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`Exhibit 5
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`Paper No. __
`Filed: July 1, 2014
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`ANTARES PHARMA, INC., LEO PHARMA A/S and LEO PHARMA INC.,
`
`
`Petitioners
`
`v.
`
`MEDAC GESELLSCHAFT FUER KLINISCHE SPEZIALPRÄPARATE MBH
`
`Patent Owner
`
`____________
`
`Case No.: Not yet assigned
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 8,664,231
`
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`

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`Patent No. 8,664,231
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`Table of Contents
`
`I.
`
`Introduction ................................................................................................................. 1
`
`II. Grounds for Standing ................................................................................................. 1
`
`III. Mandatory Notices ..................................................................................................... 1
`
`A.
`
`B.
`
`C.
`
`Real Party-In-Interest ...................................................................................... 1
`
`Related Matters ................................................................................................ 1
`
`Lead and Back-Up Counsel, and Service Information ............................... 1
`
`Payment of Fees .......................................................................................................... 2
`
`Identification of Challenge ........................................................................................ 2
`
`A. Overview of the ’231 Patent .......................................................................... 2
`
`IV.
`
`V.
`
`1.
`
`2.
`
`3.
`
`The ’231 Specification ......................................................................... 2
`
`The ’231 Claims .................................................................................... 3
`
`The ’231 Prosecution History ............................................................ 6
`
`B.
`
`Claim Construction of Challenged Claims ................................................... 9
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`“Subcutaneously” ................................................................................. 9
`
`“Pharmaceutically acceptable solvent” .............................................. 9
`
`“Injection device” .............................................................................. 10
`
`“Ready-made syringe” ....................................................................... 10
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`“Pen injector” ..................................................................................... 10
`
`C.
`
`Statement of Precise Relief Requested for Each Claim Challenged ....... 10
`
`1.
`
`2.
`
`Claims for Which Review Is Requested .......................................... 10
`
`Statutory Grounds of Challenge ...................................................... 10
`
`D. Overview of the Cited Art ............................................................................ 12
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`Patent No. 8,664,231
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`E.
`
`Level of Skill in the Art ................................................................................. 14
`
`VI. Detailed Explanation of the Challenge .................................................................. 15
`
`A. Ground 1: U.S. Patent 6,544,504 (“Grint;” Ex. 1003) anticipates
`claims 1, 2, 4, 5, 6, 11, 12, 13, 17, and 22 under 35 U.S.C. § 102(b). ...... 15
`
`1.
`
`Claim chart for Ground 1. ................................................................ 18
`
`B.
`
`Ground 2: Claims 7, 8, 9, 10, 14, 15, 16, 19, 20, and 21 are
`rendered obvious by U.S. Patent 6,544,504 (“Grint;” Ex. 1003) in
`view of Insulin Admin. (Ex. 1015). ............................................................... 22
`
`1.
`
`Claim chart for Ground 2. ................................................................ 24
`
`C.
`
`Ground 3: Claim 18 is rendered obvious by U.S. Patent 6,544,504
`(“Grint;” Ex. 1003) in view of Alsufyani (Ex. 1006). ................................. 27
`
`1.
`
`Claim chart for Ground 3. ................................................................ 28
`
`D. Grounds 4-6: Claims 1-22 are obvious under 35 U.S.C. § 103(a)
`over primary references the PDR for Mexate® (Ex. 1007) or Hospira
`(Ex. 1009) and Brooks (Ex. 1008), further in view of Insulin Admin.
`(Ex. 1015) and Alsufyani (Ex. 1006). ............................................................ 28
`
`1.
`
`Discussion of the primary references. ............................................. 28
`
`a.
`
`b.
`
`c.
`
`The primary reference “the PDR for Mexate®” teaches
`MTX at concentrations between 2 and 125 mg/ml
`for intramuscular injection to treat psoriasis....................... 28
`
`The primary reference “Hospira” teaches 100 mg/ml
`MTX for intramuscular injection to treat psoriasis. ........... 30
`
`The primary reference Brooks (Ex. 1008) teaches that
`intramuscular and subcutaneous injections of MTX
`are interchangeable. ................................................................ 31
`
`2.
`
`Ground 4: Claims 1-5, 11, 12, 13, 17, and 22 of the ’231
`patent are obvious over the PDR for Mexate® (Ex. 1007) or
`Hospira (Ex. 1009) in view of Brooks (Ex. 1008). ........................... 32
`
`a.
`
`Claim chart for Ground 4 showing exemplary
`citations in the PDR for Mexate® (Ex. 1007). ....................... 34
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`Patent No. 8,664,231
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`b.
`
`c.
`
`Claim chart for ground 4 showing exemplary
`citations in Hospira (Ex. 1009). .............................................. 37
`
`Claim chart for ground 4 showing exemplary
`citations in Brooks (Ex. 1008) ................................................ 39
`
`3.
`
`Ground 5: Claims 7-10, 14-16, and 19-21 are rendered
`obvious by the PDR for Mexate® (Ex. 1007) or Hospira (Ex.
`1009) and Brooks (Ex. 1008), in view of Insulin Admin. (Ex.
`1015). ................................................................................................... 41
`
`E. Grounds 6-8: Claims 1-22 are rendered obvious by primary
`references Hoekstra (Ex. 1004) and Jorgensen (Ex. 1005), further in
`view of Insulin Admin. (Ex. 1015) and secondary reference
`Alsufyani (Ex. 1006). ...................................................................................... 43
`
`1.
`
`Discussion of the Primary References ............................................ 43
`
`a.
`
`b.
`
`The primary reference Hoekstra (Ex. 1004) teaches
`subcutaneous administration of MTX at high doses. ........ 43
`
`The primary reference Jørgensen (Ex. 1005) teaches
`that the volume of subcutaneously injected solutions
`should be formulated to contain less than one
`milliliter (mL). ......................................................................... 43
`
`2.
`
`Ground 6: Claims 1-6, 11, 12, 13, 17, and 22 are rendered
`obvious by Hoekstra (Ex. 1004) and Jørgensen (Ex. 1005). .............. 45
`
`a.
`
`Claim chart for Ground 6 showing exemplary
`citations in Hoekstra (Ex. 1004) and Jørgensen (Ex.
`1007). ........................................................................................ 46
`
`3.
`
`4.
`
`Ground 7: Claims 7-10, 14-16, and 19-21 are rendered
`obvious by Hoekstra (Ex. 1004) and Jørgensen, in view of
`Insulin Admin. (Ex. 1015). .................................................................. 49
`
`Ground 8: Claim 18 is rendered obvious by Hoekstra (Ex.
`1004) and Jørgensen (Ex. 1005), in view of secondary
`reference Alsufyani (Ex. 1006). .......................................................... 50
`
`F.
`
`Secondary Considerations Do Not Rebut the Prima Facie Case of
`Obviousness. .................................................................................................. 51
`
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`Patent No. 8,664,231
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`1.
`
`2.
`
`3.
`
`4.
`
`Any toxicity associated with MTX after subcutaneous
`injection is dose, not concentration dependent. ............................ 52
`
`The bioavailability of MTX after subcutaneous injection is
`dose, not concentration, dependent. ............................................... 55
`
`Applicant’s evidence of unexpected results is not based on
`a comparison of the claimed invention to the closest prior
`art. ........................................................................................................ 57
`
`Zackheim Does Not Teach Away From the Claimed
`Invention ............................................................................................. 59
`
`VII. Conclusion ................................................................................................................. 60
`
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`Patent No. 8,664,231
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Federal Cases
`Atlas Powder Co. v. IRECO, Inc.,
`190 F.3d 1342 (Fed. Cir. 1999) ............................................................................... 16, 17
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ........................................................................................ 17
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) ..................................................................................... 17
`
`Galderma Labs. v. Tolmar Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ........................................................................................ 60
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ............................................................................................................. 33
`
`In re De Blauwe,
`736 F.2d 699 (Fed. Cir. 1984) ........................................................................................ 57
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 32, 33, 46
`
`Ruiz v. A.B. Chance Co.,
`234 F.3d 654 (Fed. Cir. 2000) ........................................................................................ 51
`
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ........................................................................................ 16
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ........................................................................................ 16
`Federal Statutes
`35 U.S.C. § 102...................................................................................................................... 10
`
`35 U.S.C. § 102(b) ........................................................................................ 11, 15, 18, 27
`
`35 U.S.C. § 103............................................................................................................ 8, 10, 33
`
`35 U.S.C. § 103(a) ......................................................................................................passim
`
`
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`Patent No. 8,664,231
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`35 U.S.C. § 311...................................................................................................................... 10
`
`35 U.S.C. § 371........................................................................................................................ 2
`Regulations
`37 C.F.R. § 42.8(b)(1) ............................................................................................................. 1
`
`37 C.F.R. § 42.8(b)(2) ............................................................................................................. 1
`
`37 C.F.R. § 42.15(a) ................................................................................................................ 2
`
`37 C.F.R. § 42.100(b) ............................................................................................................. 9
`
`37 C.F.R. § 42.103(a) .............................................................................................................. 2
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`
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`Patent No. 8,664,231
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`LIST OF EXHIBITS
`
`
`Exhibit 1001 U.S. 8,664,231 to Heiner WILL, titled, “Concentrated Methotrexate
`Solutions,” filed on March 4, 2009, and issued on March 4, 2014
`(“the ’231 Patent”).
`Exhibit 1002 Excerpts from File History for U.S. Patent No. 8,664,231.
`Exhibit 1003 U.S. 6,544,504 to Paul GRINT et al., titled, “Combined Use of
`Interleukin 10 and Methotrexate for Immunomodulatory Therapy,”
`filed on Jun. 26, 2000, and issued on April 8, 2003 (“Grint”).
`Exhibit 1004 Hoekstra et al. (2004) J. Rheumatol 31(4):645-648 (“Hoekstra”).
`Exhibit 1005
`Jørgensen et al. (1996) Ann Pharmacother 30:729-32 (“Jørgensen”).
`Exhibit 1006 Alsufyani et al. (2003) J. Rheumatol 31:179-82 (“Alsufyani”).
`Exhibit 1007
`1985 Ed. Physician’s Desk Reference for Mexate® (“the PDR for
`Mexate®”).
`Exhibit 1008 Brooks et al. (1990) Arthritis and Rheum. 33(1):91-94 (“Brooks”).
`Exhibit 1009 Product Summary for the “Methotrexate 100 mg/ml Injection”
`product by Hospira UK Ltd., Date of First Authorization 13 March
`1987, Date of Revision of the Text 22 November 2005 (“the Hospira
`reference”).
`Exhibit 1010 Zackheim (1992) J. Am. Acad. of Derm. 23(6) p. 1008 (“Zackheim”).
`Exhibit 1011 Müller-Ladner (2010) The Open Rheumatology Journal 4:15-22.
`(“Müller-Ladner”).
`Exhibit 1012 Weinblatt Declaration; Dated June 17, 2014 (“Weinblatt Decl.”).
`Exhibit 1013 Gammon Declaration; Dated June 27, 2014 (“Gammon Decl.”).
`Exhibit 1014 Pincus et al. (2003) Clin Exp Rheumatol (Suppl. 31):S179-S185
`(“Pincus”).
`Insulin Administration, Diabetes Care, 26:1 S121-124 (2003) (“Insulin
`Admin”)
`Exhibit 1016 Complaint in Medac Pharma, Inc. v. Antares Pharma, Inc., Nos.
`1:14-cv-01498-JBS-KMW
`Exhibit 1017 Portion of EPO prosecution for EP Application No. 07 786 239.9
`and Certified English Translation of the same.
`Exhibit 1018 Weinblatt (1993) “Methotrexate,” in Textbook of Rheumatology, 4th
`Edition, Chapter 47, (Kelley et al., eds. 1993) (“Weinblatt 1993”)
`Exhibit 1019 Hoffmeister (1983) “Methotrexate therapy in rheumatoid arthritis: 15
`years experience,” Am J Med 75:69-73 (1993)
`Exhibit 1020 Weinblatt (1995) Efficacy of Methotrexate in Rheumatoid Arthritis,
`Br. J. Rheum. 34(suppl. 2):43-48 (“Weinblatt 1995”)
`Exhibit 1021 Weinblatt et al. (1985) “Efficacy of Low-Dose Methotrexate in
`Rheumatoid Arthritis,” New England J. Med. 312:818-822 (“Weinblatt
`
`Exhibit 1015
`
`
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`Patent No. 8,664,231
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`1985”)
`Exhibit 1022 Hoffmeister (1972) Methotrexate in rheumatoid arthritis. Arthritis
`rheum. 15 (Suppl.): S114 (abstract) (“Hoffmeister 1972”)
`Exhibit 1023 Weinblatt et al. (1994) Methotrexate in Rheumatoid Arthritis: a 5
`Year Prospective Multicenter Study, Arth. Rheum. 37(10):1492-1498
`(“Weinblatt 1994”)
`Exhibit 1024 Weinblatt et al. (1992) Long-Term Prospective Study of Methotrexate
`the Treatment of Rheumatoid Arthritis: 84-Month Update, Arth.
`Rheum. 35(2):129-137 (“Weinblatt 1992”)
`Exhibit 1025 Gubner et al. (1951) Therapeutic suppression of tissue reactivity. II.
`Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J
`Med Sci., 22:176-82 (“Gubner”)
`Exhibit 1026 Black et al. (1964) Methotrexate therapy in psoriatic arthritis. Double-
`blind study on 21 patients. J Am Med Assoc 189:743-7 (“Black”)
`Exhibit 1027 Feagan et al. (1995) Methotrexate for the Treatment of Crohn’s
`Disease, New England J. Med. 332(5):292-297 (“Feagan”)
`Exhibit 1028 Furst et al. (1989) Increasing Methotrexate Effect with Increasing
`Dose in the Treatment of Resistant Rheumatoid Arthritis, J. Rheum
`16(3):313-20 (“Furst”)
`Exhibit 1029 Giannini, et al. (1992) Methotrexate in resistant juvenile rheumatoid
`arthritis—results of the U.S.A.-U.S.S.R. double-blind, placebo-
`controlled trial. N. Engl.. Med. 326:1043 (“Giannini”)
`Exhibit 1030 Michaels, et al. (1992) Weekly Intravenous Methotrexate in the
`Treatment of Rheumatoid Arthritis, Arthritis and Rheumatism
`25(3):339-341 (“Michaels”)
`Exhibit 1031 Weinblatt Curriculum Vitae
`Exhibit 1032 Gammon Curriculum Vitae
`
`
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`Patent No. 8,664,231
`
`I.
`
`Introduction
`Petitioners Antares Pharma, Inc., Leo Pharma A/S and Leo Pharma Inc.,
`
`request an Inter Partes Review (IPR) of claims 1-22 (collectively, the “Challenged
`
`Claims”) of U.S. Patent No. 8,664,231 (Ex. 1001).
`
`II. Grounds for Standing
`Petitioners certify that the ’231 Patent is available for IPR and that the
`
`Petitioners are not barred or estopped from requesting IPR challenging the claims of
`
`the ’231 Patent on the grounds identified in this petition.
`
`III. Mandatory Notices
`A. Real Party-In-Interest
`The real parties-in-interest are Antares Pharma, Inc., Leo Pharma, Inc., and
`
`Leo Pharma A/S. 37 C.F.R. § 42.8(b)(1).
`
`B. Related Matters
`The ’231 Patent is presently the subject of a lawsuit filed on March 7, 2014, by
`
`medac Pharma, Inc. and medac Gesellschaft für klinische Spezialpräparate mbH
`
`against Petitioners in the U.S. District Court for the District of New Jersey: Case No.
`
`1:14-cv-01498-JBS-KMW. 37 C.F.R. § 42.8(b)(2). Ex. 1016.
`
`C.
`Lead and Back-Up Counsel, and Service Information
`Lead counsel is Sanya Sukduang, Reg. No. 46,390, of FINNEGAN,
`
`HENDERSON, FARABOW, GARRETT & DUNNER, LLP, 901 New York
`
`Avenue, NW Washington, DC 20001-4413, P: 202-408-4377/F: 202-408-4400,
`
`
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`1
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`Patent No. 8,664,231
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`Sanya.Sukduang@finnegan.com. Back-up counsel is Thomas Jenkins, Reg. No.
`
`30,830,857, also of FINNEGAN, HENDERSON, FARABOW, GARRETT &
`
`DUNNER, LLP, 901 New York Avenue, NW Washington, DC 20001-4413, P: 202-
`
`408-4088/F: 202-408-4400, thomas.jenkins@finnegan.com. Petitioners consent to
`
`electronic service.
`
`IV. Payment of Fees
`The required fees are submitted herewith in accordance with 37 C.F.R.
`
`§§ 42.103(a) and 42.15(a). If any additional fees are due during this proceeding, the
`
`Office is authorized to charge such fees to Deposit Account No. 06-0916.
`
`V.
`
`Identification of Challenge
`A. Overview of the ’231 Patent
`1.
`The ’231 Specification
`The ’231 patent is a §371 National Stage Entry of PCT Application No.
`
`PCT/EP2007/006491, filed July 20, 2007, which claims the benefit of German
`
`Application No. DE 10 2006 033 837, filed July 21, 2006. Ex. 1001 at Front Cover.
`
`The ’231 patent is titled “Concentrated Methotrexate Solutions,” and it
`
`describes and claims a method of treating inflammatory autoimmune diseases with
`
`“concentrated” methotrexate (MTX), wherein the MTX is administered
`
`subcutaneously (i.e., under the skin). The ’231 specification acknowledges that
`
`methods of treating inflammatory autoimmune diseases with MTX were known in the
`
`art at the time of filing, as was the subcutaneous route of administration. Id. at 2:34-
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`2
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`Patent No. 8,664,231
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`36; 2:41-42. Thus, the only alleged improvement in the ’231 patent is the use of
`
`“concentrated” MTX solutions (“more than 30 mg/ml” are claimed) in performing
`
`the methods disclosed in the prior art. Id. at 1:1-10; see also Ex. 1002 at 20, 3/21/2012
`
`Office Action (“OA”) Response. Although each claim of the ’231 patent is directed to
`
`a method of treating a patient having an inflammatory autoimmune disease with
`
`“concentrated” MTX, the ’231 patent does not include a single working example
`
`showing administration of any concentration of MTX to a patient.
`
`2.
`The ’231 Claims
`Claim 1, the only independent claim in the ’231 patent, recites a method for
`
`treating inflammatory autoimmune diseases in a pateint in need thereof, comprising
`
`subcutaneously administering to said patient a medicament comprising methotrexate
`
`in a pharmaceutically acceptable solvent at a concentration of more than 30 mg/ml.
`
`Ex. 1001 at 8:43-47.
`
`Claim 2 depends from claim 1, and recites that the MTX is present at a
`
`concentration of more than 30 mg/ml to 100 mg/ml. Id. at 8:48-50.
`
`Claim 3 depends from claim 2, and recites that the MTX is present at a
`
`concentration of 50 mg/ml. Id. at 8:50-52.
`
`Claim 4 depends from claim 1, and recites that the pharmaceutically
`
`acceptable solvent is selected from water, water for injection purposes, water
`
`comprising isotonization additives and sodium chloride solution. Id. at 8:53-56.
`
`
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`3
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`Claim 5 depends from claim 1, and recites that the inflammatory autoimmune
`
`disease is selected from rheumatoid arthritis, juvenile arthritides, vasculitides,
`
`collagenoses, Crohn’s disease, colitis ulcerosa, bronchial asthma, Alzheimer’s disease,
`
`multiple sclerosis, Bechterew’s disease, joint arthroses, or psoriasis. Id. at 8:57-62.
`
`Claim 6 depends from claim 5, and recites that the inflammatory autoimmune
`
`disease is rheumatoid arthritis. Id. at 8:63-64.
`
`Claim 7 depends from claim 1, and recites that the medicament is present in a
`
`form suitable for patient self-administration. Id. at 8:65-67.
`
`Claim 8 depends from claim 1, and recites that the medicament is contained in
`
`an injection device for a single application. Id. at 9:1-3.
`
`Claim 9 depends from claim 8, and recites that the injection device contains a
`
`dosage of 5 to 40 mg of methotrexate. Id. at 9:4-5.
`
`Claim 10 depends from claim 8 or claim 9, and recites that the inejction
`
`device is a ready-made syringe. Id. at 9:6-7.
`
`Claim 11 depends from claim 1, and recites that the medicament is contained
`
`in a storage container. Id. at 9:8-9.
`
`Claim 12 depends from claim 11, and recites that the storage container
`
`contains a total dosage amount of 5 to 5,000 mg. Id. at 9:10-11.
`
`Claim 13 depends from claim 11, and recites that the storage container is an
`
`injection botte, a vial, a bag, a glass ampoule, or a carpule. Id. at 9:12-14.
`
`
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`Claim 14 depends from claim 13, and recites that the storage container is a
`
`carpule and wherein said carpule is suitable for administering the medicament by
`
`means of an injection device. Id. at 9:15-18.
`
`Claim 15 depends from claim 14, and recites that the carpule and the pen
`
`injector are provided such that multiple applications of single dosages can be
`
`administered. Id. at 9:19-21.
`
`Claim 16 depends from claim 15, and recites that the single dosages per
`
`application can be adjusted to 5 to 40 mg each of methotrexate. Id. at 10:1-3.
`
`Claim 17 depends from claim 4, and recites that the sodium chloride solution
`
`is isotonic sodium chloride solution. Id. at 10:4-5.
`
`Claim 18 depends from claim 6, and recites that the rheumatoid arthritis is
`
`juvenile rheumatoid arthritis. Id. at 10:6-7.
`
`Claim 19 depends from claim 9, and recites that the injection device contains
`
`a dosage selected from 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0, 22.5, 25.0, 27.5, 30.0, 32.5,
`
`35.0, 37.5, or 40.0 mg of methotrexate. Id. at 10:8-11.
`
`Claim 20 depends from claim 14, and recites that the injection device is a pen
`
`injector. Id. at 10:12-13.
`
`Claim 21 depends from claim 16, and recites that the single dosages of
`
`methotrexate per application is adjusted to be 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0,
`
`22.5, 25.0, 27.5, 30.0, 32.5, 35.0, 37.5, or 40.0 mg. Id. at 14-17.
`
`
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`5
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`Claim 22 depends from claim 1, and recites that the methotrexate is present at
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`a concentration of from 40 mg/ml to 80 mg/ml. Id. at 18-20.
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`3.
`The ’231 Prosecution History
`The application that led to the ’231 patent was rejected in a first, non-final, OA
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`dated December 21, 2011. Ex. 1002 at 2-12, 12/21/11 OA. At the time of this OA,
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`claims 1-11 and 13-17 were pending. Claim 1, the only independent claim, recited uses
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`of methotrexate at a concentration of more than 30 mg/ml for subcutaneous
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`administration to treat inflammatory autoimmune diseases. Id. at 1. The Examiner
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`rejected claims 1-11 and 13-17 as obvious under 35 U.S.C. § 103(a) over Hoekstra (Ex.
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`1004) in view of various secondary references. Id. at 6-10. The Examiner alleged that
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`Hoekstra taught methods for adminstering MTX to patients via the subcutaneous
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`route, wherein the total dosage (in mg) of MTX was greater than 25 mg per week. Id.
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`The Examiner recognized that Hoekstra did not teach the claimed “more than 30
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`mg/ml” concentrations of MTX, but concluded that the claims were nevertheless
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`obvious because “the determinination of the optimum characterization of the
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`composition and dosage amounts would have been a matter well within the purview
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`of one of ordinary skill in the art, at the time of invention, through no more than
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`routine experimentation.” Id. Secondary references were cited by the Examiner that
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`allegedly taught the additional elements of the dependent claims.
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`Applicant responded to the obviousness rejection on March 21, 2012, by
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`arguing that Hoekstra “clearly represents the closest prior art” but does not provide
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`any teaching with regard to “the crucial feature of the present invention,” that is “the
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`particularly high concentration of the active agent methotrexate in the solution, i.e.,
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`more than 30 mg/mL.” Ex. 1002 at 20, 3/21/2012 OA Response. Applicant argued,
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`without evidentiary support, that the claimed invention “is not a mere optimization of
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`ranges or regimens which is obtained by mere routine experimentation” because
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`“methotrexate clearly is an active agent which is also used in cancer therapy, so that a
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`person skilled in the art would have been very cautious to increase the concentration
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`of the active agent in a subcutaneously administerd solution.” Id. at 9. Applicant
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`argued further, again without evidentiary support, that “it was not at all obvious at the
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`time of the present invention that toxicity and bioavailability of methotrexate
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`solutions with higher concentrations would be acceptable.” Id. Although Applicant
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`admitted that highly concentrated forms of MTX were “on the market” as of the
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`priority date of the invention, it erroneously asserted that they were “solely marketed
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`and approved for treatement of cancer….” Id. at 10.
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`Additionally, in an attempt to rebut the Examiner’s prima facie case of
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`obviousness, Applicant submitted a copy of a 2010 scientific article by Müller-Ladner
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`(Ex. 1011), and argued that the article provided evidence of unexpected results. Ex.
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`1002 at 21, 3/21/2012 OA Response. Applicant alleged that Müller-Ladner described a
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`comparison between a 50 mg/ml solution of MTX (high-concentration formulation;
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`“HC”) and a 10 mg/ml solution of MTX (medium-concentration formulation,
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`“MC”), and concluded that subcutaneous injection of the 50 mg/ml MTX solution in
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`patients with RA was better tolerated than the subcutaneous injection of the 10
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`mg/ml MTX solution. Id. Despite the fact that Applicant had previously acknowleged
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`that the Hoekstra reference, disclosing a 25 mg/ml concentration of MTX for
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`subcutaneous administration, was the closest prior art, Applicant nevertheless
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`concluded that the “improvement” seen with the higher concentrated 50 mg/ml
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`MTX solution was a “surprising technical effect which was unexpectedly observed”
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`when compared to the higher volume, but less concetrated 10 mg/ml MTX solution.
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`Id.
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`In this same March 21, 2012 response, Applicant argued that Zackheim (Ex.
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`1010), cited by the Examiner in the § 103 rejection, taught away from the invention
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`because when administering a dose of MTX greater than 50 mg, the authors “chose”
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`to maintain the concentration of MTX at 25 mg/ml and to use two injection sites
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`with 25 mg/ml at each site, rather than to increase the concentration of the
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`methotrexate solution to 50 mg/ml, for example, and administer only a single
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`injection. Id. at 10.
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`A telephone interview was conducted between Applicant’s representative and
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`the Examiner on December 23, 2013, where “[a]llowable subject matter was
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`discussed….” Ex. 1002 at 25, 12/23/13 Examiner Interview. A Notice of Allowance
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`was issued on January 7, 2014. Id. at 1. The Examiner stated in the Reasons for
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`Allowance that Applicant’s arguments submitted on March 21, 2012, were persuasive,
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`and that “the limitation ‘at a concentration of more than 30 mg/ml’ is novel and not
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`in a range that would have been found obvious through optimaization.” Id. at 3.
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`Presumably based on Applicant’s misrepresentation that highly concentrated forms of
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`MTX were “solely marketed and approved for treatment of cancer,” (see OA
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`Response at 10), the Examiner determined that “Applicant is correct in stating that
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`this concentration would have been avoided and above the maximum range in the
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`art.” Id.
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`B.
`Claim Construction of Challenged Claims
`A claim subject to IPR receives the “broadest reasonable construction in light
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`of the specification of the patent in which it appears.” 37 C.F.R. § 42.100(b). Unless
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`otherwise noted below, Petitioners accept, for purposes of IPR only, that the claim
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`terms of the ’231 patent are presumed to take on their ordinary and customary
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`meaning that they would have to one of ordinary skill in the art.
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`1.
`“Subcutaneously”
`The term “subcutaneously” means:“under the skin.” Weinblatt Decl. (Ex.
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`1012) at ¶ 48; Ex. 1001 at 5:1-5.
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`2.
`“Pharmaceutically acceptable solvent”
`The term “pharmaceutically acceptable solvent” means: “a solvent that is safe
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`for administration to patients, including humans, that will not interfere with the active
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`pharmaceutical substance or other component in the solution.” Gammon Decl. (Ex.
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`1013) at ¶ 21; Ex. 1001 at 3:28-36.
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`3.
`“Injection device”
`The term “injection device” means: “a device that permits a medicament to be
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`injected into a patient.” Gammon Decl. (Ex. 1013) at ¶ 25; Ex. 1001 at 4:19-39.
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`4.
`“Ready-made syringe”
`The term “ready-made syringe” means: “a device containing a medicament that
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`permits the medicament to be injected into a patient.” Gammon Decl. (Ex. 1013) at ¶
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`29; Ex 1001 at 4:55-59, 5:28-41.
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`5.
`“Pen injector”
`The term “pen injector” means: “a device that injects a dose of medicament
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`into a patient via a powered or manually inserted hypodermic needle, wherein the
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`device may be for single use or multiple uses, and may be disposable or reusable.”
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`Gammon Decl. (Ex. 1013) at ¶ 33; Ex. 1001 at 6:55-7:27.
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`C.
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`Statement of Precise Relief Requested for Each Claim Challenged
`1.
`Claims for Which Review Is Requested
`Petitioners request IPR under 35 U.S.C. § 311 of claims 1-22 of the ’231 Patent,
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`and such cancellation of these twenty-two claims as unpatentable.
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`2.
`Statutory Grounds of Challenge
`Claims 1-22 are unpatentable under 35 U.S.C. §§ 102 and/or 103 for the
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`following reasons:
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`Ground Proposed Rejections for the ’231 Patent
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`Exhibit No(s).
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`1
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`2
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`3
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`4
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`5
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`6
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`7
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`
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`Claims 1, 2, 4-6, 11-13, 17, and 22 are
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`1003
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`anticipated under 35 U.S.C. § 102(b) by US
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`
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`Patent No. 6,544,504 (Grint).
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`Claims 7-10, 14-16, and 19-21 are obvious under
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`1003 and 1015
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`35 U.S.C. § 103(a) in view of US Patent No.
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`
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`6,544,504 (Grint