IPR2014-01091
`U.S. Patent No. 8,664,231
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`
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`Attorney Docket No.
`110670-0006-651
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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 FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`Patent Owner
`
`___________________________________
`
`Case No. IPR2014-01091
`Patent Number 8,664,231
`
`Before JACQUELINE WRIGHT BONILLA, Administrative Patent Judge
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`UNDER 37 C.F.R. § 42.107
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`
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`TABLE OF CONTENTS
`
`Attorney Docket No.
`110670-0006-651
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`
`B.
`
`C.
`
`D.
`
`Introduction .................................................................................................................... 1
`I.
`II. Overview Of The ‘231 Patent ..................................................................................... 8
`III. Background On The Treatment Of Inflammatory Autoimmune Diseases With
`Methotrexate ................................................................................................................... 9
`IV. The Disclosure of the ‘231 Patent ............................................................................ 13
`V.
`Claim Construction ..................................................................................................... 19
`VI. The ‘231 Patent Claims Are Not Anticipated ......................................................... 20
`There Is No Reasonable Likelihood That Grint Anticipates
`A.
`Claims 1, 2, 4, 5, 6, 11, 12, 13, 17, and 20 (Ground 1) ............................... 21
`VII. The ‘231 Patent Claims Would Not Have Been Obvious .................................... 27
`There Is No Reasonable Likelihood That Grint Renders
`A.
`Claims 7-10, 14-16, And 19-21 Obvious In View Of Insulin
`Admin. (Ground 2) ........................................................................................... 28
`There Is No Reasonable Likelihood That Grint Renders
`Claim 18 Obvious In View Of Alsufyani (Ground 3) ................................. 29
`There Is No Reasonable Likelihood That The PDR for Mexate®
`or Hospira Renders Claims 1-5, 11, 12, 13, 17, And 22
`Obvious In View Of Brooks (Ground 4) ...................................................... 30
`There Is No Reasonable Likelihood That The PDR for Mexate®
`Or Hospira Renders Claims 7-10, 14-16, And 19-21 Obvious
`In View Of Brooks And Insulin Admin. (Ground 5) ..................................... 38
`There Is No Reasonable Likelihood That Hoekstra Renders
`Claims 1-6, 11, 12, 13, 17, And 22 Obvious In View Of
`Jørgensen (Ground 6) ......................................................................................... 39
`There Is No Reasonable Likelihood That Hoekstra Renders
`Claims 7-10, 14-16, And 19-21 Obvious In View Of Jørgensen
`And Insulin Admin. (Ground 7) ...................................................................... 41
`There Is No Reasonable Likelihood That Hoekstra Renders
`Claim 18 Obvious In View Of Jørgensen And Alsufyani
`(Ground 8) ........................................................................................................ 41
`VIII. Secondary Considerations .......................................................................................... 42
`IX. Conclusion .................................................................................................................... 42
`
`
`
`E.
`
`F.
`
`G.
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`TABLE OF AUTHORITIES
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`
`CASES
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`Attorney Docket No.
`110670-0006-651
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`
`Page(s)
`
`In re Arkley,
`455 F.2d 586, 587 (C.C.P.A. 1972) ................................................................................. 22
`
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359, 1371 (Fed. Cir. 2008) ............................................................................. 22
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) ........................................................................................ 19
`
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ................................................................................. 22, 24
`
`In re Suitco Surface, Inc.,
`603 F.3d 1255 (Fed. Cir. 2010) ........................................................................................ 19
`
`Warner Chilcott Labs. Ir., Ltd. v. Impax Labs., Inc.,
`2012 U.S. Dist. LEXIS 60386 (D.N.J. Apr. 30, 2012) ................................................. 22
`
`STATUTES
`
`35 U.S.C. § 102 ........................................................................................................................... 3
`
`35 U.S.C. § 314 ............................................................................................................ 1, 2, 7, 42
`
`OTHER AUTHORITIES
`
`37 C.F.R. § 42.100(b) .............................................................................................................. 19
`
`37 C.F.R. § 42.107 ..................................................................................................................... 1
`
`37 C.F.R. § 42.108(c) ................................................................................................................. 2
`
`37 C.F.R. § 42.120 .............................................................................................................. 1, 20
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`77 Fed. Reg. 48680, 48694 (Aug. 14, 2012) ........................................................................... 2
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
`110670-0006-651
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`
`EXHIBITS
`
`British Society for Paediatric and Adolescent Rheumatology,
`“Methotrexate Patient Information Leaflet,” St. Albans (2011)
`U.S. Patent No. 8,480,631 to Sadowski et al., entitled “Hazardous Agent
`Injection System,” filed September 7, 2012, issued July 9, 2013
`Breslin, et al., “Improving Tolerance and Bioavailability of Methotrexate
`by Switching from Oral to Subcutaneous Route of Administration,”
`Rheumatology 388 (2005)
`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)
`ACR Minisymposium, Novel Approaches to Biological Response
`Modification in Rheumatoid Arthritis, Sunday, November 14, 1999,
`Weinblatt et al. rHUIL-10 (Tenovil) Plus Methotrexate (MTX) in Active
`Rheumatoid Arthritis (RA) Phase I/II Study
`Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 7th
`Ed, 1985, 1263-67
`U.S. Patent No. 5,593,671 to Kerwar et al., entitled “Method of
`Attenuating Lung Capillary Leak in a Mammal,” filed July 1, 1994, issued
`January 14, 1997
`Annotated version of U.S. Patent No. 6,544,504 to Grint et al., entitled
`“Combined Use of Interleukin 10 and Methotrexate for
`Immunomodulatory Therapy,” filed June 26, 2000, issued April 8, 2003
`Condit, The Acute Toxicity of Amethopterin in Man, Cancer, 13:222-228
`(1960)
`Condit, The Duration of the Effects of the Folic Acid Antagonists in
`Man, Cancer, 13:229-235 (1960)
`Condit et al., The Effect of Amethopterin on Erythropoiesis in Man,
`Cancer, 13:245-249 (1960)
`Bertino, Methotrexate: Clinical Pharmacology and Therapeutic
`Application, Cancer and Chemotherapy, 3:359-375 (1981)
`Evans, Methotrexate, Applied Pharmacokinetics: Principles of Therapeutic Drug
`Monitoring, 16:518-548 (1980)
`Jolivet et al., The Pharmacology and Clinical Use of Methotrexate, N.
`Engl. J. Med., 309:1094-1104 (1983)
`Product Insert for the “Methotrexate Injection, USP” product (10
`mg/ml or 25 mg/ml) by Hospira, Inc., Lake Forest, IL 60045, Product
`of Australia (Revised October 2011)
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`2001
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`2002
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`2003
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`2004
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`2005
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`2006
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`2007
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`2008
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`2009
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`2010
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`2011
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`2012
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`2013
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`2014
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`2015
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
`110670-0006-651
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`
`Hoekstra, et al., Bioavailability of Higher Dose Methotrexate Comparing
`Oral and Subcutaneous Administeration in Patients with Rheumatoid
`Arthritis, J. Rheumatol 31(4):645-648 (2004)
`Meier, et al., “Biopharmazie: Theorie und Praxis der Pharmakokinetik,”
`Thieme Verlag, Stuttgart (1981)
`Product Insert for “Methotrexat,” manufactured by EBEWE Pharma
`Ges.m.b.H., A-4866 Unterach, Austria, available at
`http://www.old.health.gov.il/units/pharmacy/trufot/alonim/791.pdf
`Sasson, et al., “Hypodermoclysis: An Alternative Infusion Technique,”
`Am. Family Physician, 64(9):1575-1578
`Balis, et al., “Pharmacokinetics of Subcutaneous Methotrexate,” Journal of
`Clinical Oncology 6(12):1882-1886 (1988)
`Press Release by Antares Pharma, Inc., dated April 17, 2014, entitled
`“Drug-Exposure Limitations of Oral Methotrexate at Doses Greater
`Than or Equal to 15 mg May Be Overcome with Subcutaneous
`Administration.”
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`2016
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`2017
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`2018
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`2019
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`2020
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`2021
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`IPR2014-01091
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0006-651
`
`Pursuant to 37 C.F.R. § 42.107, Patent Owner medac Gesellschaft für Klinische
`
`
`
`
`Spezialpräparate mbH (hereinafter “Medac” or “Patent Owner”) submits this
`
`Preliminary Response to the above-captioned Petition for Inter Partes Review of U.S.
`
`Patent No. 8,664,231 (“Pet.,” Paper 1).
`
`I.
`
`Introduction
`
`On its face, Petitioners’ submission fails to provide the Board with the basic
`
`evidence required to institute an inter partes review. If the Board nonetheless institutes
`
`trial on any of the challenged claims, Patent Owner will address in detail in its
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`§ 42.120 Response the numerous substantive errors and shortcomings that underlie
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`each of Petitioners’ arguments and purported evidence in support of them.
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`In this paper, where Patent Owner is not permitted to submit testimonial
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`evidence (Rule § 42.107(c)), Patent Owner addresses only the meaning of certain of
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`the challenged claim terms and the single issue made pertinent by Rule § 42.107:
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`Petitioners’ failure to demonstrate a reasonable likelihood that at least one of the
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`challenged claims is unpatentable. Indeed, Petitioners have failed to demonstrate, as
`
`to any of the challenged claims, a reasonable likelihood of success on any of the
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`asserted grounds of invalidity. Because of this threshold failure, the Petition should
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`be denied and no inter partes review should be instituted. 35 U.S.C. § 314.
`
`The challenged patent, U.S. Patent No. 8,664,231 (“the ‘231 patent”) (Ex.
`
`1001), relates to concentrated methotrexate solutions, and in particular to methods for
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
`110670-0006-651
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`the treatment of inflammatory autoimmune diseases using a medicament comprising
`
`
`
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`methotrexate and a pharmaceutically acceptable solvent at a concentration of more
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`than 25 mg/ml. (‘231 patent (Ex. 1001), 1:4-10.) All claims are directed to species of
`
`that method for
`
`the
`
`treatment of
`
`inflammatory autoimmune diseases by
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`subcutaneously administering to a patient a medicament comprising methotrexate in a
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`pharmaceutically acceptable solvent at a concentration of more than 30 mg/ml. (Id. at
`
`8:43-10:20.)
`
`To justify institution of an inter partes review, Petitioners must make a prima facie
`
`showing, for each asserted ground, that, as a factual and legal matter, there is a
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`reasonable likelihood that at least one of the challenged claims is unpatentable. See,
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`e.g., 37 C.F.R. § 42.108(c); 35 U.S.C. § 314; 77 Fed. Reg. 48680, 48694 (Aug. 14, 2012).
`
`But, as is apparent even from Petitioners’ own arguments and evidence, they cannot
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`meet that burden for any asserted ground or for any challenged claim. Medac,
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`therefore, respectfully requests that the Petition be denied, and no inter partes review
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`instituted.
`
`Indeed, what Petitioners have improperly done is to start with the invention of
`
`the ‘231 patent and then try to piece that invention together from bits and pieces of
`
`the documents on which they rely. Not only is this impermissible hindsight but it
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`ignores the real world -- until Medac’s invention no art taught or suggested using high
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`concentration methotrexate solutions to treat inflammatory autoimmune diseases by
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`subcutaneous injection. Taking the assertions of Petitioners and their experts at face
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`
`
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`value, the best that can be said is the pieces were there: high concentration
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`methotrexate solutions existed and methotrexate was used to treat inflammatory
`
`autoimmune diseases, but no one, in the almost 75 years since methotrexate was
`
`discovered and then used to treat psoriasis and rheumatoid arthritis, had treated those
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`diseases with high concentration methotrexate subcutaneously. What better evidence
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`of invention?
`
`As demonstrated in more detail below, only one (1) of Petitioners’ eight (8)
`
`grounds asserts anticipation. In that sole 35 U.S.C. § 102 argument, Petitioners
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`impermissibly pick and choose from disparate portions of the allegedly “anticipatory”
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`U.S. Patent No. 6,544,504 (Ex. 1003) (hereinafter “Grint”). (Pet. at 15-18.) Nowhere
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`does Grint explicitly or inherently teach that methotrexate at a concentration of more
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`than 30 mg/ml should be administered subcutaneously for the treatment of
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`inflammatory autoimmune diseases. Instead, Grint discloses a variety of routes of
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`administration of methotrexate, a range of doses, a range of concentrations, and
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`numerous potential diseases for treatment. It does not correlate any specific route of
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`administration to any specific dose or any specific concentration for treating any
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`specific disease. For each of these reasons, Petitioners’ papers on their face fail to
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`demonstrate a reasonable likelihood that any of the challenged claims are anticipated -
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`- Ground 1 -- and thus no inter partes review should be instituted on that ground.
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`Petitioners’ Grounds 2 and 3 each assert single-reference combinations of Grint
`
`
`
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`in view of Insulin Admin. (Ex. 1015) or Alsufyani (Ex. 1006) that do not remedy Grint’s
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`clear deficiencies vis-à-vis the challenged claims. As discussed in more detail below, the
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`secondary references do not disclose, even in combination with Grint, each and every
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`element of challenged claim 1. Moreover, Petitioners’ experts have failed to establish
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`that there is a reasonable likelihood that the claimed method would have been
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`obvious to one of skill in the art in view of either combination. For both reasons
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`there is no reasonable likelihood that any of the challenged claims would have been
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`obvious over the combinations of Grounds 2 and 3, and no inter partes review should
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`be instituted on those grounds.
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`Petitioners’ Ground 4 alleges obviousness in view of alternate combinations --
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`the PDR for Mexate® (Ex. 1007) or Hospira (Ex. 1009) -- in view of Brooks (Ex. 1008).
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`Again, Petitioner has failed to show that there is a reasonable likelihood that any of
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`the challenged claims would have been obvious over these combinations. Petitioners
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`rightly concede that neither primary reference teaches subcutaneous injection of
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`concentrated methotrexate. Petitioners therefore try to create the impression that
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`each of those references in combination with Brooks, which they assert suggests that
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`intramuscular and subcutaneous injections result in similar bioavailability, renders the
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`claimed subcutaneous injection method obvious. As an initial matter, fourteen (14)
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`years later, Hoekstra (Ex. 1004), a reference that Petitioners rely on in Grounds 6-8,
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`made perfectly plain that Brooks’ suggestion of similar bioavailability was not certain:
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`Despite the impression given by a few studies [citing Brooks
`(Ex. 1009) as Reference 15], it is not certain that the
`bioavailability
`of
`intravenous,
`intramuscular,
`and
`subcutaneous MTX is strictly comparable.
`
`(Hoekstra (Ex. 1004), p. 645.)
`
`And, even if Brooks were right about bioavailability, Brooks says nothing about
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`other concerns -- including safety -- that one of skill would have considered before
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`using unapproved routes of administration for a cytostatic drug like methotrexate.
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`Moreover, as demonstrated below, neither the PDR for Mexate® (Ex. 1007) nor Hospira
`
`(Ex. 1009) actually teach using intramuscular injections at the claimed concentrations
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`of methotrexate (more than 30 mg/ml) for the treatment of any inflammatory
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`autoimmune diseases. Thus, even if modified to include the subcutaneous injections
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`of Brooks, the primary references would not teach administering the claimed
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`concentration of methotrexate for treating the claimed indications. For these reasons,
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`there is no reasonable likelihood that any of the challenged claims would have been
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`obvious over the combinations of Ground 4, and no inter partes review should be
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`instituted on this ground.
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`Petitioners’ Ground 5 asserts a single-reference combination of the Ground 4
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`references in view of Insulin Admin. (Ex. 1015). These combinations do not remedy
`
`the clear deficiencies of the Ground 4 references explained above. And, as
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`demonstrated in more detail below, Insulin Admin. (Ex. 1015), which relates to the
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`
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`preparation and administration of insulin-containing medicaments, is not relevant to
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`the preparation or administration of the cytostatic drug methotrexate. Moreover,
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`Petitioners’ experts have failed to establish that methotrexate could be substituted for
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`insulin in such preparations and administrations. Again, therefore, there is no
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`reasonable likelihood that any of the challenged claims would have been obvious
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`under Ground 5 and no inter partes review should be instituted on this ground.
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`Petitioners’ Ground 6 alleges obviousness in view of Hoekstra (Ex. 1004) and
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`Jørgensen (Ex. 1005). As an initial matter, the PTO already cited and considered
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`Hoekstra during prosecution of the ‘231 patent and issued the challenged claims over it.
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`Petitioners and their experts have pointed to nothing that should change the PTO’s
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`view that the claims are patentable over Hoekstra.
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`Hoekstra (Ex. 1004) examined the bioavailability of methotrexate at absolute
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`doses of 25 mg to 40 mg per week in rheumatoid arthritis patients. It concluded that
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`at the higher absolute doses subcutaneous administration led to higher bioavailability
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`than oral administration and hypothesized that such higher doses “may be clinically
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`useful.” (Hoekstra (Ex. 1004) at 647.) The Petitioners, however, assert that Hoekstra’s
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`high dose of methotrexate (e.g., 40 mg) would have been formulated into a single 1 ml
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`volume (e.g., 40 mg/ml) because Jørgensen states that volumes of 1 ml and less reduce
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`pain and increase compliance in subcutaneous administration. Jørgensen, however,
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`discusses only volume of injection (not concentration or dose) and does not refer to
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`
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`methotrexate or the treatment of inflammatory autoimmune diseases. By contrast,
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`other references that specifically refer to methotrexate (e.g., Zackheim (Ex. 1010) cited
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`by Petitioners) explicitly teach that two injections of 25 mg/ml should be used for high
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`doses. Thus, again, there is no reasonable likelihood that any of the challenged claims
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`are obvious under Ground 6, and no inter partes review should be instituted on this
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`ground.
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`Petitioners’ Grounds 7 and 8 each purport to combine Hoekstra and Jørgensen
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`with Insulin Admin. (Ex. 1015) or Alsufyani (Ex. 1006). Neither secondary reference
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`remedies the clear deficiencies of the Hoekstra and Jørgensen combination. As discussed
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`above and demonstrated in more detail below, Insulin Admin. relates to insulin and not
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`the very different cytostatic drug methotrexate. And, Alsufyani merely reports that
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`methotrexate is useful in the treatment of juvenile arthritis. It says nothing about
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`using concentrations greater than 30 mg/ml in that treatment. Moreover, Petitioners’
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`experts fail to establish that one of skill in the art would have achieved the claimed
`
`result with either of the combinations. Thus, again, there is no reasonable likelihood
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`that any of the challenged claims are obvious under Grounds 7 and 8, and no inter
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`partes review should be instituted on those grounds.
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`The very purpose of the threshold imposed by 35 U.S.C. § 314 is to avoid the
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`empty and wasteful exercise that Petitioners ask this Board to commence. Because
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`the Petition and Petitioners’ experts fail to show a reasonable likelihood that any of
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`
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`the challenged claims under any asserted ground are unpatentable, Petitioners’ request
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`for institution of inter partes review should be denied.
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`II. Overview Of The ‘231 Patent
`U.S. Patent No. 8,664,231 (Ex. 1001) issued on March 4, 2014 from the United
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`States national stage filing of an international (PCT) application, filed July 20, 2007.
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`The ‘231 patent claims priority to a German application: (DE) 10 2006 033 837, filed
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`on July 21, 2006. Thus, as Petitioners have acknowledged, the ‘231 patent is entitled
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`to a priority date of no later than July 21, 2006. (Pet. at 2.) The ‘231 patent is
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`assigned to Medac.
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`The ‘231 patent has a single independent claim directed to a method for the
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`treatment of inflammatory autoimmune diseases in a patient by the subcutaneous
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`administration of high concentration methotrexate solutions:
`
`inflammatory
`treatment of
`the
`for
`1. A method
`in a patient
`in need thereof,
`autoimmune diseases
`comprising subcutaneously administering to said patient a
`medicament comprising methotrexate in a pharmaceutically
`acceptable solvent at a concentration of more than 30
`mg/ml.
`
`(‘231 patent (Ex. 1001), 8:43-47.)
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`Attorney Docket No.
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`III. Background On The Treatment Of Inflammatory Autoimmune Diseases
`With Methotrexate
`
`
`
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`Methotrexate is a pharmaceutically active substance that was discovered in the
`
`early 1950s. (‘231 patent (Ex. 1001), 1:14-17.) Its chemical name is N-{4-[(2,4-
`
`diamino-6-pteridinylmethyl)methylamino]-benzoyl}-L-glutamic acid. (Id. at 1:14-16.)
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`Methotrexate was traditionally used as a cancer treatment, primarily to treat breast
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`cancer and childhood leukemia. (Id. at 1:24-27.) When used as a chemotherapeutic
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`agent in the treatment of cancer, methotrexate is administered in very high doses. (See
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`id. at 1:56-60.)
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`Soon after the discovery of methotrexate, it was also found to be effective in
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`the treatment of psoriasis, an inflammatory autoimmune disease. (Id. at 1:28-30.)
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`Methotrexate was also used in the treatment of rheumatoid arthritis, another
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`inflammatory autoimmune disease, in individual cases in the 1950s. (Id. at 1:30-32.)
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`In the treatment of rheumatoid arthritis, methotrexate is classified as a disease
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`modifying anti-rheumatic drug (“DMARD”), also referred to as a “basic therapeutic”.
`
`(Id. at 1:42-45.) Rheumatoid arthritis (“RA”) is a chronic disease. As a result,
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`treatment of RA with methotrexate (and other basic therapeutics) is generally long-
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`term, and often continued throughout the patient’s lifetime. (Id. at 1:49-55.)
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`Relative to treatment of cancer, the treatment of autoimmune diseases (such as
`
`rheumatoid arthritis) with methotrexate has typically involved significantly lower
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`doses (sometimes up to 1,000 times lower.) (Id. at 1:56-59.) The use of methotrexate
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`IPR2014-01091
`U.S. Patent No. 8,664,231
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`in treatment of autoimmune diseases is therefore referred to as “low-dosage
`
`
`
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`methotrexate therapy.” (Id. at 1:59-60.) A common dosage of methotrexate for
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`treatment of rheumatoid arthritis ranges from 5 mg to 30 or 40 mg per week. (Id. at
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`1:60-65.)
`
`Initially, methotrexate was administered for the treatment of autoimmune
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`diseases, particularly RA, orally using tablets. (Id. at 1:67-68.) Generally, each tablet
`
`contained 2.5 mg of methotrexate. (See, e.g., British Society for Paediatric and
`
`Adolescent Rheumatology, “Methotrexate Patient Information Leaflet,” St. Albans
`
`(2011) (Ex. 2001).) This means that doses at the higher end of the 5-40 mg/week
`
`range required ingestion of a large number of tablets, e.g., a dosage of 25 mg would
`
`require ten tablets. Nonetheless, historically, oral administration of methotrexate was
`
`the preferred method of administration due to its ease of use. (See, e.g., U.S. Patent
`
`No. 8,480,631 (“the ‘631 patent”) (Ex. 2002) at 1:29-31.)
`
`Orally administered methotrexate, however, was commonly associated with
`
`severe gastrointestinal side effects. (See, e.g., Breslin, et al., “Improving Tolerance and
`
`Bioavailability of Methotrexate by Switching from Oral to Subcutaneous Route of
`
`Administration,” Rheumatology 388 (2005) (Ex. 2003).) Furthermore, variable and
`
`reduced bioavailability was observed at the higher doses of orally administered
`
`methotrexate.
`
`
`
`(‘631 patent
`
`(Ex. 2002) at 1:32-34;
`
`see also Balis,
`
`et al.,
`
`“Pharmacokinetics of Subcutaneous Methotrexate,” Journal of Clinical Oncology
`
`
`
`- 10 -
`
`

`
`IPR2014-01091
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0006-651
`
`6(12):1882-1886 (1988) (Ex. 2020) at 1885-86.) In other words, the plasma
`
`
`
`
`concentration of oral methotrexate was found to plateau at a certain dosage, above
`
`which there was no increased concentration despite the administration of higher doses.
`
`(See Balis (Ex. 2020) at 1885-86.)
`
`Parenteral methotrexate, on the other hand, is resorbed more reliably than
`
`tablets and without a dose plateau. (‘231 patent (Ex. 1001) at 2:1-3.) In fact,
`
`methotrexate is rapidly and nearly completely absorbed into the blood stream
`
`following parenteral administration. (See, e.g., ‘631 patent (Ex. 2002) at 19:37-40; see
`
`also Balis (Ex. 2020) at 1882; 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) (Ex. 2004) (sponsored by Antares Pharama, Inc., one of
`
`Petitioners).) In an April 17, 2014, Antares Press Release (Ex. 2021), accompanying
`
`publication of Schiff (Ex. 2004), Dr. Schiff stated:
`
`The study results show for the first time that plasma levels
`of oral dosed MTX are no greater for 20 mg or 25 mg
`doses than for 15 mg doses . . . . If a patient fails to
`respond to 15 mg of MTX orally, it may be more effective
`to switch to a subcutaneous regimen rather than continue
`to raise the oral dose.
` These findings may have
`implications on future prescribing habits of specialists.
`
`(Press Release (Ex. 2021) at p. 1). Thus, in 2014, Antares was telling the world that
`
`subcutaneous administration of methotrexate was surprisingly advantageous over oral
`- 11 -
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`
`
`

`
`IPR2014-01091
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0006-651
`
`administration. By contrast, the earliest priority date of the ‘231 patent was eight (8)
`
`
`
`
`years earlier, in 2006.
`
`One form of parenteral administration of methotrexate is intravenous
`
`administration. The bioavailability of methotrexate is close to 100% when
`
`administered intravenously because the methotrexate “does not get destroyed in the
`
`gastrointestinal tract and cleared from the subject’s body” and “does not have any
`
`tissue architecture or constituents to traverse prior to being systematically available.”
`
`(‘631 patent (Ex. 2002), 17:56-62.) Other forms are intramuscular (into the muscle) or
`
`subcutaneous (under the skin). Subcutaneous injection presents certain difficulties.
`
`(‘231 patent (Ex. 1001) at 2:44-45.) This is especially true for patients who require
`
`higher dosages -- a high volume solution (sometimes up to 3 ml) must be
`
`administered under the skin. (Id. at 2:45-52.) Large volumes of liquid administered
`
`under the skin can be painful, especially for children. (Id. at 2:47-52.)
`
`Injectable methotrexate
`
`is known
`
`in the art, and has generally been
`
`administered for the treatment of rheumatoid arthritis (and other autoimmune
`
`diseases) by way of manual syringes. (Id. at 2:4-36.) In January 2013 with the
`
`European launch of its METEX™ pen, Medac became the first company in the world
`
`to offer subcutaneous injectable methotrexate using an autoinjector. Antares Pharma,
`
`Inc., one of the Petitioners, subsequently launched its OTREXUP® autoinjector in the
`
`United States in January 2014.
`
`
`
`- 12 -
`
`

`
`IPR2014-01091
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0006-651
`
`Traditionally, the maximum concentration of injectable methotrexate for the
`
`
`
`
`treatment of rheumatoid arthritis was 25 mg/ml. (Id. at 2:26-30.) Indeed, before the
`
`invention of the ‘231 patent, there was no evidence that methotrexate administered
`
`subcutaneously at a concentration greater than 25 mg/ml would be safe, particularly
`
`in view of the fact that methotrexate is cytostatic and has considerable side effects.
`
`(See, e.g., PDR for Mexate® (Ex. 1007), “WARNINGS” at 762.) Prior to Medac’s
`
`invention, when a patient required a methotrexate dosage higher than 25 mg, the
`
`approach was either: (a) to increase the volume of the injection to more than 1 ml; or
`
`(b) to administer multiple injections. (Zackheim (Ex. 1010).) Either of these options
`
`allows the concentration of subcutaneously injected methotrexate to remain at 25
`
`mg/ml while providing an increase in the absolute weekly dose of methotrexate.
`
`IV. The Disclosure of the ‘231 Patent
`The ‘231 patent is entitled “Concentrated Methotrexate Solutions.” It explicitly
`
`states the need that Medac’s inventor was attempting to satisfy:
`
`There is [] a need for pharmaceutical formulations of
`methotrexate which can be administered to the patient,
`including children, as easily and pain-free as possible, while
`providing good bioavailability, over a long period of time at
`regular intervals, in particular weekly, which therefore leads
`to a high degree of patient compliance. As an added
`advantage, the patient should be able to self-administer the
`pharmaceutical formulation.
`
`
`
`- 13 -
`
`

`
`IPR2014-01091
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0006-651
`
`(‘231 patent (Ex. 1001) at 2:53-60.) The patent then states the object of the invention:
`
`
`
`
`The object underlying the present invention is therefore to
`provide a pharmaceutical formulation for the treatment of
`inflammatory
`autoimmune
`diseases,
`in
`particular
`rheumatoid arthritis, which overcomes the disadvantages of
`the prior art preparations . . . .
`
`(Id. at 2:61-65.) The patented method achieves this objective and solves the problem
`
`of the prior art through the use of concentrated methotrexate solutions administered
`
`subcutaneously; this allows lower volumes of methotrexate to be administered for a
`
`given dose, while still retaining the bioavailability advantages of
`
`injectable
`
`methotrexate. The effect of this method is a dosage form of methotrexate which
`
`exhibits good biological availability and can be administered over a prolonged period
`
`of time largely free of pain, resulting in high patient compliance.
`
`The ‘231 patent describes numerous embodiments of the invention, all of
`
`which relate to the use of methotrexate for parenteral administration at a
`
`concentration of more than 25 mg/ml in the treatment of inflammatory autoimmune
`
`diseases. (Id. at 3:1-15.) Certain embodiments relate to ready-made syringes
`
`containing such a pharmaceutical solution. (Id. at 3:7-10.) Others relate to carpules
`
`containing such a pharmaceutical solution to be used in conjunction with pen
`
`injectors. (Id. at 3:11-15.)
`
`The ‘231 patent discloses numerous concentration ranges for methotrexate that
`
`
`
`- 14 -
`
`

`
`IPR2014-01091
`U.S. Patent No. 8,664,231
`
`Attorney Docket No.
`110670-0006-651
`
`are effective when administered parenterally for the treatment of inflammatory
`
`
`
`
`autoimmune diseases. (Id. at 3:16-27.) From among these specified ranges, t