UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`KOIOS PHARMACEUTICALS LLC
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FUER KLINISCHE SPEZIALPRÄPARATE MBH
`
`Patent Owner
`____________
`
`IPR2016-01370
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`
`
`
`PETITION FOR INTER PARTES REVIEW
`
`
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`
`
`

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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`
`
`Table of Contents
`
`Petition
`
`I.
`
`INTRODUCTION ...................................................................................................... 1
`
`II. GROUNDS FOR STANDING ..................................................................................... 2
`
`III. MANDATORY NOTICES .......................................................................................... 2
`
`A. Real Party-In-Interest .................................................................................... 2
`
`B. Related Matters.............................................................................................. 2
`
`C. Lead and Back-Up Counsel, and Service Information ................................. 3
`
`IV. PAYMENT OF FEES ................................................................................................ 4
`
`V. OVERVIEW OF THE CHALLENGE ............................................................................ 4
`
`A. Summary of the Challenge ............................................................................ 4
`
`B. Claims Challenged and Asserted Grounds of Unpatentability ..................... 9
`
`C. Claim Construction .....................................................................................10
`
`D. Level of Skill in the Art ...............................................................................11
`
`VI. DETAILED EXPLANATION OF THE CHALLENGE .................................................... 12
`
`A. Ground 1: Grint Anticipates Claims 1, 2, 4-6, 11-13, 17, and 22. .............12
`
`1. Anticipation Standard. ..........................................................................12
`
`2. Ground 1 Claim Chart. .........................................................................13
`
`3. Ground 1 Detailed Analysis. ................................................................16
`
`B. Ground 2: Claims 7-10, 14-16, and 19-21 are Rendered Obvious by Grint
`in View of Arthur, or Further in View of Moitra or Insulin Admin. .................22
`
`1. Ground 2 Claim Chart. .........................................................................23
`
`2. Ground 2 Detailed Analysis. ................................................................26
`
`C. Ground 3: Claim 18 is Rendered Obvious by Grint in View of Alsufyani. 28
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`IPR2016-01370
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`Petition
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`1. Ground 3 Claim Chart. .........................................................................28
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`2. Ground 3 Detailed Analysis. ................................................................29
`
`D. Ground 4: Claims 1-6, 11-13, 17-18, and 22 are Anticipated by Wyeth. ...30
`
`1. Ground 4 Claim Chart. .........................................................................31
`
`2. Ground 4 Detailed Analysis. ................................................................33
`
`E. Ground 5: Claims 1-22 are Obvious Over Wyeth in View of Brooks and
`Arthur, Further in View of Moitra or Insulin Admin. .......................................38
`
`1. Ground 5 Claim Chart. .........................................................................38
`
`2. Ground 5 Detailed Analysis. ................................................................44
`
`F. Ground 6: Claims 1-22 are Obvious Over Hoekstra and Jørgensen in View
`of Arthur and/or Insulin Admin. ........................................................................48
`
`1. Ground 6 Claim Chart. .........................................................................48
`
`2. Ground 6 Detailed Analysis. ................................................................52
`
`G. Secondary Considerations Do Not Rebut Obviousness. .............................54
`
`1. MTX Toxicity from Subcutaneous Injection is Dose, Not
`Concentration, Dependent. ..........................................................................54
`
`2. MTX Bioavailability from Subcutaneous Injection is Dose, Not
`Concentration, Dependent. ..........................................................................56
`
`3. Medac’s Reliance on Mü ller-Ladner to Show Unexpected Results is
`Specious. .....................................................................................................57
`
`4. Zackheim Does Not Teach Away. ........................................................60
`
`5. Schiff Does Not Show That the Invention Is “Surprisingly
`Advantageous” Over the Prior Art. .............................................................61
`
`VII. THE FACTS AND EQUITIES SUPPORT INSTITUTION UNDER § 325(D) ............... 61
`
`VIII. CONCLUSION. ................................................................................................. 62
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`
`
`
`Table of Authorities
`
`Petition
`
`Cases
`Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342 (Fed. Cir. 1999) ........................13
`
`Atofina v. Great Lakes Chemical Corp., 441 F.3d 991 (Fed. Cir. 2006) ................21
`
`Ex Parte Ravi Arora, Anna Lee Tonkovich, Dongming Qiu, & Laura J. Silva,
`
`APPEAL 2013-004020, 2015 WL 5171024 (Aug. 28, 2015) ..............................21
`
`Galderma Labs v. Tolmar Inc., 737 F.3d 731 (Fed. Cir. 2013) ...............................61
`
`Ineos USA LLC v. Berry Plastics Corp., 783 F.3d 865 (Fed. Cir. 2015) ......... 20, 21
`
`Titanium Metals Corp. v. Banner, 778 F.2d 775 (Fed.Cir.1985) ............................13
`
`Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628 (Fed. Cir. 1987) ....12
`
`iii
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`
`
`
`List of Exhibits
`
`Petition
`
`
`
`Exhibit 1001
`
`Exhibit 1002
`Exhibit 1003
`
`Exhibit 1004
`Exhibit 1005
`Exhibit 1006
`Exhibit 1007
`
`Exhibit 1008
`Exhibit 1009
`
`Exhibit 1010
`Exhibit 1011
`
`Exhibit 1012
`Exhibit 1013
`Exhibit 1014
`
`Exhibit 1015
`
`Exhibit 1016
`
`Exhibit 1017
`
`Exhibit 1018
`
`Exhibit 1019
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`Exhibit 1020
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`Exhibit 1021
`
`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”).
`Excerpts from File History for U.S. Patent No. 8,664,231.
`U.S. 6,544,504 to Paul Grint et al., titled, “Combined Use of
`Interleukin 10 and Methotrexate for Immunomodulatory Therapy,”
`filed on June 26, 2000, and issued on April 8, 2003 (“Grint”).
`Hoekstra et al. (2004) J. Rheumatol. 31(4):645-47 (“Hoekstra”).
`Jørgensen et al. (1996) Ann. Pharmacother. 30:729-32 (“Jørgensen”).
`Alsufyani et al. (2003) J. Rheumatol. 31:179-82 (“Alsufyani”).
`Declaration of Dr. Elena Massarotti, dated June 2, 2016, in
`support of Medac’s Preliminary Response in IPR2016-00649.
`Brooks et al. (1990) Arthritis and Rheum. 33(1):91-94 (“Brooks”).
`Medac’s Preliminary Response in IPR2016-00649, dated June
`2, 2016.
`Zackheim (1992) J. Am. Acad. of Derm. 23(6) p. 1008 (“Zackheim”).
`Mü ller-Ladner (2010) The Open Rheumatology Journal 4:15-22.
`(“Mü ller-Ladner”).
`Weinblatt Declaration; Dated June 17, 2014 (“Weinblatt Decl.”).
`Gammon Declaration; Dated June 27, 2014 (“Gammon Decl.”).
`Pincus et al. (2003) Clin. Exp. Rheumatol. (Suppl. 31):S179-S185
`(“Pincus”).
`Insulin Administration, Diabetes Care, 26:1 S121-S124 (2003)
`(“Insulin Admin”).
`Complaint in Medac Pharma, Inc. v. Antares Pharma, Inc., Nos.
`1:14-cv-01498-JBS-KMW.
`Portion of EPO prosecution for EP Application No. 07 786 239.9
`and Certified English Translation of the same.
`Weinblatt (1993) “Methotrexate,” in Textbook of Rheumatology, 4th
`Edition, Chapter 47, (Kelley et al., eds. 1993) (“Weinblatt 1993”).
`Schiff et al., “Head-to-head, randomized, crossover study of
`oral versus subcutaneous methotrexate in patients with
`rheumatoid arthritis,” Ann. Rheum. Dis. 0:1-3 (2014)
`(“Schiff”).
`Weinblatt (1995) Efficacy of Methotrexate in Rheumatoid Arthritis,
`Br. J. Rheum. 34(suppl. 2):43-48 (“Weinblatt 1995”).
`Product Label for the “Methotrexate Sodium for Injection” product by
`Wyeth, Date of First Authorization August 10, 1959, Date of
`
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Petition
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`Supplement Approval January 27, 2004, Obtained from Archive.org as
`of April 29, 2005 (“Wyeth”), and Internet Archive Affidavit.
`2003 Ed. of Physician’s Desk Reference for “Methotrexate Sodium for
`Injection” by Wyeth (“the PDR for Wyeth”).
`Arthur et al. (2002) A Study of Parenteral Use of Methotrexate in
`Rheumatic Conditions, J. Clinical Nursing 2002;11:256-63 (“Arthur”).
`Arthur et al. (2001) Self-Injection of Gold and Methotrexate, J.
`Rheumatol. 2001;28(1):212 (“Arthur 2001”).
`Moitra et al. (2005) Caveats to the use of parenteral methotrexate in the
`treatment of rheumatic disease, Rheumatology 2005;44:256-57
`(“Moitra”).
`Product Label for “Methotrexate For Injection, USP” by
`Bigmar, Date of First Authorization February 26, 1999,
`Obtained from Archive.org as of February 16, 2005
`(“Bigmar”).
`Feagan et al. (1995) Methotrexate for the Treatment of Crohn’s
`Disease, N. Engl. J. Med. 332(5):292-97 (“Feagan”).
`Furst et al. (1989) Increasing Methotrexate Effect with Increasing
`Dose in the Treatment of Resistant Rheumatoid Arthritis, J. Rheum.
`16(3):313-20 (“Furst”).
`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(16):1043, 1045, 1048-49
`(“Giannini”).
`FDA Arthritis Advisory Committee.
`Results from Body Surface Area Calculator for Medication
`Doses (“BSA Calculation”).
`Miller Declaration and Curriculum Vitae (“Miller Decl.”).
`Schiff Declaration and Curriculum Vitae (“Schiff Decl.”).
`Noroozi Declaration (“Noroozi Decl.”).
`Kamholz Declaration (“Kamholz Decl.”).
`
`Exhibit 1022
`
`Exhibit 1023
`
`Exhibit 1024
`
`Exhibit 1025
`
`Exhibit 1026
`
`Exhibit 1027
`
`Exhibit 1028
`
`Exhibit 1029
`
`Exhibit 1031
`Exhibit 1032
`
`Exhibit 1033
`Exhibit 1034
`Exhibit 1035
`Exhibit 1036
`
`
`
`v
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`

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`IPR2016-01370
`U.S. Patent No. 8,664,231
`
`I.
`
`INTRODUCTION
`
`
`
`Petition
`
`Petitioner Koios Pharmaceuticals LLC (“Koios”) requests inter partes
`
`review (IPR) of claims 1-22 of U.S. Patent No. 8,664,231. Ex. 1001.
`
`Koios is a generic pharmaceutical company. Koios’s mission is to increase
`
`Americans’ access to affordable pharmaceuticals by promoting generic
`
`competition. Noroozi Decl. (Ex. 1035) ¶ 1. To that end, Koios challenges
`
`pharmaceutical patents that claim public knowledge for private profit. Id.
`
`Patent Owner medac GMBH, and its U.S. subsidiary Medac Pharma, Inc.
`
`(collectively, “Medac” or “Patent Owner”) produce and sell Rasuvo®. Rasuvo
`
`treats inflammatory autoimmune diseases, such as rheumatoid arthritis. Rasuvo
`
`contains a single active ingredient, methotrexate (“MTX”), which has been used to
`
`treat inflammatory diseases since the 1950s. Schiff Decl. (Ex. 1034) at ¶¶ 19-21.1
`
`Yet the ’231 patent, granted in 2014, protects Rasuvo from generic competition
`
`until 2029. As a result, Rasuvo can cost $6,000 per patient per year. Koios seeks to
`
`introduce generic competition to Rasuvo.
`
`
`1 Medac agrees (as it must) that Dr. Schiff is at least one of ordinary skill in the art.
`
`See Ex. 1009 at 22 (“Dr. Schiff, one of ordinary skill in the art….”). Koios retained
`
`Dr. Schiff in October 2015.
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`1
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`II. GROUNDS FOR STANDING
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`
`
`Petition
`
`Petitioner certifies that the ’231 patent is available for IPR and that
`
`Petitioner is not barred or estopped from requesting IPR of the ’231 patent.
`
`III. MANDATORY NOTICES
`
`A. Real Party-In-Interest
`
`Koios Pharmaceuticals LLC is the sole entity with authority to direct or
`
`control decisions or activities relating to this Petition or proceedings related to this
`
`Petition. Noroozi Decl. (Ex. 1035) ¶ 2.; 37 CFR § 42.8(b)(1). All of the costs
`
`associated with the Petition are expected to be borne by Koios. Id. Koios has
`
`entered into a partnership with a pharmaceutical company for the development and
`
`commercialization of a generic equivalent to Rasuvo. Id. This Petition, however,
`
`was not brought at the behest of any person or entity other than Koios, and is
`
`entirely under Koios’s control. Id. Accordingly, Koios is the sole real party-in-
`
`interest. See Hughes Network Sys., LLC et al v. California Institute of Tech.,
`
`IPR2015-00059 (PTAB) (Paper 42) (“The key to a real party-in-interest inquiry is
`
`the relationship between the potential unnamed real party-in-interest and the
`
`proceeding. . . .”).
`
`B. Related Matters
`
`The ’231 patent was previously at issue in a district court action and IPR.
`
`See Medac Pharma Inc. v. Antares Pharma, Inc., 1:14-cv-1498 (D.N.J.); Antares
`
`2
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`

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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Pharma, Inc. v. Medac Pharma Inc., IPR2014-01091 (PTAB). The Board
`
`
`
`Petition
`
`instituted that IPR on January 6, 2015. Id. (Paper 7). The parties subsequently
`
`settled in April 2015 and jointly moved to terminate. Id. (Paper 17). The Board
`
`terminated on April 30, 2015, prior to a decision on the merits. Id. (Paper 21); 37
`
`CFR § 42.8(b)(2).
`
`The ’231 patent has also been challenged by Frontier Therapeutics, LLC,
`
`IPR2016-00649 (PTAB). That petition is pending and had not received an
`
`institution decision as of this filing.
`
`Koios has no relationship with either Antares or Frontier. Noroozi Decl.
`
`(Ex. 1035) at ¶ 2.
`
`C.
`
`Lead and Back-Up Counsel, and Service Information
`
`Lead counsel is Scott E. Kamholz, M.D., Ph.D., Reg. No. 48,543, of Foley
`
`Hoag LLP, 1717 K Street, N.W., Washington D.C. 20006-5350, Phone 202-261-
`
`7356, Fax 202-467-9656; skamholz@foleyhoag.com. Backup counsel is DeAnn F.
`
`Smith, Reg. No. 36,683, of Foley Hoag LLP, 155 Seaport Blvd., Boston MA
`
`02210-2600, Phone 617-832-1230, Fax 617-832-7000; dsmith@foleyhoag.com.
`
`Koios consents to electronic service at ipr2016-01370@foleyhoag.com.
`
`3
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`IV. PAYMENT OF FEES
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`
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`Petition
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`The requisite fees have been submitted with this Petition in accordance with
`
`37 C.F.R §§ 42.103(a) and 42.15(a). The Office may charge any additional fees
`
`required for this proceeding to Deposit Account No. 06-1448.
`
`V. OVERVIEW OF THE CHALLENGE
`
`A.
`
`Summary of the Challenge
`
`The ’231 patent claims priority to German Application No. DE 10 2006 033
`
`837, filed July 21, 2006. Ex. 1001. It is titled “Concentrated Methotrexate
`
`Solutions.” Ex. 1001. It describes and claims methods of treating inflammatory
`
`autoimmune diseases with “concentrated” MTX administered subcutaneously.2 It
`
`contains 22 claims, with a single independent claim.
`
`
`2 It is critical here to emphasize the distinction between “concentration” and
`
`“dosage.” The ’231 patent describes the use of “highly concentrated” but “low
`
`dose” methotrexate solutions. Ex. 1001 at 1:56-60 (“Contrary to chemotherapy in
`
`the treatment of tumors, methotrexate as a basic therapeutic in the treatment of
`
`rheumatoid arthritis is dosed significantly lower, . . . which is why the
`
`antirheumatic therapy is also referred to as ‘low-dosage methotrexate therapy.’”).
`
`The purported invention of the ’231 patent was to administer the traditional “low
`
`dose” of MTX used for autoimmune therapy in a higher concentration solution,
`
`
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`4
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Petition
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`Claim 1 recites a method for treating inflammatory autoimmune diseases via
`
`subcutaneous administration of a pharmaceutically acceptable solvent containing
`
`methotrexate at a concentration of more than 30 mg/ml. Ex. 1001. The remaining
`
`twenty-one dependent claims:
`
`• cover various concentrations of methotrexate up to 100 mg/ml;
`
`• specify solvents that constitute the “pharmaceutically acceptable
`
`solvent”;
`
`• specify that the “inflammatory autoimmune diseases” are RA,
`
`juvenile arthritides, psoriasis, and several other inflammatory
`
`autoimmune diseases; cover various dosage amounts; and
`
`• cover various self-administration devices, including a ready-made
`
`syringe and pen injection device, as well as storage containers (such
`
`as a vial or carpule) for containing the medicament. Id.
`
`
`thereby allowing the patient to receive the same dosage via less injection
`
`volume. Ex. 1001 at 5:14-18 (“The medicaments provided by the present invention
`
`on the other hand contain highly concentrated solutions of the active substance
`
`methotrexate which results in a reduction of the amount of liquid to be
`
`administered with a certain weekly active substance dosage.”) (emphasis added).
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`5
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Petition
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`During prosecution, Medac identified the invention as the use of
`
`concentrated MTX for the treatment of inflammatory autoimmune diseases in
`
`subcutaneous form. Ex. 1002 at 20–22. In support, Medac wrongly asserted
`
`(without any evidence) that previously available high-concentration MTX
`
`solutions were “solely marketed and approved for treatment of cancer . . . .” Id. at
`
`22. Medac further argued, without any evidence, that “it was not at all obvious at
`
`the time of the present invention that toxicity and bioavailability of methotrexate
`
`solutions with higher concentrations would be acceptable” and that “a person
`
`skilled in the art would have been very cautious to increase the concentration of the
`
`active agent in a subcutaneously administered solution.” Id. at 21. Presumably
`
`relying on those representations, the Examiner issued a Notice of Allowance on
`
`January 7, 2014. Id. at 26.
`
`As this Petition will demonstrate, Medac’s assertions were false, and each of
`
`the claims of the ’231 patent was either anticipated or obvious as of July 2006.
`
`Since at least 1951, MTX has been a known treatment for inflammatory
`
`autoimmune diseases such as rheumatoid arthritis (RA) and psoriasis. Ex. 1001 at
`
`1:28-32; Schiff Decl. (Ex. 1034) at ¶¶ 19-21; Ex. 1014 at S179-80.
`
`The administration of MTX via subcutaneous injections at concentrations
`
`above 30 mg/ml was also both anticipated and obvious as of July 21, 2006.
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`6
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`Petition
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`It was anticipated by the Grint patent, issued in April 2003, which described
`
`methods for treating inflammatory autoimmune diseases via subcutaneous MTX
`
`injections at concentrations up to 40 mg/ml. See Section VI.A, infra; Schiff Decl.
`
`(Ex. 1034) at ¶¶ 48-71.
`
`It was also anticipated by Wyeth (Ex. 1021, published prior to July 2006),
`
`the product insert for an FDA-approved product, which taught subcutaneous
`
`administration of a 50 mg/ml concentration MTX solution for the treatment of
`
`inflammatory autoimmune diseases. See Section VI.D, infra; Schiff Decl.
`
`(Ex. 1034) at ¶¶ 72-87.
`
`The claimed subject matter of the ’231 patent was also obvious because:
`
`(1) The product disclosed in Wyeth (Ex. 1021) was FDA-approved for the
`
`intramuscular injection of a 50 mg/ml MTX concentration solution for
`
`treating rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriasis,
`
`Schiff Decl. (Ex. 1034) at ¶¶ 88-89; and
`
`(2) Brooks (Ex. 1008) (1990) taught that subcutaneous injection of MTX is
`
`equal in safety and efficacy to, and more convenient than, intramuscular
`
`injection. Schiff Decl. (Ex. 1034) at ¶¶ 90-97.
`
`Accordingly, skilled artisans would have had reason, with a reasonable
`
`expectation of success, to subcutaneously administer the MTX solution disclosed
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`in Wyeth to patients with inflammatory autoimmune diseases. Schiff Decl.
`
`
`
`Petition
`
`(Ex. 1034) at ¶ 98; Miller Decl. (Ex. 1033) at ¶ 63.
`
`The invention of the ’231 patent was further obvious because:
`
`(1) Hoekstra (Ex. 1004) (2004) taught treating inflammatory autoimmune
`
`diseases via subcutaneous MTX at dosages up to 40 mg using a 25 mg/ml
`
`concentration, Schiff Decl. (Ex. 1034) at ¶¶ 99-100; and
`
`(2) Jørgensen (Ex.1005) (1996) taught that subcutaneously injected solutions
`
`should be less than 1 ml to reduce pain and increase compliance. Schiff
`
`Decl. (Ex. 1034) at ¶¶ 101-04; Miller Decl. (Ex. 1033) at ¶¶ 67-72.
`
`Jørgensen’s teachings would have led the skilled artisan to increase
`
`Hoekstra’s MTX concentration above 40 mg/ml to reduce subcutaneous injection
`
`volume below 1 ml. Id.3
`
`Finally, there was nothing novel about the use of subcutaneous MTX self-
`
`administration devices in July 2006. Arthur (2002) (Ex. 1023) conducted a
`
`successful study in which “[p]atients were taught to self-administer their
`
`
`3 The skilled artisan would have understood, prior to 2006, how to optimize the
`
`relationship between concentration, dosage, and volume based on the following
`
`simple mathematical formula: dosage (in mg)/concentration (in mg/ml) = solution
`
`volume (in ml). Miller Decl. (Ex. 1033) at ¶ 40.
`
`8
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`IPR2016-01370
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`methotrexate subcutaneously” and were given “pre-filled syringes,” which they
`
`
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`Petition
`
`used to “self-administer[ ] their MTX by the SC route at home for 3 consecutive
`
`weeks.” Ex. 1023 at 256, 259. And Moitra (2005) reported 91 patients receiving
`
`subcutaneous MTX injections, of whom “77 had successfully been taught to self-
`
`inject.” Ex. 1025 at 256. There was thus nothing inventive about placing the
`
`concentrated MTX of Grint or Wyeth into various self-injection devices. See, e.g.,
`
`Ex. 1001 at 6:60-67; Miller Decl. (Ex. 1033) at ¶¶ 42-44, 51-52.
`
`Accordingly, this Petition demonstrates that Petitioner will prevail in
`
`showing that all claims of the ’231 patent are unpatentable.
`
`B. Claims Challenged and Asserted Grounds of Unpatentability
`
`Petitioner challenges the patentability of claims 1-22 of the ’231 patent on
`
`the following grounds:
`
`References4
`
`Basis
`
`Claims Challenged
`
`Grint (Ex. 1003)
`
`§ 102(b) 1, 2, 4-6, 11-13, 17, and 22
`
`Grint and Arthur alone, or further in view
`of either Moitra or Insulin Admin. (Exs.
`1003, 1023, 1024, 1025, 1015)
`Grint and Alsufyani (Exs. 1003, 1006)
`
`§ 103(a) 7-10, 14-16, and 19-21
`
`§ 103(a) 18
`
`Wyeth (Exs. 1021, 1022)
`
`§ 102(b) 1-6, 11-13, 17-18, and 22
`
`
`4 See Kamholz Decl. (Ex. 1036) concerning authentication of exhibits.
`
`9
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Wyeth and Brooks and Arthur, further in
`view of Moitra, or Insulin Admin. (Exs.
`1021, 1022, 1008, 1023, 1024, 1025,
`1015)
`Hoekstra and Jørgensen (Exs. 1004 and
`1005)
`Hoekstra, Jørgensen, and Arthur in further
`view of Insulin Admin. (Exs. 1004, 1005,
`1023, 1015)
`Hoekstra, Jørgensen, and Alsufyani (Exs.
`1004, 1005, and 1006)
`
`Petition
`
`§ 103(a) 1-22
`
`§ 103(a) 1-6, 11-13, 17, and 22
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`§ 103(a) 7-10, 14-16, and 19-21
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`§ 103(a) 18
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`The challenges are supported by the expert declarations of Dr. Michael H.
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`Schiff, M.D. (Ex. 1034) and Professor Donald Miller, Pharm.D. (Ex. 1033).
`
`C. Claim Construction
`
`In IPR proceedings, the Board gives claim terms “the broadest reasonable
`
`construction in light of the specification of the patent . . . .” 37 CFR § 42.100(b).
`
`Petitioner provides constructions for five claim terms of the ’231 patent, and
`
`otherwise accepts, for purposes of this Petition only, that any other claim terms are
`
`presumed to take on the ordinary and customary meaning that they would have to
`
`one of ordinary skill in the art.
`
`“Subcutaneously”: Under the skin. Schiff Decl. (Ex. 1034) at ¶¶ 44-47;
`
`Ex. 1001 at 5:1-5.
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`“Pharmaceutically acceptable solvent”: A solvent that is safe 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. Miller Decl.
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`
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`Petition
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`(Ex. 1033) at ¶¶ 24-26; Ex. 1001 at 3:28-36.
`
`“Injection device”: A device that permits a medicament to be injected into
`
`a patient. Miller Decl. (Ex. 1033) at ¶¶ 28-30; Ex. 1001 at 4:19-39.
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`“Ready-made syringe”: A device containing a medicament that permits the
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`medicament to be injected into a patient. Miller Decl. (Ex. 1033) at ¶¶ 32-34;
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`Ex. 1001 at 4:55-59; 5:28-40.
`
`“Pen injector”: A device that injects a dose of medicament into a patient
`
`via a powered or manually inserted hypodermic needle, wherein the device may be
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`for single use or multiple uses, and may be disposable or reusable. Miller Decl.
`
`(Ex. 1033) at ¶¶ 36-38; Ex. 1001 at 6:55-7:27.
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`D.
`
`Level of Skill in the Art
`
`The cited art demonstrates the level of skill in the art. Further, a person of
`
`ordinary skill in the art would have either a Pharm.D. or Ph.D. in pharmaceutical
`
`sciences, pharmacology, or a related discipline; an M.D. or D.O. with experience
`
`in using oral and injectable MTX to treat inflammatory autoimmune diseases; or a
`
`person with a lesser degree with several years of experience in formulating and/or
`
`administering methotrexate for injection, such as a nurse or pharmacy technician.
`
`Schiff Decl. (Ex. 1034) at ¶ 35; Miller Decl. (Ex. 1033) at ¶ 19. A person of
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`ordinary skill in the art would collaborate with others having expertise in, for
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`Petition
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`example, methods of treating disease and administering medicines. Id.
`
`VI. DETAILED EXPLANATION OF THE CHALLENGE
`
`A. Ground 1: Grint Anticipates Claims 1, 2, 4-6, 11-13, 17, and 22.
`
`U.S. Patent 6,554,504 (“Grint,” Ex. 1003) issued on April 8, 2003 and is
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`prior art under § 102(b). Grint was not considered by the United States Patent and
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`Trademark Office (“USPTO”) during prosecution of the ’231 patent.
`
`Grint demonstrates that methods for treating inflammatory autoimmune
`
`diseases via subcutaneous injections of MTX at concentrations greater than 30
`
`mg/ml were known before July 21, 2006, and anticipates claims 1, 2, 4-6, 11-13,
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`17, and 22—as the claim chart and discussion below show.
`
`1.
`
`Anticipation Standard.
`
`A prior art reference anticipates a claim if that reference discloses every
`
`limitation of the claimed invention, either explicitly or inherently. Verdegaal Bros.
`
`v. Union Oil Co. of California, 814 F.2d 628, 631 (Fed. Cir. 1987); 35 U.S.C. §
`
`102(b). Moreover, “if granting patent protection on the disputed claim would allow
`
`the patentee to exclude the public from practicing the prior art, then that claim is
`
`anticipated, regardless of whether [the claim] also covers subject matter not in the
`
`prior art.” Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1349 (Fed. Cir. 1999),
`
`citing Titanium Metals Corp. v. Banner, 778 F.2d 775, 781 (Fed.Cir.1985).
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`Petition
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`2.
`
`Ground 1 Claim Chart.
`
`Claim
`
`Exemplary Citations in Grint (Ex. 1003)
`
`1 [pre]. A method for the
`treatment of inflammatory
`autoimmune diseases in a
`patient in need thereof,
`comprising
`
`1a. subcutaneously
`administering to said patient
`a medicament comprising
`methotrexate
`
`1b. in a pharmaceutically
`acceptable solvent at a
`
`“The invention relates to a method for controlling
`autoimmune diseases, such as rheumatoid arthritis,
`inflammatory bowel disease, multiple sclerosis and
`psoriasis.” Ex. 1003 at 1:12-15.
`
`“The present invention provides a method for
`treating autoimmune disease . . . .” Ex. 1003 at
`2:23-24.
`
`“Individuals suitable for treatment by the methods
`of the invention include any individual at risk
`(predisposed) for developing rheumatoid arthritis,
`or an individual exhibiting clinical symptoms.”
`Ex. 1003 at 3:4-9.
`
`“As can be seen from the dosage regimens, the
`amount of methotrexate administered is to be
`sufficient to relieve the autoimmune disease
`symptoms prevalent in diseases such as arthritis
`and psoriasis.” Ex. 1003 at 7:9-13.
`
`Schiff Decl. (Ex. 1034) at ¶¶ 49, 52, 58.
`“Methotrexate may also be administered
`parenterally . . . .” Ex. 1003 at 5:64.
`
`“The dose of MTX was 12.–25 mg/week (oral,
`subcutaneous or intramuscular) . . . .” Ex. 1003 at
`7:56-57.
`
`“MTX (oral/intramuscular/SC) . . . .” Ex. 1003 at
`8:1-2.
`
`Schiff Decl. (Ex. 1034) at ¶¶ 51, 59.
`“Expressed in proportions, methotrexate is
`generally present in from about 0.1 to about 40
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`mg/ml of carrier.” Ex. 1003 at 6:66-7:1.
`
`“Methotrexate is compounded for convenient and
`effective administration in effective amounts . . . .”
`Ex. 1003 at 6:60-63.
`
`“The pharmaceutical forms suitable for injectable
`use include sterile aqueous solutions or
`dispersions . . . . [That] carrier can be a solvent or
`dispersion medium containing, for example, water,
`ethyl alcohol, polyol . . . , suitable mixtures thereof,
`and vegetable oils.” Ex. 1003 at 6:3-15.
`
`Schiff Decl. (Ex. 1034) at ¶¶ 49-50, 52, 60-61.
`See, supra, at claim 1b.
`
`
`
`Schiff Decl. (Ex. 1034) at ¶¶ 62-63.
`“The carrier can be a solvent or dispersion medium
`containing . . . water, ethyl alcohol, polyol (for
`example, glycerol, propylene glycol, and liquid
`polyethylene glycol and the like), suitable mixtures
`thereof, and vegetable oils.” Ex. 1003 at 6:11-15.
`
`“In many cases, it will be preferable to include
`isotonic agents, for example, sugars or sodium
`chloride.” Ex. 1003 at 6:22-24.
`
`Schiff Decl. (Ex. 1034) at ¶ 64.
`“The invention relates to a method for controlling
`autoimmune diseases, such as rheumatoid arthritis,
`inflammatory bowel disease, multiple sclerosis and
`psoriasis.” Ex. 1003 at 1:12-15.
`
`“As can be seen from the dosage regimens, the
`amount of methotrexate administered is to be
`sufficient to relieve the autoimmune disease
`symptoms prevalent in diseases such as arthritis
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`concentration of more than
`30 mg/ml.
`
`2. The method according to
`claim 1, wherein the
`methotrexate is present at a
`concentration of more than
`30 mg/ml to 100 mg/ml.
`4. The method according to
`claim 1, wherein the
`pharmaceutically acceptable
`solvent is selected from
`water, water for injection
`purposes, water comprising
`isotonization additives and
`sodium chloride solution.
`
`5. The method according to
`claim 1, wherein the
`inflammatory autoimmune
`disease is selected from
`rheumatoid arthritis,
`juvenile arthritides,
`vasculitides, collagenoses,
`Crohn’s disease, colitis
`ulcerosa, brochial asthma,
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`Alzheimer’s disease,
`multiple sclerosis,
`Bechterew’s disease, joint
`arthroses, or psoriasis.
`6. The method according to
`claim 5, wherein the
`inflammatory autoimmune
`disease is rheumatoid
`arthritis.
`11. The method according
`to claim 1, wherein the
`medicament is contained in
`a storage container.
`
`12. The method according
`to claim 11, wherein the
`total storage container
`contains a total dosage
`amount of 5 to 5,000 mg.
`
`13. The method according
`to claim 11, wherein the
`storage container is an
`injection bottle, a vial, a
`bag, a glass ampoule, or a
`carpule.
`17. The method according
`to claim 4, wherein the
`sodium chloride solution is
`isotonic sodium chloride
`solution.
`22. The method according
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`
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`Petition
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`and psoriasis.” Ex. 1003 at 7:9-13.
`
`Schiff Decl. (Ex. 1034) at ¶ 65.
`
`See, supra, at claim 5.
`
`“It is especially advantageous to formulate
`parenteral compositions in dosage unit form . . . .
`Dosage unit form as used herein refers to
`physically discrete units suited as unitary dosages
`for the mammalian subjects to be treated; each unit
`containing a predetermined quantity of active
`material calculated to produce the desired
`therapeutic effect in association with the required
`pharmaceutical carrier.” Ex. 1003 at 6:52-59.
`
`Miller Decl. (Ex. 1033) at ¶ 47.
`“A unit dosage form can, for example, contain
`methotrexate in amounts ranging from about 0.1 to
`400 mg, with from 1 to 35 mg being preferred, and
`10 to 25 being most preferred.” Ex. 1003 at 6:52-
`66.
`
`Miller Decl. (Ex. 1033) at ¶ 48.
`Grint teaches that MTX can be in “unit dosage
`form” containing MTX. A “unit dosage form”
`containing MTX would include an injection bottle,
`vial, bag, glass ampoule, or carpule.
`
`Mille