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`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
`
`
`
`
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
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`

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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Petitioner’s Reply
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`
`INTRODUCTION...................................................................................................... 1
`I.
`II. THE EVIDENCE PROVES UNPATENTABILITY AS TO ALL CLAIMS ON ALL
`GROUNDS .................................................................................................................... 3
`A. Ground 1: Grint Anticipates Claims 1, 2, 4-6, 11-13, 17, and 22. ............... 3
`1.
`Petitioner’s expert, establishes that Grint anticipates. .................................... 3
`2.
`Dr. Zizic, and its CEO, Terri Shoemaker. ....................................................... 7
`B. Ground 2: Claims 7-10, 14-16, and 19-21 are Obvious In Light of Grint in
`View of Arthur, or Further in View of Moitra or Insulin Admin. ......................16
`C. Ground 3: Claim 18 is Rendered Obvious by Grint in View of Alsufyani. 17
`D. Ground 4: Claims 1-6, 11-13, 17-18, and 22 are Anticipated by Wyeth. ...18
`III. THE EVIDENCE REFUTES PATENT OWNER’S OTHER DECLARATIONS ..................21
`IV. PATENT OWNER’S REMAINING “SECONDARY CONSIDERATIONS” ARE
`IRRELEVANT AND UNPERSUASIVE .............................................................................24
`VIII. CONCLUSION...................................................................................................26
`
`Patent Owner’s arguments were refuted by the testimony of its expert,
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`Table of Contents
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`The testimony of Patent Owner’s own expert, along with that of
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`Petitioner’s Reply
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`Updated List of Exhibits
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`
`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”).
`Excerpts from File History for U.S. Patent No. 8,664,231.
`Exhibit 1002
`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 June 26, 2000, and issued on April 8, 2003
`(“Grint”).
`Exhibit 1004 Hoekstra et al. (2004) J. Rheumatol. 31(4):645-47 (“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 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”).
`Exhibit 1009 Medac’s Preliminary Response in IPR2016-00649, dated June
`2, 2016.
`Zackheim (1992) J. Am. Acad. of Derm. 23(6) p. 1008
`(“Zackheim”).
`Exhibit 1011 Mü ller-Ladner (2010) The Open Rheumatology Journal 4:15-22.
`(“Mü ller-Ladner”).
`Exhibit 1012 Weinblatt Declaration; Dated June 17, 2014 (“Weinblatt Decl.”).
`Exhibit 1013 Gammon Declaration; Dated June 27, 2014 (“Gammon Decl.”).
`Exhibit 1014
`Pincus et al. (2003) Clin. Exp. Rheumatol. (Suppl. 31):S179-S185
`(“Pincus”).
`Insulin Administration, Diabetes Care, 26:1 S121-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.
`Exhibit 1018 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
`
`Exhibit 1008
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`Exhibit 1010
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`Exhibit 1015
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`Exhibit 1016
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`Exhibit 1017
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`Exhibit 1019
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`Petitioner’s Reply
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`
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`Exhibit 1021
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`Exhibit 1022
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`oral versus subcutaneous methotrexate in patients with
`rheumatoid arthritis,” Ann. Rheum. Dis. 0:1-3 (2014)
`(“Schiff”).
`Exhibit 1020 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 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”).
`Exhibit 1023 Arthur et al. (2002) A Study of Parenteral Use of Methotrexate in
`Rheumatic Conditions, J. Clinical Nursing 2002;11:256-63
`(“Arthur”).
`Exhibit 1024 Arthur et al. (2001) Self-Injection of Gold and Methotrexate, J.
`Rheumatol. 2001;28(1):212 (“Arthur 2001”).
`Exhibit 1025 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”).
`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(16):1043, 1045,
`1048-49 (“Giannini”).
`FDA Arthritis Advisory Committee.
`Results from Body Surface Area Calculator for Medication
`Doses (“BSA Calculation”).
`Exhibit 1033 Miller Declaration and Curriculum Vitae (“Miller Decl.”).
`Exhibit 1034
`Schiff Declaration and Curriculum Vitae (“Schiff Decl.”).
`Exhibit 1035 Noroozi Declaration (“Noroozi Decl.”).
`
`Exhibit 1026
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`Exhibit 1027
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`Exhibit 1028
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`Exhibit 1031
`Exhibit 1032
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Petitioner’s Reply
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`Exhibit 1039
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`Exhibit 1036 Kamholz Declaration.
`Exhibit 1037 Deposition Transcript of Dr. Thomas Zizic, taken August 25,
`2017.
`Exhibit 1038 Deposition Transcript of Terri Shoemaker, taken August 30,
`2017.
`Correspondence between counsel for Koios and Medac, beginning
`April 26, 2017.
`Exhibit 1040 Decision of the U.K. High Court in Accord Healthcare Limited v.
`Medac Gesellschaft für Klinische Spezialpräparate mbH, January
`13, 2016.
`Practical Law report on the Court of the Hague Decision,
`published August 31, 2016.
`Exhibit 1042 Non-Final Rejection of U.S. Patent Application No. 14/635,542,
`filed November 14, 2106.
`Exhibit 1043 Notice of Abandonment of U.S. Patent Application No.
`14/635,542, filed June 6, 2017.
`
`Exhibit 1041
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`Petitioner’s Reply
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`I.
`
`INTRODUCTION
`Medac alleges that it invented administering methotrexate subcutaneously in
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`concentrations above 30 mg/ml for treating inflammatory autoimmune diseases.
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`Two European courts and the U.S. Patent and Trademark Office have recently
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`concluded otherwise. In January 2016, Mr. Justice Birss of the U.K. High Court
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`concluded that the claims of the European counterpart to the ’231 patent, EP 2 046
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`332, were obvious as of July 21, 2006. Ex. 1040. In July 2016, the Hague reached
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`the same conclusion. Ex. 1041. In November 2016, the U.S. PTO rejected Medac’s
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`attempt to obtain essentially identical claims to those of the ’231 patent on the
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`basis that the proposed claims were obvious as of July 21, 2006, on multiple
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`grounds. Ex. 1042. That rejection came from the same examiners who granted the
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`’231 patent. Medac had no response, and abandoned the application. Ex 1043.
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`The testimony of Koios’s experts, Dr. Schiff and Dr. Miller, compels the
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`same unpatentability finding as to all claims. Medac had repeatedly championed
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`Dr. Schiff’s expertise prior to learning of his opinions as to the ’231 patent,
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`identifying him as a “rheumatology leader,” Ex. 2008 at 1, 5, and citing his
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`writings (albeit speciously). Ex. 1009 at 22.
`
`Faced with the quality of Dr. Schiff and Dr. Miller’s opinions in this
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`proceeding, Medac refused to take their depositions, despite Koios’s express
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`invitation. Ex. 1039. Instead, Medac launched a personal attack on Dr. Schiff,
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`U.S. Patent No. 8,664,231
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`which Koios has now debunked through the deposition testimony of Medac’s
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`
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`Petitioner’s Reply
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`CEO. See Section II.A.2.c, infra.
`
`By contrast, Medac’s lead expert, Dr. Zizic, admitted during his deposition
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`that he had personally thought of administering methotrexate in concentrations
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`above 25 mg/ml for the treatment of inflammatory autoimmune diseases prior to
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`July 2006, and would have readily done so. Ex. 1037 at 114:15-22. Dr. Zizic
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`further admitted that he and others of ordinary skill in the art would have
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`administered the 50 mg/ml concentration solution of Wyeth to patients for the
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`treatment of inflammatory autoimmune diseases prior to July 2006. Id. at 119:10-
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`122:6. And Dr. Zizic acknowledged that he was regularly prescribing methotrexate
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`for subcutaneous administration, and self-administration, prior to July 2006. Id. at
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`16:5-11. Critically, Dr. Zizic explained that the only reason he did not administer
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`higher concentration methotrexate solutions to patients prior to July 2006 was that
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`his clinic only had access to pre-formulated methotrexate vials that came in a 25
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`mg/ml concentration, and that formulating higher concentration solutions using
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`lyophilized powder was logistically cumbersome. Id. at 114:23-115:2.
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`Despite all of the above, Medac continues to sell high-priced Rasuvo to
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`patients throughout the United States, immune from generic competition until 2029
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`due to the protection it enjoys from the existence of the ’231 patent.
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`U.S. Patent No. 8,664,231
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`Petitioner’s Reply
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`Cancelling the ’231 patent will not make up for the money that patients have
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`paid for an “invention” that should have never belonged to Medac. It will not make
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`up for the hardship incurred by those that could not afford to buy Rasuvo and had
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`no generic alternative. But cancelling the ’231 patent will help prevent further
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`harm. And it is the only reasonable outcome the evidence supports.
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`II. THE EVIDENCE PROVES UNPATENTABILITY AS TO ALL CLAIMS ON ALL
`GROUNDS
`A. Ground 1: Grint Anticipates Claims 1, 2, 4-6, 11-13, 17, and 22.
`1.
`The testimony of Patent Owner’s own expert, along with
`that of Petitioner’s expert, establishes that Grint anticipates.
`In its Petition, Koios showed that Grint teaches each element of claims 1, 2,
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`4-6, 11-13, 17, and 22. Pet. at 12-22. In support, Koios provided detailed expert
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`testimony from Dr. Michael Schiff. Id.; Ex. 1034 ¶¶ 48-67.
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`After institution, Koios invited Patent Owner to take Dr. Schiff’s deposition.
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`Ex. 1039. Patent Owner refused. Id. Accordingly, Patent Owner has no cross-
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`examination testimony from Dr. Schiff with which to challenge his opinions.
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`By contrast, Koios took the deposition of Patent Owner’s expert, Dr. Zizic,
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`whose testimony now further proves that Grint anticipates the Ground 1 claims.
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`Claim 1 recites: [pre] “A method for the treatment of inflammatory
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`autoimmune diseases in a patient in need thereof, comprising” [1a]
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`“subcutaneously administering to said patient a medicament comprising
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`methotrexate” [1b] “in a pharmaceutically acceptable solvent at a concentration of
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`Petitioner’s Reply
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`
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`more than 30 mg/ml.”
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`Dr. Zizic’s testimony establishes that Grint teaches each element of claim 1.
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`Dr. Zizic acknowledged that Grint “is specifically talking about inflammatory
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`autoimmune diseases,” meeting Claim 1’s preamble. Ex. 1037 at 100:6-9. He
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`further admitted that Grint teaches administering a methotrexate solution in a
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`concentration up to 40 mg/ml, id. at 100:10-23, and that Grint teaches that
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`methotrexate was commonly available in that concentration, meeting limitation 1b.
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`Id. at 108:24-109:4. Dr. Zizic also acknowledged that Grint teaches subcutaneous
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`administration, meeting limitation 1a. Id. at 99:19-23. Indeed, Dr. Zizic testified
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`that prior to July 2006, he personally and “regularly” prescribed subcutaneous
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`administration of methotrexate for treating inflammatory autoimmune diseases, Ex.
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`1037 at 16:5-11, demonstrating that a person of skill in the art would have had no
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`hesitation in understanding Grint to teach the same.
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`Moreover, and critically, Dr. Zizic admitted that a person of skill in the art
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`would have known, prior to July 2006, that it was both effective and convenient to
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`subcutaneously administer a 35 mg/ml concentration methotrexate solution to
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`deliver a 35 mg dose of methotrexate using a 1 ml solution. Id. at 111:8-24.
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`Petitioner’s Reply
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`
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`That testimony, from Patent Owner’s own expert, identically matches the
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`testimony of Petitioner’s expert, Dr. Schiff, who opined that a “skilled artisan
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`would have recognized that a 35 mg/ml concentration of MTX (within the range
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`disclosed by Grint) could be used to administer a 35 mg dose (within the
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`‘preferred’ dosage range disclosed by Grint) using a 1 ml solution” and that
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`“[s]uch a formulation would be consistent with Grint’s teaching that methotrexate
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`should be ‘compounded for convenient and effective administration in effective
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`amounts….’” Ex. 1034 ¶ 52 (citing and quoting Grint (Ex. 1003) at 6:60-63).
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`Petitioner’s Reply
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`In its Institution Decision, the Board credited that testimony from Dr. Schiff.
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`Paper 13 at 14-15 (quoting Ex. 1034 ¶ 52); id. at 16 (finding that Dr. Schiff’s
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`testimony supports the assertion that “a skilled artisan would have understood
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`Grint to disclose subcutaneous administration of methotrexate in concentrations
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`greater than 30 mg/ml for the treatment of inflammatory autoimmune diseases.”).
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`Dr. Zizic’s testimony, along with Dr. Schiff’s testimony (which Patent
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`Owner did not challenge through any cross-examination), now proves that Grint
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`anticipates claim 1.
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`With respect to claims 2 and 22, Petitioner demonstrated that, when the prior
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`art discloses a range that overlaps with a claimed range, the prior art anticipates
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`unless Patent Owner can demonstrate that the claimed range is critical to the
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`operability of the alleged invention. Pet. at 19-20. Petitioner further demonstrated
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`that Grint’s teaching of a 40 mg/ml concentration overlaps with the concentrations
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`recited in claims 2 and 22, and that there is no evidence that the ranges recited in
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`claims 2 and 22 are critical to the operability of the purported inventions. Pet. at
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`19-22. At the time of institution, the Board agreed. Paper 13 at 17-18. Patent
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`Owner has not put forth any evidence of criticality since institution. Accordingly,
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`the record establishes that Grint also anticipates claims 2 and 22.
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`Petitioner’s Reply
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` Petitioner also demonstrated that Grint anticipates claims 4-6, 11-13, and
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`17. Pet. at 13-22. Patent Owner does not dispute that evidence with respect to the
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`limitations of those dependent claims, and they are thus anticipated as well.
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`Patent Owner’s arguments were refuted by the testimony of
`2.
`its expert, Dr. Zizic, and its CEO, Terri Shoemaker.
`Patent Owner’s Preliminary Response and Response briefs raised various
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`fallacious arguments as to why Dr. Schiff’s testimony should be given “no weight”
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`and why Grint does not anticipate. The evidence of record, including testimony
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`from Patent Owner’s own expert and its CEO, refute each of those arguments.
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`a. Medac Arg. 1: “no one used MTX at concentrations
`above 25 mg/mL [subcutaneously to treat RA] before
`July 2006.” POR at 1-2 (emphasis original); passim.
`Medac repeatedly asserts that, prior to July 2006, no one administered MTX
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`subcutaneously in concentrations above 25 mg/mL to treat RA. Medac does not
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`prove that assertion, but instead argues that Koios has not shown otherwise. Medac
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`then asserts that this purported fact proves that claim 1 was inventive and
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`patentable as of July 2006. POR at 4 (“What better evidence of invention? What
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`better evidence that Petitioner has not met its preponderance of the evidence
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`burden than these uncontroverted facts?”).
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`That argument fails on two levels. At a general level, Medac relies on the
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`purported absence of a pre-July 2006 commercial embodiment of claim 1 to argue
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`that claim 1 cannot be anticipated. That argument fails because anticipation does
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`Petitioner’s Reply
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`not require proof that a commercial embodiment of a claimed invention existed
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`and was actually used before the priority date. Rather, anticipation is established
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`by mere publications such as Grint and Wyeth. 35 U.S.C. § 102(a)(1). Medac’s
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`assertion thus does nothing to contradict the express teachings of Grint, or to
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`diminish Grint’s evidentiary weight. Simply put, the purported absence of a
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`commercial embodiment of the claim pre-dating the priority date does not negate
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`the anticipatory teachings of prior art publications.
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`At a second level, Medac relies on the allegation the no one used the
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`invention of claim 1 before July 2006 as evidence that no one had thought of the
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`idea of claim 1 prior to July 2006, i.e., that the teachings in Grint (and later Wyeth)
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`cannot mean what they say because (according to Medac) no one followed them.
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`The testimony of Medac’s own expert, Dr. Zizic, thoroughly refutes that
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`second argument. Patent Owner’s expert admitted at his deposition that, prior to
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`July 2006, he had thought of administering methotrexate in concentrations
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`above 25 mg/ml to his patients, and wanted to do so. Ex. 1037 at 114:15-22. He
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`further testified that the only reason he did not do so was because he did not have
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`access to commercially packaged methotrexate solutions in those concentrations.
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`Id. at 114:23-115:2.
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`Petitioner’s Reply
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`As Dr. Zizic explained, prior to July 2006 he only had access to ready-made
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`methotrexate solutions that came in a concentration of 25 mg/mL, which
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`(obviously) could not be made more concentrated. Id. at 113:8-16. He further
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`explained that if he had sought a more concentrated MTX solution using
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`lyophilized powder, he would have required a safe and sterile lab where such a
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`cytotoxic formulation could be prepared, which was a significant barrier to
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`preparing more concentrated MTX solutions. Id. at 113:17-114:7.
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`Petitioner’s Reply
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`Dr. Zizic’s testimony thus establishes that persons of ordinary skill in the art,
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`such as himself, had thought of the invention of claim 1 prior to July 2006, and
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`would have practiced the invention without meaningful hesitation. It also
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`demonstrates that those of skill in the art reading Grint prior to July 2006 would
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`not have doubted that Grint teaches administering MTX subcutaneously in
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`concentrations above 30 mg/ml for treating inflammatory autoimmune diseases.
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`Dr. Zizic’s testimony also independently corroborates the testimony of Dr.
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`Schiff, who explained that he did not use MTX in concentrations above 25 mg/ml
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`prior to July 2006 “because the methotrexate solutions that were available in my
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`office at the time were in 25 mg/ml format, and not because I had any concerns,
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`doubts, or misgivings about the safety, efficacy, or advantages of using a more
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`concentrated MTX solution, such as a slightly more concentrated 30 mg/ml
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`solution.” Ex. 1034 ¶ 123. Dr. Zizic’s testimony thus establishes that there is no
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`inconsistency between Dr. Schiff’s opinions as to the prior art, and his clinical
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`practice prior to July 2006.
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`Petitioner’s Reply
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`b. Medac Arg. 2: “MTX is a cytotoxic agent, and doctors
`knew from experience that increasing concentrations
`of such agents could the [sic] increase risk of toxicity
`to patients, such as ulceration.” POR at 14, 29. “It
`was Medac who first showed that MTX
`concentrations above 30 mg/ml were safe and
`effective.” POR at 41.
`Medac also argues that physicians would not have understood Grint to teach
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`subcutaneous administration of MTX in concentrations above 30 mg/ml and at 40
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`mg/ml for the treatment of inflammatory autoimmune diseases prior to July 2006
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`because doctors would have feared toxicity side effects from higher concentration
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`MTX solutions. See e.g., POR at 14, 29. In support, Medac cites to paragraph 26 of
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`Dr. Zizic’s declaration. See, e.g., id. at 29 (citing Ex. 2092 ¶ 26). Medac also
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`asserts that it showed the world that MTX concentrations above 30 mg/ml were
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`actually safe and effective. POR at 41.
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`Dr. Zizic’s testimony once again refutes Medac’s arguments. As a threshold
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`matter, Dr. Zizic testified that he agrees with Dr. Schiff that the concentration of
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`methotrexate in a solution has no affect on systemic toxicity, e.g., gastrointestinal
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`toxicity or nephrotoxicity. Ex. 1037 at 77:19-78:21. Dr. Zizic specifically testified
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`that to the extent his declaration expresses disagreement with Dr. Schiff on that
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`issue, he was mistaken, and his statements were borne out of a misunderstanding of
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`Dr. Schiff’s opinions. Id.
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`Petitioner’s Reply
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`Dr. Zizic also testified as to his concerns that the concentration of a
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`methotrexate solution could cause local toxicity, i.e., tissue irritation. Id. He
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`acknowledged that in order to specify how much additional irritation a higher
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`concentration methotrexate solution would cause a patient, a study would have to
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`be performed. Id. at 41:25-42:8. He then admitted that there are no studies
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`showing that increasing methotrexate concentrations from 25 mg/ml to 30 mg/ml
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`would cause any additional irritation. Id. at 44:6-15; id. at 22:14-23:6.
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`Accordingly, neither Dr. Zizic nor any of Patent Owner’s experts have provided
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`(or can provide) evidence that a person of skill would have avoided moving from a
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`methotrexate concentration of 25 mg/ml (which Patent Owner asserts was
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`“conventional”) to a slightly higher concentration of more than 30 mg/ml because
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`of concerns regarding local toxicity, i.e., tissue irritation.
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`Instead, directly to the contrary, Dr. Zizic admitted that prior to July 2006, a
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`person of skill in the art would have administered a 50 mg/ml methotrexate
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`solution subcutaneously for the treatment of inflammatory autoimmune diseases
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`if, for instance, that were the only MTX solution available to them. Id. at 119:10-
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`122:6. That testimony demonstrates that those of skill in the art, such as Dr. Zizic,
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`would not have been so concerned about potential tissue irritation concerns so as to
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`forego the use of methotrexate solutions in concentrations above 30 mg/ml.
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`Petitioner’s Reply
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`Dr. Zizic further testified that, prior to July 2006, he would not have been
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`concerned about increasing the concentration of the methotrexate solution being
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`administered from 25 mg/ml to 50 mg/ml so long as the total dosage administered
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`remained the same (e.g., 25 mg total dose). Id. at 135:8-136:3.
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`As to Medac’s argument that it taught the world that MTX in concentrations
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`above 30 mg/ml did not create significant toxicity concerns, Dr. Zizic
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`acknowledged that there is nothing in the ’231 patent providing such a teaching.
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`Ex. 1037 at 98:4-99:9. And Medac has provided no evidence in support of such an
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`assertion.
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`There is simply no evidence that a person of skill in the art, prior to July
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`2006, would have been so concerned about the potential incremental local toxicity
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`associated with moving from a 25 mg/ml concentration MTX solution to a 30
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`mg/ml+ concentration solution that the POSA would not have used the slightly
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`more concentrated 30 mg/ml+ MTX solution. Dr. Zizic’s deposition establishes
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`otherwise, and so too does the testimony of Dr. Schiff, who opined that “MTX is
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`not an irritant and generally does not cause skin reactions or concerns with local
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`toxicity.” Ex. 1034 ¶ 34. Thus, the only evidence, from both Dr. Schiff and Dr.
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`Zizic, is to the contrary.
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`Petitioner’s Reply
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`c. Medac Arg. 3: “Dr. Schiff was provided Confidential
`Information . . . . [and] his acting as an expert here is
`improper. . . . Given Dr. Schiff’s relationship with
`Medac . . . the Board should give Dr. Schiff’s
`testimony little to no weight.” POPR at 18-19.
`In support of its Preliminary Patent Owner Response (POPR), Medac
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`provided a declaration from its CEO, Terri Shoemaker, asserted that Dr. Schiff had
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`received Confidential Information from Medac during a one-day consulting
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`engagement in 2012, and claimed that as a result his testimony on behalf of Koios
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`in this proceeding was “improper” and should be given “no weight.”
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`The Board rightly rejected those arguments for several reasons, including
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`that “there is no indication that Dr. Schiff is relying on any of Patent Owner’s
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`confidential information. . . .” Paper 13 at 11-12.
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`The subsequent testimony of Medac’s CEO, Terri Shoemaker, now
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`demonstrates that Medac’s personal attack on Dr. Schiff’s participation in this
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`proceeding was entirely without basis.
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`Medac’s CEO testified that she could not recall anyone at Medac ever
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`providing Dr. Schiff any information regarding the novelty or inventiveness of the
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`claims of the ’231 patent. Ex. 1038 at 12:13-13:22.
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`She also could not identify any information in Dr. Schiff’s declaration that
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`she considered “improper” in light of Dr. Schiff’s one-day meeting with Medac in
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`2012. Id. at 38:21-39:6. Indeed, she had not even seen Dr. Schiff’s declaration. Id.
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`Petitioner’s Reply
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`Accordingly, there was nothing improper about Dr. Schiff’s testimony, and
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`there is no basis for discounting or disregarding any of his testimony based on his
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`irrelevant one-day engagement with Medac, which occurred long after the priority
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`date of the ’231 patent.
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`d. Medac Arg. 4: “The Board . . . incorrectly placed the
`burden of proving criticality on Medac, instead of
`Petitioner.” POR at 26.
`Medac argues that Koios has not met its burden as to claims 2 and 22
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`because the burden is on Koios to show that the ranges recited in those claims are
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`not critical to the alleged inventions, which Medac alleges Koios has not done.
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`POR at 26. That argument fails on two levels.
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`First, the Board correctly held that the burden as to criticality of a claimed
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`range lies with the patent owner, which must establish criticality in order to avoid a
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`finding that an overlapping range recited by the prior art anticipates. Paper 13 at
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`15-18; Ineos USA LLC v. Berry Plastics Corp., 783 F.3d 865, 871 (Fed. Cir. 2015)
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`(“when the prior art discloses a range, rather than a point, the court must evaluate
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`whether the patentee has established that the claimed range is critical to the
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`operability of the claimed invention.”) (emphasis added); Hospira, Inc., v.
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`Genentech, Inc., IPR2016-01837, 2017 WL 1253838, at *5 (Mar. 30, 2017) (citing
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`ClearValue, Inc. v. Pearl River Polymers, Inc., 668 F.3d 1340, 1344–45 (Fed. Cir.
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`2012)).
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`Petitioner’s Reply
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`Second, Koios has put forth evidence that the recited ranges in claims 2 and
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`22 are not critical to the alleged invention of those claims, and that there is no
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`reasonable difference in how the alleged inventions operate within those ranges.
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`See Pet. at 21 (citing Schiff Decl. (Ex. 1034) at ¶¶ 36, 63). And after the Board’s
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`Institution Decision, Medac’s CEO testified that she had every opportunity to
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`provide evidence of the criticality of the ranges recited in claims 1, 2, and 22, but
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`she had nothing to offer on the issue. Ex. 1038 at 32:12-33:9. Tellingly, none of
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`Medac’s declarants have provided such evidence, and there is no such evidence in
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`the disclosure of the ’231 patent. Pet. at 21; Ex. 1034 ¶¶ 36, 63. Rather, the
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`teachings of the’231 patent expressly refute any possibility of “criticality.” Id.
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`B. Ground 2: Claims 7-10, 14-16, and 19-21 are Obvious In Light of
`Grint in View of Arthur, or Further in View of Moitra or Insulin Admin.
`Claims 7-10, 14-16, and 19-21 limit the method of claim 1 to various self-
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`administration devices and dosages. In the Petition, Koios demonstrated that these
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`claims are obvious based on Grint in view of Arthur alone, or further in view of
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`Moitra or Insulin Admin.
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`Medac does not provide expert testimony to contradict Koios’s evidence as
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`to these claims. See POR at 45-47. Instead, it merely reiterates its arguments as to
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`why Grint allegedly does not anticipate claim 1, id., which we have refuted
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`repeatedly.
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`Petitioner’s Reply
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`The testimony of Medac’s expert, Dr. Zizic, further supports a finding of
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`obviousness as to these claims. Specifically, Dr. Zizic testified that prior to July
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`2006, he prescribed methotrexate for the treatment of inflammatory autoimmune
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`diseases for subcutaneous administration in a form where the patient would
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`administer their own methotrexate. Ex. 1037 at 17:20-2. These prescriptions were
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`primarily in vial and syringe format. Id. at 18:6-13. Dr. Zizic explained that there
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`were numerous reasons why he prescribed MTX for subcutaneous self-
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`administration, including convenience to the patients, less pain compared to
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`intramuscular injection, lower costs to healthcare system from avoided office visits
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`or nurse visits to patients, and so forth. Id. at 18:24-19:15.
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`Accordingly, the evidence and argument set forth in the Petition, along with
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`Dr. Zizic’s further testimony, make clear that claims 7-10, 14-16, and 19-21 are
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`obvious.
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`C. Ground 3: Claim 18 is Rendered Obvious by Grint in View of
`Alsufyani.
`The Petition provided a detailed explanation as to why a person of skill in
`
`the art would have been motivated to combine the teachings of Grint and Alsufyani
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`with an expectation of success, and why the combination would meet all aspects of
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`claim 18. Pet. at 28-30.
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`Petitioner’s Reply
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`Patent Owner’s Response has no serious argument to the contrary. See POR
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`at 47. Instead, Patent Owner merely refocuses on Grint, without addressing
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`Petitioner’s argument that Alsufyani’s teachings would have required a person of
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`skill in the art to administer a 35 mg dose to a 56-inch tall child weighing 75
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`pounds, thus motivating the POSA to use a methotrexate concentration solution of
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`35 mg/ml (as taught in Grint) in order to administer only 1 ml of solution and thus
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`avoid administering two injections. Pet. at 28-30; Ex. 1034 ¶ 71.
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`D. Ground 4: Claims 1-6, 11-13, 17-18, and 22 are Anticipated by
`Wyeth.
`In its Petition, Koios demonstrated that Wyeth is an FDA-approved label that
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`teaches administering methotrexate subcutaneously in a concentration of 50 mg/ml
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`for the treatment of an inflammatory autoimmune disease, and that it anticipates
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`claims 1-6, 11-13, 17-18, and 22.
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`Petitioner also provided evidence from the Bigmar reference, which is the
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`FDA-approved label for a generic equivalent to the 1 gram vial product of Wyeth,
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`and reiterates that the 1 gram vial of methotrexate should be reconstituted to a
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`concentration of 50 mg/ml. Pet. at 34-35; Ex. 1034 ¶ 79.
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`Patent Owner’s Response argues that a person of skill in the art would only
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`understand the 20 mg vial product of Wyeth to be appropriate for treating
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`inflammatory autoimmune diseases, and would only understand the 1 gram vial
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`product of Wyeth to be appropriate for treating cancer. POR at 35. Patent Owner
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`Petitioner’s Reply
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`thus ass