`1001.)
`
`I.
`
`INTRODUCTION
`
`The Challenged Claims cover methods of selecting a 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 ’278 patent, it was already known in the prior art
`
`that the standard of care for managing urea cycle disorders 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]; Ex. 1009, 1.) Glyceryl tri-[4-phenylbutyrate] 1
`
`(“GPB”), the drug in the Challenged Claims, was a well-known nitrogen
`
`
`1 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.)
`
`
`
`1
`
`
`
`scavenging drug in the art prior to the filing of the ’278 patent. (See e.g., Ex. 1004,
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`[0020].)
`
`The Challenged Claims are directed to the purported discovery of a method
`
`by which GPB is administered to 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 ’278 Patent. (See e.g., Ex. 1015, Fig. 17.2.) Furthermore, it was well-known in
`
`the prior art to the ’278 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.) And, given the known advantages of
`
`GPB over other nitrogen scavenging drugs such as PBA, the prior art described
`
`methods of transitioning a patient from PBA therapy to GPB therapy. (See e.g.,
`
`Ex. 1004, [0109-113].)
`
`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
`
`
`
`2
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`family as the ’278 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 merely by 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.
`
`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, excess2 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
`
`
`2 Excess amino acids refer to amino acids beyond those necessary for ordinary
`
`bodily functions. (Ex. 1002 ¶29.)
`
`
`
`3
`
`
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`IPR Petition of U.S. Patent No. 9,254,278
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`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:
`
`
`
`
`(Ex. 1002 ¶29.)
`
`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 due to deficient
`
`enzymes or transporters in the urea cycle, often due to genetic conditions. (Id.,
`
`101–103; Ex. 1004, [0005].) 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
`
`
`
`4
`
`
`
`above and how a disorder in the urea cycle causes toxic ammonia to build-up in the
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`unshaded pathway:
`
`
`
`(Ex. 1002 ¶30.) 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].)
`
`
`
`5
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`
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`IPR Petition of U.S. Patent No. 9,254,278
`
`C. Nitrogen Scavenging Drugs
`
`In addition to diet modifications, the prior art standard of care was to
`
`administer nitrogen scavenging drugs to patients having UCDs. (Ex. 1015, 219.)
`
`As admitted in the ’278 Patent specification, such drugs were known, and were
`
`primarily based on the archetypical nitrogen scavenging drug, phenylacetic acid
`
`(“PAA”). (Ex. 1001, 1:55–2:3.)
`
`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 ’278 Patent. In 1996, Horizon
`
`began marketing sodium phenylbutyrate (“PBA”), under the brand name
`
`Buphenyl. PBA is rapidly metabolized to PAA after administration. (Ex. 1011, 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
`
`
`
`6
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`IPR Petition of U.S. Patent No. 9,254,278
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`therapeutic efficacy through the PAA that is formed after administration. (Ex.
`
`1004, [0022].)
`
`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 ¶31.)
`
`
`
`
`Thus, nitrogen scavenging drugs PAA and its prodrugs (GPB and PBA)
`
`were well-known in the prior art to the ’278 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
`
`7
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`IPR Petition of U.S. Patent No. 9,254,278
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`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 a way to determine an appropriate dose of
`
`GPB is by estimating that one gram of GPB can manage one to two grams of
`
`dietary protein in excess of the amount of protein that can be processed by the
`
`patient’s endogenous nitrogen elimination capacity. (Ex. 1004, [0092].) The
`
`selected dosage of GPB is “[c]ommonly” around 19 grams per day. (Id., [0179-
`
`180].) The ’859 Publication also states that an effective dosage of GPB could be
`
`determined based on the known 60% to 75% rate of conversion of GPB to urinary
`
`PAGN. (Id., claim 6.) Thus, the prior art provided methods by which patients
`
`could be readily transitioned from PAA therapy (or PBA therapy) to GPB therapy.
`
`(Ex. 1010, 222, 224; Ex. 1004, [0109-0113].)
`
`
`
`8
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`IPR Petition of U.S. Patent No. 9,254,278
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`Because GPB is digested by pancreatic lipases (Ex. 1010, 224, Ex. 1019,
`
`4:66-5:2), a person of ordinary skill in the art (“POSA”) would have been
`
`concerned that patients in whom pancreatic lipase activity was low would convert
`
`GPB to PBA at too slow a rate to provide clinical efficacy. (Ex. 1002 ¶32.)
`
`Accordingly, a POSA would have monitored such patients’ plasma ammonia levels
`
`closely, to ensure that the administered doses of GPB was sufficient to provide a
`
`therapeutic nitrogen-scavenging effect. (Id.)
`
`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
`
`
`
`9
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`
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`IPR Petition of U.S. Patent No. 9,254,278
`
`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,
`
`219-20.) Even if a patient’s plasma ammonia was normal, elevated levels of amino
`
`acids could signal an impending hyperammonemic crisis. (Id., 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 ¶33.) 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].)
`
`
`
`10
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`IPR Petition of U.S. Patent No. 9,254,278
`
`III. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`
`Petitioner certifies that (1) the ’278 Patent, issued on February 9, 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
`
`complaint relating to the ’278 Patent. Petitioner was served with a complaint
`
`alleging infringement of the ’278 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
`
`
`
`11
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`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.
`
`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 ’278 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.,
`
`IPR2017-01159 (“the Lupin IPR”). Claims 1-3 were argued to be obvious over the
`
`’859 Publication; claims 4-7 and 12-15 were argued to be obvious over Blau,
`
`Simell and the ’859 Publication; and claims 8-11 were argued to be obvious over
`
`Blau, Simell, the ’859 Publication, and Brusilow ’979 Patent.3 Petitioner is not a
`
`party or real party-in-interest to the Lupin IPR, and has not sought and does not
`
`
`3 Brusilow ’979 Patent refers to U.S. Patent No. 5,968,979, issued on October 19,
`
`1999 (Ex. 1019).
`
`
`
`12
`
`
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`IPR Petition of U.S. Patent No. 9,254,278
`
`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.
`
`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
`
`Backup Counsel
`
`David H. Silverstein
`Reg. No. 61,948
`Axinn, Veltrop & Harkrider LLP
`114 West 47th Street, 24th Floor
`New York, NY 10036
`Tel: 212-261-5651
`Fax: 212-728-2201
`dsilverstein@axinn.com
`
`
`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 ’278 PATENT
`
`The ’278 Patent was filed on August 3, 2015 and is a continuation of
`
`Application No. 13/775,000, filed on February 22, 2013, now U.S. Patent
`13
`
`
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`No. 9,095,559 (“’559 Parent Patent”), which is a continuation of Application
`
`No. 13/417,137, filed on March 9, 2012, now U.S. Patent No. 8,404,215 (“’215
`
`Parent Patent”). The ’278 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”).
`
`The ’278 Patent claims priority to and has the same specification as the
`
`unpatentable ’215 Parent Patent. The earliest effective filing date of the
`
`’278 Patent is September 30, 2011.4 The ’278 Patent is set to expire on March 9,
`
`2032.
`
`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 ’278 Patent.
`
`
`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.
`
`
`
`14
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`Unpatentable ’215
`Patent, Exemplary Claim
`1
`
`’278 Patent,
`Exemplary Claims 4 and
`85
`
`’278 Patent,
`Exemplary Claim 12
`
`A method for adjusting the
`dosage of a nitrogen
`scavenging drug in a
`subject who has previously
`been administered an
`initial dosage of the
`nitrogen scavenging drug,
`comprising:
`
`
`A method for adjusting the
`dosage of [GPB] in a
`subject being treated for a
`urea cycle 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 method for adjusting
`the dosage of [GPB] in a
`subject being treated for a
`urea cycle disorder who
`has previously been
`administered an initial
`dosage of sodium
`phenylbutyrate and who
`has a fasting plasma
`ammonia level less than
`the upper limit of normal
`for plasma ammonia level,
`the method comprising:
`
`a) measuring a fasting
`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 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
`
`
`5 Bolded text found in curly brackets is found in claim 4 only. Bolded and
`
`italicized text in curly brackets is only found in claim 8.
`
`
`
`15
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`Unpatentable ’215
`Patent, Exemplary Claim
`1
`
`’278 Patent,
`Exemplary Claims 4 and
`85
`
`’278 Patent,
`Exemplary Claim 12
`
`c) administering an
`adjusted dosage of the
`nitrogen scavenging
`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.
`
`c) administering an
`adjusted dosage of [GPB],
`wherein the adjusted
`dosage is greater than the
`initial dosage if the fasting
`plasma ammonia level is
`greater than half the upper
`limit of normal for plasma
`ammonia level, and
`
`c) administering an
`initial dosage of [GPB],
`wherein the initial
`dosage is determined by
`the amount of the initial
`dosage of sodium
`phenylbutyrate
`
`
`
`{wherein the method
`further comprises
`restricting the subject's
`dietary protein intake}
`{wherein the method
`further comprises
`monitoring the subject’s
`ammonia levels if the
`[GPB] is not being
`adequately digested by the
`subject’s pancreatic
`lipases}.
`
`
`d) administering an
`adjusted dosage of
`[GPB], wherein the
`adjusted dosage is
`greater than the initial
`dosage of {GPB} if the
`fasting plasma ammonia
`level is greater than half
`the upper limit of
`normal for plasma
`ammonia level.
`
`
`As can be seen in the above chart, there are very few differences between the
`
`unpatentable ’215 Parent Patent claims and the Challenged Claims.
`
`
`
`16
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`- 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.
`
`- Second, although the Challenged Claims require that the subject have “a
`
`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, the Challenged Claims recite a method of treating UCD that includes
`
`restricting the subject’s dietary protein intake or monitoring the subject’s
`
`ammonia levels if GPB is not being adequately digested by the subject’s
`
`pancreatic lipases. The same prior art that invalidated the ’215 Parent
`
`
`
`17
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`Patent) claims, such as Fernandes (Ex. 1015, 217-19) and the ’859
`
`Publication (Ex. 1004, [0022, 0083]), disclose these additional steps.do
`
`- Fifth, the Challenged Claims recite a method of treating UCD wherein the
`
`subject was previously administered sodium phenylbutyrate and then
`
`switched to GPB. It was well-known that UCD subjects can be switched
`
`from sodium phenylbutyrate to GPB. (See, e.g., Ex. 1004, [009-113].)
`
`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 (“POSA”) is a hypothetical person who
`
`is presumed to know all of the relevant prior art, has ordinary creativity, is not an
`
`automaton, and is capable of combining teachings of the prior art. IPR2013-
`
`00116, Paper 68, 9, 37 (citing KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 420–21
`
`(2007)).
`
`With respect to the ’278 Patent, Petitioner submits that a POSA is a
`
`physician or scientist with a Ph.D. or M.D. degree and specialized training in the
`
`diagnosis or treatment of inherited metabolic disorders, such as UCD and other
`
`nitrogen retention disorders. (Ex. 1002 ¶40.) Today, such a person may also have
`
`
`
`18
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`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. (Id.) A POSA would easily have understood the
`
`prior art references referred to herein and would have been capable of drawing
`
`inferences from them. (Id.)
`
`VIII. STATEMENT OF THE PRECISE RELIEF REQUESTED AND
`THE REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b))
`
`Petitioner requests inter partes review and cancellation of claims 1–15 on
`
`the ground listed in the tables below.6
`
`Ground Basis
`
`References
`
`§ 102 The ’859 Publication
`
`1
`
`2
`
`Challenged ʼ278
`Patent Claims
`
`Independent Claim: 1
`
`Dependent Claims: 2, 3
`
`§ 103 Fernandes in view of the ’859
`Publication and Lee or Lichter-
`Konecki, optionally in further view
`of Blau or Simell
`
`Independent Claim: 1
`
`Dependent Claims: 2, 3
`
`
`6 The ’859 Publication, Fernandes, Blau, Simell, Lichter-Konecki, and Lee were
`
`before the PTO but not in the combinations stated herein. All of the cited
`
`references are prior art under 35 U.S.C. § 102(b) except for Lichter-Konecki,
`
`which is prior art under 35 U.S.C. § 102(a).
`
`
`
`19
`
`
`
`IPR Petition of U.S. Patent No. 9,254,278
`
`Ground Basis
`
`References
`
`3
`
`4
`
`§ 103 Fernandes in view of the ’859
`Publication, optionally in view of
`Blau, Simell and/or Lee
`
`§ 103 Fernandes in view of the ’859
`Publication and Lee or Lichter-
`Konecki, optionally in further view
`of Blau or Simell
`
`Challenged ʼ278
`Patent Claims
`
`Independent Claims: 4,
`8, 12
`
`Dependent Claims: 6,
`7, 10, 11, 14, 15
`
`Dependent Claims: 5,
`9, 13
`
`Per 37 C.F.R. § 42.6(c), copies of the references are filed as exhibits
`
`herewith. Additionally, Petitioner provides the declaration of Dr. Neal Sondheimer
`
`in support of the grounds for challenging the claims. (Ex. 1002.)7
`
`Claims 1, 4, 8 and 12 are the four independent claims of the ’278 Patent.
`
`Independent claim 1 recites:
`
`Claim 1
`
`A method of treating a subject with a urea cycle disorder,
`the method comprising:
`
`administering to the subject in need thereof [GPB] in an
`amount sufficient to produce a fasting plasma ammonia
`level that is less than half the upper limit of normal for
`
`
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