`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________________
`
`
`FRONTIER THERAPEUTICS, LLC
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`
`Patent Owner
`
`____________________
`
`Inter Partes Review Case No. Unassigned
`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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`TABLE OF CONTENTS
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`I.
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`Page
`INTRODUCTION ............................................................................................ 1
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`II. OVERVIEW ..................................................................................................... 1
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`III. GROUNDS FOR STANDING - § 42.104(a) ................................................... 5
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`IV. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8 .................................... 5
`
`A. Real Party in Interest .............................................................................. 5
`
`B. Related Matters ....................................................................................... 5
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`C. Lead and Backup Counsel ...................................................................... 6
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`V. SERVICE INFORMATION ............................................................................. 6
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`VI. PAYMENT OF FEES UNDER §§ 42.15(a) AND 42.103 ............................... 6
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`VII. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) .............................................. 6
`
`VIII. THE ’231 PATENT .......................................................................................... 7
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`IX. LEVEL OF ORDINARY SKILL IN THE ART ............................................14
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`X. CLAIM CONSTRUCTION ............................................................................14
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`A.
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`B.
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`C.
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`D.
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`E.
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`“Subcutaneously” .................................................................................15
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`“Pharmaceutically acceptable solvent” ................................................15
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`“Injection device” .................................................................................15
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`“Ready-made syringe” ..........................................................................15
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`“Pen Injector” .......................................................................................16
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`XI. RELIEF REQUESTED ...................................................................................16
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`A. Claims for Which Review is Requested ...............................................16
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`B.
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`Statutory Grounds of Challenge ...........................................................16
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`C. Overview of the Prior Art .....................................................................17
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`XII. DETAILED EXPLANATION OF THE CHALLENGE ...............................19
`
`A. Ground 1: U.S. Patent No. 6,544,504 (Grint, Ex. 1003) anticipates
`claims 1, 2, 4-6, 11-13, 17, and 22 under pre-AIA 35 U.S.C. § 102(b)……19
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`Patent No. 8,664,231
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`B. Ground 2: Claims 7-10, 14-16, and 19-21 are obvious over U.S. Patent
`No. 6,554,504 (Grint, Ex. 1003) in view of Insulin Admin. (Ex. 1015). ......28
`
`C. Ground 3: Claim 18 is obvious over U.S. Patent No. 6,554,504 (Grint,
`Ex. 1003) in view of Alsufyani (Ex. 1006). ..................................................33
`
`D. Grounds 4 and 5: Claims 1-5, 7-17, and 19-22 are obvious under pre-
`AIA 35 U.S.C. § 103(a) over primary references PDR (Ex. 1007) or Hospira
`(Ex. 1009) and Brooks (Ex. 1008), in further view of Insulin Admin. (Ex.
`1015) and Alsufanyi (Ex. 1006). ...................................................................34
`
`XIII. Secondary Considerations Do Not Rebut the Prima Facie Case of
`Obviousness ....................................................................................................49
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`A. Any toxicity associated with MTX after subcutaneous injection is dose–not
`concentration–dependent. ..............................................................................50
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`B. The bioavailability of MTX after subcutaneous injection is dose–not
`concentration–dependent ...............................................................................54
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`C. Applicant’s evidence of unexpected results is not based on a
`comparison of the claimed invention to the closest prior art ........................55
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`D. Zackheim does not teach away from the claimed invention ................58
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`XIV. CONCLUSION ...............................................................................................59
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`Patent No. 8,664,231
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`
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`TABLE OF AUTHORITIES
`
`
`A. Cases
`
`
`Atlas Powder Co. v. IRECO, Inc.,
`
`190 F.3d 1342 (Fed. Cir. 1999) ..............................................................................21
`
`
`Atofina v. Great Lakes Chem. Corp.,
`441 F.3d 991 (Fed. Cir. 2006) ...............................................................................22
`
`
`ClearValue, Inc. v. Pearl River Polymers, Inc.,
`668 F.3d 1340 (Fed. Cir. 2012) ........................................................................22, 23
`
`
`Galderma Labs. v. Tolmar Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ................................................................................59
`
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ...................................................................................................40
`
`
`In re De Blauwe,
`736 F.2d 699 (Fed. Cir. 1984) ................................................................................56
`
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ...............................................................................................39
`
`
`Ruiz v. A.B. Chance Co.,
`234 F.3d 654 (Fed. Cir. 2000) ................................................................................49
`
`
`Titanium Metals Corp. v. Banner,
`778 F.2d 775 (Fed. Cir. 1985) ................................................................................21
`
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ................................................................................21
`
`B.
`
`
`
`35 U.S.C. § 102.............................................................................................16
`
`Statutes
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`Patent No. 8,664,231
`Patent No. 8,664,231
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`35 U.S.C. § 102(b) ...........................................................................16, 20, 24
`35 U.S.C. § 102(b) ........................................................................... 16, 20, 24
`
`35 U.S.C. § 103.........................................................16, 17, 31, 34, 35, 42, 49
`35 U.S.C. § 103 ......................................................... 16,17, 31, 34, 35, 42, 49
`
`35 U.S.C. § 103(a) .................................................................................passim
`35 U.S.C. § 103(a) .................................................................................passim
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`35 U.S.C. § 311.............................................................................................16
`35 U.S.C. § 311 ............................................................................................. 16
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`35 U.S.C. § 371...............................................................................................7
`35 U.S.C. § 371 ............................................................................................... 7
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`
`
`C. Rules
`Rules
`
`
`37 C.F.R. § 42.8(b)(1) ....................................................................................5
`37 CPR. § 42.8(b)(1) .................................................................................... 5
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`37 C.F.R. § 42.8(b)(2) ....................................................................................5
`37 CPR. § 42.8(b)(2) .................................................................................... 5
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`37 C.F.R. § 42.15(a) ....................................................................................4,6
`37 CPR. § 42.15(a) ....................................................................................4,6
`
`37 C.F.R. § 42.100(b) ...................................................................................15
`37 CPR. § 42.100(b) ................................................................................... 15
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`37 C.F.R. § 42.103(a) ..................................................................................4,6
`37 CPR. § 42.103(a) ..................................................................................4,6
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`Patent No. 8,664,231
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`TABLE OF EXHIBITS
`
`
`Description
`Exhibit No.
`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® (“PDR”).
`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
`(“Hospira”).
`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 Dr. Gershwin Declaration (“Gershwin Decl.”).
`Exhibit 1013 Mr. Gammon Declaration (“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
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`Exhibit 1015
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`Patent No. 8,664,231
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`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
`(“Hoffmeister 1983”)
`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,” N. Engl. J. Med. 312:818-822
`(“Weinblatt 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.
`Doubleblind 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, N. Engl. 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. J. 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 Dr. Gershwin’s Curriculum Vitae
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`Patent No. 8,664,231
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`Exhibit 1032 Mr. Gammon’s Curriculum Vitae
`Exhibit 1033 Petition for Inter Partes Review by Antares Pharma Inc. et al.,
`PTAB-IPR2014-01091, Paper No. 7, January 6, 2015 (’091
`IPR Institution).
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`I. INTRODUCTION
`
`Frontier Therapeutics, LLC (“Petitioner”) files this Petition for Inter Partes
`
`Review (“Petition”) seeking cancellation of claims 1-22 (“challenged claims”) of
`
`U.S. Pat. No. 8,664,231 to Will, titled “Concentrated Methotrexate Solutions”
`
`(“the ’231 Patent”) (Ex. 1001).
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`II. OVERVIEW
`
`This Petition advances five grounds of invalidity against claims 1-22 of the
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`’231 Patent, including the same grounds that were previously instituted by the
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`Patent Trial and Appeal Board (“the Board”) in an earlier-filed inter partes review.
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`See ’091 IPR Institution (Ex. 1033). With particular regard to those grounds, the
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`Petitioner asserts that the challenged claims of the ’231 Patent are: anticipated
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`under 35 U.S.C. § 102(b) by Grint (Ex. 1003), and/or are obvious under 35 U.S.C.
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`§ 103(a) over one or more of 1) Grint; 2) Insulin Admin. (Ex. 1015); 3) Alsufyani
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`(Ex. 1006); 4) PDR (Ex. 1007); 5) Hospira (Ex. 1009); and 6) Brooks (Ex. 1008).
`
`Each of the limitations of the challenged claims of the ’231 Patent is taught
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`by the prior art. First, as explained by the Board in the ’091 IPR Institution with
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`respect to claims 1, 2, 4-6, 11-13, 17, and 22, “Grint discloses a method for treating
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`inflammatory autoimmune diseases in a patient, including rheumatoid arthritis,
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`comprising administering a medication comprising methotrexate in a
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`pharmaceutically acceptable solvent.” P. 8. The Board also noted that “Grint
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`Patent No. 8,664,231
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`discloses a treatment method that involves administering methotrexate
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`parenterally, including subcutaneously, from a unit dosage form containing
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`methotrexate at a concentration of more than 30 mg/ml, i.e., 0.1 to about 40 mg/ml
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`of carrier.” Id. at 8-9. This, according to the Board, “reasonably establishes that
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`Grint correlates treatment of a specific disease with a specific route of
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`administration (subcutaneous) and use of a specific concentration range of a
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`methotrexate solution.” Id. at 9.
`
`The Board was not persuaded by the Patent Owner’s contention that a
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`skilled artisan would not look to the “lower end of the dosage and concentration”
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`disclosed in Grint. According to the Board, the Patent Owner failed to provide any
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`evidence demonstrating that “a skilled artisan would have understood that only the
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`lower end of Grint’s disclosed concentration range for a parenteral unit dosage
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`form would have applied to a subcutaneous injection.” Id. at 10. More simply,
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`however, the Board recognized this argument as being a red herring because “the
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`claims at issue do not recite administering any specific dosages ranges.” Id.
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`With regard to claims 7-10, 14-16, and 19-21, the Board concluded there
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`was a “reasonable likelihood” that those claims were obvious over Grint and
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`Insulin Admin. Id. at 13. While Grint “does not expressly disclose that its
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`methotrexate is packaged in a form suitable for self-administration,” Insulin
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`Admin. discloses “the use of a ‘pen-like device,’ i.e., an injection device or a pen
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`injector, and the use of a ‘prefilled syringe,’ i.e., a ‘ready-made syringe’ for self-
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`administration of insulin.” Id. at 12 (citation omitted). Though it was
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`acknowledged that Insulin Admin. does not specifically teach an injection device
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`comprising methotrexate, this alone was not deemed significant given “the ’231
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`Patent acknowledges that ready-made syringes containing methotrexate were also
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`known in the prior art.” Id. at 13.
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`The Board similarly held that the additional limitations provided by
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`dependent claim 18 are likely obvious over Grint and Alsufyani, at least because
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`“one of ordinary skill in the art would have been motivated, with a reasonable
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`expectation of success, to use highly concentrated solutions of methotrexate to
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`treat juvenile rheumatoid arthritis, based on the combined teachings of Grint and
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`Alsufyani.” Id. at 15.
`
`The Board further held that claims 1-5, 11-13, 17, and 22 are likely obvious
`
`over the PDR or Hospira in view of Brooks. Id. at 22. With particular regard to
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`claim 3, the Board found that the “PDR and Hospira each teach a method for
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`treating psoriasis, an inflammatory autoimmune disease, comprising administering
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`methotrexate in a pharmaceutically acceptable solvent at a concentration of more
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`than 50 mg/ml.” Id. at 20. Though the Board conceded that “the PDR and Hospira
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`Patent No. 8,664,231
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`each teach administering the methotrexate injection intramuscularly, Petitioner has
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`shown sufficiently at this stage in the proceeding that a person of ordinary skill in
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`the art would have had a reason to administer the injections disclosed by the PDR
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`and Hospira subcutaneously based upon the teachings of Brooks.” Id. at 21. For
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`similar reasons, the Board concluded that claims 7-10, 14-16, and 19-21 are likely
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`obvious over the PDR or Hospira in view of Brooks and Insulin Admin. Id. at 22-
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`23.
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`In light of the foregoing positions taken by the Board, the Petitioner
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`advances Grounds 1-5 below, which detail the lack of novelty and nonobviousness
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`of the challenged claims. See infra, § XII.
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`Moreover, the Patent Owner cannot demonstrate secondary indicia of
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`nonobviousness of claims 1-22. At no time during the proceedings of the ’091 IPR
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`did Patent Owner attempt to argue secondary indicia of nonobviousness in an
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`effort to overcome Petitioner's strong case of prima facie obviousness.
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`Unsurprisingly, the Patent Owner consciously neglected to reiterate the secondary
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`consideration positions it previously advanced during the prosecution of the ’231
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`Patent, which were contradictory and ultimately meritless. See infra, § XIII.
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`For at least these reasons and those discussed below in further detail,
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`Petitioner has a reasonable likelihood of prevailing on the assertion that the
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`challenged claims are anticipated and/or obvious in view of the prior art references
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`discussed herein.
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`III. GROUNDS FOR STANDING - § 42.104(a)
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`
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`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the patent for
`
`which review is sought is available for inter partes review and that the Petitioner is
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`not barred or estopped from requesting an inter partes review challenging the
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`patent claims on the grounds identified in this Petition.
`
`IV. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`
`A. Real Party in Interest
`
`
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`In accordance with 37 C.F.R. § 42.8(b)(1), the Petitioner, Frontier
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`Therapeutics, LLC, is identified as the real party-in-interest. No person or entity
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`other than Frontier Therapeutics, LLC has authority to direct or control (i) the
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`timing of, filing of, content of, or any decisions or other activities relating to this
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`Petition or (ii) any timing, future filings, content of, or any decisions or other
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`activities relating to the future proceedings related to this Petition.
`
`B. Related Matters
`
`
`
`In accordance with 37 C.F.R. § 42.8(b)(2), Petitioner identifies the following
`
`matters: Judicial Matters: Medac Pharma, Inc. et al. v. Antares Pharma Inc. et al.,
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`NJD-1-14-cv-01498 (D.N.J.). Administrative matters: pending U.S. Patent Appl.
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`No. 14/635,542; Petition for Inter Partes Review by Antares Pharma Inc. et al.,
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`Patent No. 8,664,231
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`PTAB-IPR2014-01091.
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`C. Lead and Backup Counsel
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`
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`In accordance with 37 C.F.R. § 42.8(b)(3), Petitioner identifies counsel:
`
`Lead Counsel
`
`Back-Up Counsel
`
`Dr. Gregory Gonsalves
`Reg. No. 43,639
`2216 Beacon Lane
`Falls Church, VA 22043
`(571) 419-7252
`gonsalves@gonsalveslawfirm.com
`
`
`
`V. SERVICE INFORMATION
`
`Christopher Casieri
`McNeely, Hare & War LLP
`12 Roszel Road, Suite C104
`Princeton, NJ 08540
`Phone: 609 731 3668
`chris@miplaw.com
`
`
`
`
`Pursuant to 37 C.F.R. § 42.8(b)(4), Petitioner consents to electronic service
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`provided to the email addresses provided immediately above.
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`VI. PAYMENT OF FEES UNDER §§ 42.15(a) AND 42.103
`
`
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`The required fees are submitted herewith.
`
`VII. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`
`Petitioner requests IPR and cancellation of claims 1-22 of the ’231 Patent
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`based on one or more of the grounds under pre-AIA 35 U.S.C. § 102(b) and 35
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`U.S.C. § 103(a) set forth herein. Petitioner’s detailed statement of the reasons for
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`the relief requested is set forth in § XII below.
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`Patent No. 8,664,231
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`VIII. THE ’231 PATENT
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`A. The Specification
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`The ’231 Patent is a §371 National Stage Entry of PCT Application No.
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`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
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`“concentrated” methotrexate (MTX), wherein the MTX is administered
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`subcutaneously (i.e., under the skin). The ’231 Patent’s specification acknowledges
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`that methods of treating inflammatory autoimmune diseases with MTX were
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`known in the art at the time of filing, as was the subcutaneous route of
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`administration. Id. at 2:34-36; 2:41-42. Thus, the only alleged improvement in the
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`’231 Patent is the use of “concentrated” MTX solutions (“more than 30 mg/ml” are
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`claimed) in performing the methods disclosed in the prior art. Id. at 1:1-10; see
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`also Ex. 1002 at 20, 3/21/2012 Office Action (“OA”) Response. Although each
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`claim of the ’231 Patent is directed to a method of treating a patient having an
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`inflammatory autoimmune disease with “concentrated” MTX, the ’231 Patent does
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`not include a single working example showing administration of any concentration
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`of MTX to a patient.
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`B. The Claims
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`Patent No. 8,664,231
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`Claim 1, the only independent claim in the ’231 Patent, recites a method for
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`treating inflammatory autoimmune diseases in a patient in need thereof,
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`comprising subcutaneously administering to said patient a medicament comprising
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`methotrexate in a pharmaceutically acceptable solvent at a concentration of more
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`than 30 mg/ml. Ex. 1001 at 8:43-47.
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`Claim 2 depends from claim 1, and recites that the MTX is present at a
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`concentration of more than 30 mg/ml to 100 mg/ml. Id. at 8:48-50.
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`Claim 3 depends from claim 2, and recites that the MTX is present at a
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`concentration of about 50 mg/ml. Id. at 8:50-52.
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`Claim 4 depends from claim 1, and recites that the pharmaceutically
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`acceptable solvent is selected from water, water for injection purposes, water
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`comprising isotonization additives and sodium chloride solution. Id. at 8:53-56.
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`Claim 5 depends from claim 1, and recites that the inflammatory
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`autoimmune disease is selected from rheumatoid arthritis, juvenile arthritides,
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`vasculitides, collagenoses, Crohn’s disease, colitis ulcerosa, bronchial asthma,
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`Alzheimer’s disease, multiple sclerosis, Bechterew’s disease, joint arthroses, or
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`psoriasis. Id. at 8:57-62.
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`Claim 6 depends from claim 5, and recites that the inflammatory
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`autoimmune disease is rheumatoid arthritis. Id. at 8:63-64.
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`Claim 7 depends from claim 1, and recites that the medicament is present in
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`a form suitable for patient self-administration. Id. at 8:65-67.
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`Claim 8 depends from claim 1, and recites that the medicament is contained
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`in an injection device for a single application. Id. at 9:1-3.
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`Claim 9 depends from claim 8, and recites that the injection device contains
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`a dosage of 5 to 40 mg of methotrexate. Id. at 9:4-5.
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`Claim 10 depends from claim 8 or claim 9, and recites that the injection
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`device is a ready-made syringe. Id. at 9:6-7.
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`Claim 11 depends from claim 1, and recites that the medicament is contained
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`in a storage container. Id. at 9:8-9.
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`Claim 12 depends from claim 11, and recites that the storage container
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`contains a total dosage amount of 5 to 5,000 mg. Id. at 9:10-11.
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`Claim 13 depends from claim 11, and recites that the storage container is an
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`injection bottle, 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
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`carpule and wherein said carpule is suitable for administering the medicament by
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`means of an injection device. Id. at 9:15-18.
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`Claim 15 depends from claim 14, and recites that the carpule and the pen
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`injector are provided such that multiple applications of single dosages can be
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`administered. Id. at 9:19-21.
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`Claim 16 depends from claim 15, and recites that the single dosages per
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`application can be adjusted to 5 to 40 mg each of methotrexate. Id. at 10:1-3.
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`Claim 17 depends from claim 4, and recites that the sodium chloride solution
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`is isotonic sodium chloride solution. Id. at 10:4-5.
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`Claim 18 depends from claim 6, and recites that the rheumatoid arthritis is
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`juvenile rheumatoid arthritis. Id. at 10:6-7.
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`Claim 19 depends from claim 9, and recites that the injection device contains
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`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,
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`32.5, 35.0, 37.5, or 40.0 mg of methotrexate. Id. at 10:8-11.
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`Claim 20 depends from claim 14, and recites that the injection device is a
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`pen injector. Id. at 10:12-13.
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`Claim 21 depends from claim 16, and recites that the single dosages of
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`methotrexate per application is adjusted to be 5.0, 7.5, 10.0, 12.5, 15.0, 17.5, 20.0,
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`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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`Claim 22 depends from claim 1, and recites that the methotrexate is present
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`at a concentration of from 40 mg/ml to 80 mg/ml. Id. at 18-20.
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`C. The Prosecution History
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`The application that led to the ’231 Patent was rejected in a first, non-final
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`OA dated December 21, 2011. Ex. 1002 at 2-12, 12/21/11 OA. At the time of this
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`OA, claims 1-11 and 13-17 were pending. Claim 1, the only independent claim,
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`recited uses of methotrexate at a concentration of more than 30 mg/ml for
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`subcutaneous administration to treat inflammatory autoimmune diseases. Id. at 1.
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`The Examiner rejected claims 1-11 and 13-17 as obvious under 35 U.S.C. § 103(a)
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`over Hoekstra (Ex. 1004) in view of various secondary references. Id. at 6-10. The
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`Examiner alleged that Hoekstra taught methods for administering MTX to patients
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`via the subcutaneous route, wherein the total dosage (in mg) of MTX was greater
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`than 25 mg per week. Id. The Examiner recognized that Hoekstra did not teach the
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`claimed “more than 30 mg/ml” concentrations of MTX, but concluded that the
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`claims were nevertheless obvious because “the determination of the optimum
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`characterization of the composition and dosage amounts would have been a matter
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`well within the purview of one of ordinary skill in the art, at the time of invention,
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`through no more than routine experimentation.” Id.
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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
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`“the particularly high concentration of the active agent methotrexate in the
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`solution, i.e., more than 30 mg/mL.” Ex. 1002 at 20, 3/21/2012 OA Response.
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`Applicant argued, without evidentiary support, that the claimed invention “is not a
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`mere optimization of ranges or regimens which is obtained by mere routine
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`experimentation” because “methotrexate clearly is an active agent which is also
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`used in cancer therapy, so that a person skilled in the art would have been very
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`cautious to increase the concentration of the active agent in a subcutaneously
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`administered solution.” Id. at 9. Applicant argued further, again without
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`evidentiary support, that “it was not at all obvious at the time of the present
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`invention that toxicity and bioavailability of methotrexate solutions with higher
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`concentrations would be acceptable.” Id. Although Applicant admitted that highly
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`concentrated forms of MTX were “on the market” as of the priority date of the
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`invention, it erroneously asserted that they were “solely marketed and approved for
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`treatment 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-
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`Ladner (Ex. 1011), and argued that the article provided evidence of unexpected
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`results. Ex.1002 at 21, 3/21/2012 OA Response. Applicant alleged that Müller-
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`Ladner described a comparison between a 50 mg/ml solution of MTX (high-
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`concentration formulation; “HC”) and a 10 mg/ml solution of MTX (medium-
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`concentration formulation, “MC”), and concluded that subcutaneous injection of
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`the 50 mg/ml MTX solution in patients with RA was better tolerated than the
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`subcutaneous injection of the 10 mg/ml MTX solution. Id. Despite the fact that
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`Applicant had previously acknowledged that the Hoekstra reference, disclosing a
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`25 mg/ml concentration of MTX for subcutaneous administration, was the closest
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`prior art, Applicant nevertheless concluded that the “improvement” seen with the
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`higher concentrated 50 mg/ml MTX solution of Müller-Ladner was a “surprising
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`technical effect which was unexpectedly observed” when compared to the higher
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`volume, but less concentrated 10 mg/ml MTX solution. 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
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`invention because when administering a dose of MTX greater than 50 mg, the
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`authors “chose” to maintain the concentration of MTX at 25 mg/ml and to use two
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`injection sites with 25 mg/ml at each site, rather than to increase the concentration
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`of the methotrexate solution to 50 mg/ml, for example, and administer only a
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`single injection. Id. at 10.
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`A telephone interview was conducted between Applicant’s representative
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`and 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
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`Allowance was issued on January 7, 2014. Id. at 1. The Examiner stated in the
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`Reasons for Allowance that Applicant’s arguments submitted on March 21, 2012,
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`were persuasive, and that “the limitation ‘at a concentration of more than 30
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`mg/ml’ is novel and not in a range that would have been found obvious through
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`optimization.” Id. at 3. Presumably based on Applicant’s misrepresentation that
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`highly concentrated forms of MTX were “solely marketed and approved for
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`treatment of cancer,” (see OA Response at 10), the Examiner determined that
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`“Applicant is correct in stating that this concentration would have been avoided
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`and above the maximum range in the art.” Id.
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`IX. LEVEL OF ORDINARY SKILL IN THE ART
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`The level of skill in the art is apparent from the cited art. Further, a person
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`having ordinary skill in the art would have either a Pharm. D. or a Ph.D. in
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`pharmacy, pharmacology, or a related discipline; an M.D. or D.O. with experience
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`in using MTX; or a BS in pharmacy with at least two years of experience
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`formulating active pharmaceutical ingredients for injection. A person of ordinary
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`skill in the art would collaborate with others having expertise i