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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`KOIOS PHARMACEUTICALS LLC
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`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FUER KLINISCHE SPEZIALPRÄPARATE MBH
`
`Patent Owner
`____________
`
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`
`
`
`
`Declaration of Dr. Michael H. Schiff
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`
`
`
`!
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`Exhibit 1034
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`

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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`Schiff Declaration
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`Table of Contents
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`INTRODUCTION ..................................................................................................... 1!
`I.!
`II.! QUALIFICATIONS .................................................................................................. 2!
`III.!MATERIALS REVIEWED ........................................................................................ 5!
`IV.!BACKGROUND OF METHOTREXATE THERAPY ...................................................... 8!
`V.! LEVEL OF SKILL IN THE ART .............................................................................. 14!
`VI.!THE ’231 PATENT .............................................................................................. 14!
`VII.!CLAIM CONSTRUCTION ..................................................................................... 17!
`A.! Claims of the ’231 patent ........................................................................... 18!
`1.! “subcutaneously” ................................................................................. 18!
`VIII.! CERTAIN REFERENCES DISCLOSE OR SUGGEST ALL CLAIMS OF THE ’231
`PATENT .................................................................................................................... 19!
`A.! Grint discloses all elements of claims 1-2, 4-6, 17, and 22 ....................... 19!
`1.! Grint discloses “a method for treating inflammatory autoimmune
`diseases in a patient in need thereof” (Claim 1) ......................................... 24!
`2.! Grint discloses “subcutaneously administering to said patient a
`medicament comprising methotrexate” (Claim 1) ..................................... 24!
`3.! Grint discloses that the methotrexate is “in a pharmaceutically
`acceptable solvent at a concentration of more than 30 mg/ml” (Claim 1) . 24!
`4.! Grint discloses that the methotrexate is “present at a concentration of
`more than 30 mg/ml to 100 mg/ml” (Claim 2) .......................................... 25!
`5.! Grint discloses the “[p]harmaceutically acceptable solvent [] selected
`additives and sodium chloride solution” (Claim 4) ................................... 26!
`6.! Grint discloses “the inflammatory autoimmune disease is selected from
`1!
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`rheumatoid arthritis, juvenile arthritis, vasculitides, collagenoses, Crohn’s
`disease, colitis ulcerosa, bronchial asthma, Alzheimer’s disease, multiple
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`from water, water for injection purposes, water comprising isotonization
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`IPR2016-01370
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`sclerosis, Bechterew’s disease, joint arthroses, or psoriasis” (Claim 5) and
`“wherein the inflammatory autoimmune disease is rheumatoid arthritis”
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`Schiff Declaration
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`more than 30 mg/ml to 100 mg/ml” (Claim 2), “50 mg/ml” (Claim 3), and
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`from water, water for injection purposes, water comprising isotonization
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`(Claim 6) .................................................................................................... 27!
`7.! Grint discloses methotrexate “present at a concentration of from 40
`mg/ml to 80 mg/ml” (Claim 22) ................................................................ 27!
`B.! Grint in view of Alsufyani teaches every element of Claim 18 ................. 27!
`C.! Wyeth (Ex. 1021) discloses all elements of Claims 1-6, 18, and 22. ......... 30!
`1.! Wyeth discloses “a method for treating inflammatory autoimmune
`diseases in a patient in need thereof” (Claim 1) ......................................... 35!
`2.! Wyeth discloses “subcutaneously administering to said patient a
`medicament comprising methotrexate” (Claim 1) ..................................... 35!
`3.! Wyeth discloses that the methotrexate is “in a pharmaceutically
`acceptable solvent at a concentration of more than 30 mg/ml” (Claim 1) . 36!
`4.! Wyeth discloses that the methotrexate is “present at a concentration of
`“from 40 mg/ml to 80 mg/ml” (Claim 22) ................................................. 36!
`5.! Wyeth discloses the “[p]harmaceutically acceptable solvent [] selected
`additives and sodium chloride solution” (Claim 4) ................................... 36!
`6.! Wyeth discloses “the inflammatory autoimmune disease is selected
`18) ............................................................................................................. 37!
`D.! Wyeth (Ex. 1021) in view of Brooks (Ex. 1008) teaches each element of
`Claims 1-6, 18, and 22 of the ’231 patent ........................................................ 37!
`1.! Wyeth discloses a 50 mg/ml methotrexate product approved by the
`diseases ....................................................................................................... 37!
`2!
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`from rheumatoid arthritis, juvenile arthritis, vasculitides, collagenoses,
`Crohn’s disease, colitis ulcerosa, bronchial asthma, Alzheimer’s disease,
`multiple sclerosis, Bechterew’s disease, joint arthroses, or psoriasis”
`(Claim 5) and “wherein the inflammatory autoimmune disease is
`rheumatoid arthritis” (Claim 6) and “juvenile rheumatoid arthritis” (Claim
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`FDA for intramuscular administration to treat inflammatory autoimmune
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`2.! Brooks teaches that subcutaneous administration of methotrexate is as
`safe and effective as, and more convenient than, intramuscular injection . 38!
`E.! Hoekstra (Ex. 1004) and Jorgensen (Ex. 1005) teach every element of
`Claims 1-6, 18, and 22 ...................................................................................... 43!
`1.! Hoekstra (Ex. 1004) ............................................................................ 43!
`2.! Jørgensen (Ex. 1005) ........................................................................... 44!
`3.! Hoekstra (Ex. 1004) and Jørgensen (Ex. 1005), in view of secondary
`reference Alsufyani (Ex. 1006) teach every element of Claim 18 ............. 46!
`IX.!SECONDARY CONSIDERATIONS .......................................................................... 47!
`A.! Any toxicity associated with MTX after subcutaneous injection is dose, not
`concentration, dependent .................................................................................. 47!
`B.! The bioavailability of MTX after subcutaneous injection is dose, not
`concentration, dependent .................................................................................. 48!
`C.! Müller-Ladner does not show unexpected results ...................................... 50!
`D.! Zackheim does not teach away from the claimed invention ....................... 54!
`E.! Schiff does not show that the invention is “surprisingly advantageous” over
`the prior art ....................................................................................................... 55!
`X.! CONCLUSION ...................................................................................................... 56
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`!
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`IPR2016-01370
`U.S. Patent No. 8,664,231
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`I, DR. MICHAEL H. SCHIFF, DECLARE THE FOLLOWING:
`I.
`INTRODUCTION
`1.
`I have been retained by Koios Pharmaceuticals LLC (“Petitioner”) as
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`Schiff Declaration
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`an independent expert consultant in this proceeding before the United States Patent
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`and Trademark Office.
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`2.
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`I understand that this proceeding involves U.S. Patent No. 8,664,231
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`(“the ’231 patent”) (Ex. 1001). I further understand that the ’231 patent claims
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`priority to German Application No. DE 10 2006 033 837, filed July 21, 2006. Ex.
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`1001 at Front Cover.
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`3.
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`I have been asked to provide information regarding the use of
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`methotrexate (“MTX”) to treat inflammatory autoimmune diseases, particularly
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`rheumatoid arthritis, and the various routes of administration used for MTX prior
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`to July 2006. I have also been asked to consider whether certain references disclose
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`or suggest the features recited in the claims of the ’231 patent.
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`4.
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`In forming my opinions, I have reviewed the previous declaration
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`submitted by Dr. Michael Weinblatt in support of another challenge to the ’231
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`patent, as well as the relevant materials cited therein, and have relied on and
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`incorporated those opinions into this declaration where appropriate. I know Dr.
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`Weinblatt personally and have co-authored a number of publications with him. I
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`have nonetheless applied my personal judgment, knowledge, and experience in
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`setting forth the opinions herein, and all opinions set forth in this declaration are
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`Schiff Declaration
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`my own. In forming my opinions, I have also reviewed and considered Medac’s
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`Preliminary Response and Dr. Elena Massarotti’s declaration in support thereof
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`with respect to a challenge brought by Frontier Therapeutics, LLC. I address a
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`number of the views expressed in those documents, and reserve the right to address
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`Dr. Massarotti’s opinions and Medac’s arguments (and any other relevant
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`information) further should the Board institute this inter partes review.
`II. QUALIFICATIONS
`5. My curriculum vitae, which includes a detailed summary of my
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`background and experience and a list of my publications and patents, is attached as
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`Exhibit A to this declaration.
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`6.
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`I am Clinical Professor of Medicine in the Rheumatology Division at
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`the University of Colorado School of Medicine in Denver.
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`7.
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`I received my M.D. from State University of New York Downstate
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`Medical Center. I was an intern and medical resident at Albany Medical Center,
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`Hospital of Union University School of Medicine. I was also a fellow in
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`rheumatology at SUNY Downstate Medical Center.
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`8.
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`I am a fellow of the American College of Rheumatology (“ACR”) as
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`well as numerous other regional and national medical societies. In addition, I
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`served as a board member of the ACR Research Education Foundation and was
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`Vice President of the foundation from 2001 to 2002. I have also held a number of
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`Schiff Declaration
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`
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`other leadership positions within the American College of Rheumatology.
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`9. I have also been a two-term president of the Colorado Society of
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`Internal Medicine, and served on the Executive Committee of the Rocky Mountain
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`Chapter of the Arthritis Foundation.
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`10.
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`I have received various awards and honors in recognition of my
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`research, including the Clinical Faculty Career Achievement Award of the
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`University of Colorado and the designation of Master by the American College of
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`Rheumatology.
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`11.
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`I have also delivered, and continue to deliver, lectures on the
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`treatment of rheumatic diseases, including a recent lecture regarding the use of
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`methotrexate for the treatment of rheumatoid arthritis delivered in March 2015 at
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`Immunology Summit 2015 in Prague, and a lecture titled “Oral to Subcutaneous
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`Methotrexate Dose Conversion Strategies in the Treatment of Rheumatoid Arthritis”
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`at the American College of Rheumatology in November 2015.
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`12.
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`I have authored or coauthored more than 50 peer reviewed original
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`scientific articles and have been a principal investigator for more than 200 research
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`projects. I have also authored more than 300 scientific abstracts. In addition to my
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`work as a researcher, I was a medical practitioner for over 30 years.
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`Schiff Declaration
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`13. The primary focus of my career has been the use of disease modifying
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`antirheumatic drugs (DMARDS) and biologics for the management of rheumatoid
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`arthritis. I have specifically written a number of articles regarding the use of
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`methotrexate for the treatment of RA, including prior to the July 2006 priority date
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`of the ’231 patent, such as “A Comparison of Etanercept and Methotrexate in
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`Patients with Early Rheumatoid Arthritis,” published in The New England Journal
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`of Medicine, Vol. 343 No. 22:1586-1593 (Nov. 30, 2000). Moreover, I have
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`specifically studied and written several articles on the use of subcutaneous
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`methotrexate and subcutaneous biologics for the treatment of RA. I have studied
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`new treatments for RA for over 40 years. To date, MTX remains the most widely
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`used drug for the treatment of RA.
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`14. Although I currently divide my time between research and consulting
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`to biotechnology companies, I maintained an active clinical rheumatology practice
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`for many years and have extensive experience treating rheumatoid arthritis and
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`other complex rheumatic diseases as a clinical physician.
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`15.
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`I have not previously served as a testifying litigation expert. I
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`previously consulted to Antares Pharma, Inc. (“Antares”) in connection with the
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`development and testing of its subcutaneous methotrexate injectable product,
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`Otrexup®, but I am not currently engaged by Antares, and was not working with
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`Antares at the time I was retained by Koios. Antares has had no involvement in or
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`knowledge of my role as a consulting expert in this matter.
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`Schiff Declaration
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` No aspect of that
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` has informed or influenced my opinions in this declaration.
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`Rather, the opinions set forth in this declaration are based on my knowledge prior
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`to July 2006 and documents publicly available prior to July 2006.
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`16.
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`I am being compensated at my standard hourly consulting rate for the
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`time I spend on this matter. No part of my compensation is dependent on the
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`outcome of this proceeding, and I have no other interest in this proceeding.
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`17.
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`I am not an attorney and offer no legal opinions, but in the course of
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`my work, I have had experience studying and analyzing patents and patent claims
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`from the perspective of a person skilled in the art. I understand that Medac regards
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`me as at least one of ordinary skill in the art. Ex. 1009 at 22 (“Dr. Schiff, one of
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`ordinary skill in the art….”).
`III. MATERIALS REVIEWED
`18.
`In forming my opinions, I have relied on my more than 40 years of
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`experience, and reviewed the following exhibits to the Petition.
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`Schiff Declaration
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`1) 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”) (Ex. 1001).
`
`2) Excerpts from File History for U.S. Patent No. 8,664,231
`(Ex.1002).
`
`3) U.S. 6,544,504 to Paul GRINT et al., titled, “Combined Use of
`Interleukin 10 and Methotrexate for Immunomodulatory
`Therapy,” filed on Jun. 26, 2000, and issued on April 8, 2003
`(“Grint”) (Ex. 1003).
`
`4) Hoekstra et al. (2004) J. Rheumatol. 31(4):645-47 (“Hoekstra”)
`(Ex. 1004).
`
`5) Jørgensen et al. (1996) Ann. Pharmacother. 30:729-32
`(“Jørgensen”) (Ex. 1005).
`
`6) Alsufyani et al. (2003) J. Rheumatol. 31:179-82 (“Alsufyani”)
`(Ex. 1006).
`
`7) Declaration of Dr. Elena Massarotti, dated June 2, 2016, in
`support of Medac’s Preliminary Response in IPR2016-00649
`(Ex. 1007).
`
`8) Brooks et al. (1990) Arthritis and Rheum. 33(1):91-94
`(“Brooks”) (Ex. 1008).
`
`9) Medac’s Preliminary Response in IPR2016-00649, dated June
`2, 2016 (Ex. 1009).
`
`10) Zackheim (1992) J. Am. Acad. of Derm. 23(6) p. 1008
`(“Zackheim”) (Ex. 1010)
`
`11) Müller-Ladner (2010) The Open Rheumatology Journal 4:15-
`22. (“Müller-Ladner”) (Ex. 1011).
`
`12) Declaration of Dr. Michael E. Weinblatt, dated June 17, 2014,
`in support of IPR2014-01091 (Ex. 1012).
`
`13) Pincus et al. (2003) Methotrexate as the “anchor drug” for the
`treatment of early rheumatoid arthritis, Clinical and
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`Schiff Declaration
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`Experimental Rheumatology, 21:S179-S185 (“Pincus”) (Ex.
`1014).
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`14) Insulin Administration Position Statements (2003), Diabetes
`Care, 26(1) S121-S124 (“Insulin Admin.”) (Ex. 1015).
`
`15) Weinblatt (1993) “Methotrexate,” in Textbook of
`Rheumatology, 4th Edition, Chapter 47, (Kelly et al., eds.
`1993) (“Weinblatt 1993”) (Ex. 1018).
`
`16) Schiff, et al., “Head-to-head, randomized, crossover study of
`oral versus subcutaneous methotrexate in patients with
`rheumatoid arthritis,” Ann. Rheum. Dis. 0:1-3 (2014)
`(“Schiff”) (Ex. 1019).
`
`17) Weinblatt (1995) Efficacy of Methotrexate in Rheumatoid
`Arthritis, Br. J. Rheum. 34(suppl. 2):43-48 (“Weinblatt 1995”)
`(Ex. 1020).
`18) 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”) (Ex.
`1021).
`
`19) 2003 Ed. of Physician’s Desk Reference for “Methotrexate
`Sodium for Injection” by Wyeth (“the PDR for Wyeth”) (Ex.
`1022).
`
`20) Arthur, et al. (2002) A Study of Parenteral Use of
`Methotrexate In Rheumatic Conditions, J. Clin. Nursing
`2002;11 256-63 (“Arthur”) (Ex. 1023).
`
`21) Arthur, et al. (2001) Self-Injection of Gold and Methotrexate, J.
`Rheumatol. 2001;28;212 (“Arthur 2001”) (Ex. 1024).
`
`22) Moitra, et al. (2005) Caveats to the use of parenteral
`methotrexate in the treatment of rheumatic disease,
`Rheumatology 2005;44:256-57 (“Moitra”) (Ex. 1025).
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`Schiff Declaration
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`23) 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”) (Ex. 1026).
`
`24) Feagan et al. (1995) Methotrexate for the Treatment of
`Crohn’s Disease, New Engl. J. Med. 332(5):292-97
`(“Feagan”) (Ex. 1027).
`
`25) Furst et al. (1989) Increasing Methotrexate Effect with
`Increasing Dose in the Treatment of Resistant Rheumatoid
`Arthritis, J. Rheum. 16(3):313-20 (“Furst”) (Ex. 1028).
`
`26) 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. New Engl. J. Med. 326:1043
`(“Giannini”) (Ex. 1029).
`
`27) Results from Body Surface Area Calculator for Medication
`Doses (“BSA Calculation”) (Ex. 1032).
`IV. BACKGROUND OF METHOTREXATE THERAPY
`19. The use of MTX for the treatment of inflammatory diseases dates
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`back to the 1950s. Its long-term safety and efficacy for the treatment of
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`inflammatory diseases such as rheumatoid arthritis (“RA”) and psoriasis is well
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`documented. Pincus (Ex. 1014) at S180.
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`20. Aminopterin, a folic acid antagonist, is the parent compound of MTX.
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`Weinblatt 1995 (Ex. 1020) at 43. Aminopterin was initially developed in the 1940s
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`for the treatment of acute childhood leukemia. Id. In 1951, a study of aminopterin
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`in patients with psoriasis, RA, and psoriatic arthritis was reported. Id. Refinement
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`of the aminopterin compound lead to the development of MTX. Id.
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`Schiff Declaration
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`21. Since the 1951 study, MTX has been studied as a therapy for
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`inflammatory diseases such as psoriasis, psoriatic arthritis, and rheumatoid arthritis.
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`Id. For example, in 1964, Black et al. reported a double-blind study of MTX versus
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`placebo in patients with active psoriatic arthritis. Id. MTX or placebo was
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`administered. Id. An improvement in both the psoriasis and arthritis occurred in the
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`treatment group. Id. at 143. Positive responses were noted within a few weeks of
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`drug administration. Id.
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`22.
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`In 1972, Hoffmeister reported the beneficial effect of low dose
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`intramuscular administration of MTX. Id.
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`23.
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`In 1985, Weinblatt organized a randomized, placebo-controlled trial
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`of short-term MTX in patients with RA. Id. at 44. This trial was designed as a 24-
`
`week crossover study. Patients received an initial MTX dose of 7.5 mg/week taken
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`in a cycled oral regimen, which was increased to 15.0 mg/week if a clinical
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`response was not noted after 6 weeks. Id. By 12 weeks (or 24 weeks for the
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`crossover from placebo to MTX group), patients had significant improvements in
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`the number of tender joints, duration of morning stiffness, and disease activity. Id.
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`This clinical study “clearly documented the efficacy and safety of methotrexate for
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`the treatment of RA.” Pincus (Ex. 1014) at S180.
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`24. MTX was approved by the FDA in 1988 as a weekly therapy for
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`treating rheumatoid arthritis. By the time of its approval, rheumatologists had
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`extensive experience with the safety and efficacy of using MTX for the treatment
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`Schiff Declaration
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`of RA, including via parenteral injection.
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`25. Subsequent long-term, controlled trials established that MTX
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`remained effective for treating RA over many years of therapy with acceptable
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`toxicity levels. Weinblatt 1995 (Ex. 1020) at 43-44.
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`26. By 1995, MTX was a well-established therapy for treating patients
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`with RA. Id. at 43 (Abstract). It has also been shown to be an effective treatment
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`for treating juvenile rheumatoid arthritis. Weinblatt 1993 (Ex. 1018) at 773. For
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`example, Giannini et al. reported in 1992 clinical effectiveness in children with
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`resistant juvenile rheumatoid arthritis. Id.; see also Alsufyani (Ex. 1006) at 179.
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`27. MTX has also been shown to be effective in treating chronically
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`active Crohn’s disease, another inflammatory autoimmune disease. Feagan (Ex.
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`1027) at Abstract. In a double-blind placebo-controlled study, MTX was
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`administered intramuscularly at doses of 25 mg. Id. at 293. It was reported that
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`MTX “improved symptoms rapidly and reduced the requirement for prednisone in
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`patients with chronically active Crohn’s disease.” Id. at 296.
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`28. MTX may be administered orally or parenterally (e.g., by intravenous,
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`intramuscular, or subcutaneous routes of administration). The historical initial dose
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`was generally 7.5 mg/week administered orally. Weinblatt 1995 (Ex. 1020) at 46.
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`The initial dose may be increased if a positive result is not indicated. However,
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`doses greater than 20 mg/week used to treat inflammatory autoimmune diseases
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`Schiff Declaration
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`
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`are generally administered intramuscularly or subcutaneously because of decreased
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`oral bioavailability. Id.; Weinblatt 1993 (Ex. 1018) at 769. Therefore,
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`intramuscular or subcutaneous routes are preferred for patients not responding to
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`oral administration of MTX due to completeness of absorption compared to oral
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`administration. Brooks (Ex. 1008) at 91; Weinblatt 1993 (Ex. 1018) at 769.
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`29. There are several advantages to subcutaneous administration over
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`intramuscular administration. First, from my experience treating patients and as
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`evident in the literature, intramuscular injections are reported to be more painful
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`than subcutaneous injections. Brooks (Ex. 1008) at 93; Zackheim (Ex. 1010) at
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`1008 (“Subcutaneous injections were well tolerated and less painful than
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`intramuscular ones.”) (citing Brooks). In addition, subcutaneous injections may be
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`self-administered by the patient, further increasing patient compliance. Brooks (Ex.
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`1008) at 91; Zackheim (Ex. 1010) at 1008; Arthur (Ex. 1023) at 257. Intramuscular
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`injections, on the other hand, are most often performed by a medical provider in a
`hospital or clinical setting, which entails cost and inconvenience.
`30.
`In addition, it was known long before July 2006 that the
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`bioavailability of subcutaneous MTX compared to intramuscular MTX is the same.
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`Weinblatt 1993 (Ex. 1018) at 769 (“The pharmacokinetics of subcutaneous MTX is
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`the same as intramuscular methotrexate in rheumatoid arthritis.”). In the 1990s,
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`Brooks and others reported that “IM [intramuscular] and SQ [subcutaneous] are
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`Schiff Declaration
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`interchangeable routes of administration.” Brooks (Ex. 1008) at Abstract. Brooks
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`has been well known and widely cited in the field since its publication in 1990, and
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`clinicians have thus considered subcutaneous administration to be a valid and
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`effective method of administering MTX. The findings of Brooks were confirmed in
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`at least two subsequent publications. Arthur (Ex. 1023), published in 2002,
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`concluded that “there is no difference in the safety and efficacy of methotrexate
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`given by either” intramuscular or subcutaneous injection, and found “no significant
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`difference in blood serum levels between IM and SC MTX injections.” Ex. 1023 at
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`256, 260. And Moitra (Ex. 1025), published in 2005, cited Brooks for the
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`proposition that “there are no significant differences in bioavailabilty between
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`MTX administered subcutaneously and I.M., making the two routes
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`interchangeable.” Moitra (Ex. 1025) at 256.
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`31. Since at least 1989, it has been known in the field and reported in the
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`literature that MTX can present dosage-related toxicity effects. In 1989, Furst et al.
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`reported a linear dose-response study comparing placebo, 5 mg/m2, and 10 mg/m2
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`oral weekly MTX. Furst (Ex. 1028) at 313. The study demonstrated “a dose related
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`improvement in efficacy and a trend toward a dose to toxicity relationship for
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`MTX in the treatment of resistant RA.” Id. I am not aware of any study presenting
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`evidence that the concentration of MTX administered subcutaneously or
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`intramuscularly affects drug toxicity when administered for the treatment of
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`inflammatory autoimmune diseases.
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`32. Further, MTX has a “well-defined toxicity profile” shown to be
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`effective over long periods “with considerably lower toxicity than previously
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`available DMARDs [disease-modifying anti-rheumatic drugs],” and further shown
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`to “have very few clinically significant side effects.” Pincus (Ex. 1014) at S-180-
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`181.
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`33. Although MTX is generally safe, dose-related effects have been
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`reported. Physicians, including me, knew to monitor patients receiving MTX for
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`gastrointestinal, hepatic, and pulmonary toxicity, as well as bone marrow
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`suppression and stomatitis, and monitoring was and is a routine aspect of MTX
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`therapy. Id. at S-181; Weinblatt 1993 (Ex. 1018) at 776. And when adverse events
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`were noted, the physician’s response was to reduce the dose or to stop therapy, not
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`to reduce concentration. Weinblatt 1993 (Ex. 1018) at 774 (“In most patients, this
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`toxicity is generally mild and generally occurs shortly after drug administration . . .
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`[and] may improve with dose reduction or cycled oral or parenteral therapy[.]”).
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`Further, it was and is the common practice to supplement MTX with folic acid to
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`reduce or eliminate potentially toxic side-effects. Pincus (Ex. 1014) at S-181. Thus,
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`any toxic effect for oral, intramuscular, and subcutaneous MTX was known to be
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`dose—rather than concentration—dependent, and was monitored and addressed by
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`the treating physicians.
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`34.
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`In addition, it has been known in the art prior to at least 2006 that
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`MTX is not antigenic—i.e., not a substance that stimulates the productions of an
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`antibody when introduced into the body. MTX is not an irritant and generally does
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`not cause skin reactions or concerns with local toxicity.
`V.
`LEVEL OF SKILL IN THE ART
`35.
`In my opinion, based on my experience, a person having ordinary skill
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`in the art with respect to the ’231 patent would have either: a Pharm.D. or Ph.D. in
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`pharmaceutical sciences, pharmacology, or a related discipline; an M.D. or D.O.
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`with experience in using oral and injectable MTX to treat inflammatory
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`autoimmune diseases; or a person with a lesser degree with several years of
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`experience in formulating and/or administering methotrexate for injection, such as
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`a nurse or pharmacy technician. A person of ordinary skill in the art would
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`collaborate with others having expertise in, for example, methods of treating
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`disease and administering medicines. I understand that Dr. Massarotti’s views
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`regarding the level of ordinary skill in the art are largely consistent with my own.
`VI. THE ’231 PATENT
`36. The ’231 patent is related to a method of treating inflammatory
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`autoimmune diseases by subcutaneous administration of MTX at a concentration
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`of more than 30 mg/ml. The specification, however, states repeatedly that “the
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`present invention relates to the use of methotrexate . . . at a concentration of more
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`than 25 mg/ml,” and up to 150 mg/ml. Ex. 1001 at 1:5-10; see also 3:1-21; 5:24-
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`28; 6:49-54. The specification does not teach, claim, indicate, or warn that the
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`invention would operate differently at any particular concentration within that
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`range. The specification further states that the term “inflammatory autoimmune
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`disease” encompasses “all inflammatory autoimmune diseases which can
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`reasonably be treated with methotrexate,” and lists specific diseases, including
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`“rheumatoid arthritis, juvenile arthritis, vasculitides, collagenoses, Crohn’s disease,
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`colitis ulcerosa, bronchial asthma, Alzheimer’s disease, multiple sclerosis,
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`Bechterew’s disease, joint arthroses or psoriasis, as well as psoriasis arthritis and in
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`particular plaque-type psoriasis vulgaris.” Ex. 1001 at 3:57-67. Based on these
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`disclosures, one of ordinary skill in the art would conclude that if a particular dose
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`of MTX at 25 mg/ml were safe and effective for the treatment of a particular
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`inflammatory autoimmune disease using a particular administration route, then the
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`same dose at the claimed higher MTX concentrations (from 30 mg/ml to 100
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`mg/ml) would be similarly safe and effective for those same diseases. Moreover,
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`one of ordinary skill in the art would conclude that the specific claimed ranges and
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`concentrations between 30 mg/ml to 100 mg/ml—as opposed to 25 mg/ml-29.9
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`mg/ml or 100.1 mg/ml-150 mg/ml—are not critical to the operation of the
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`invention because the specification does not distinguish in any way between these
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`concentration ranges. Further supporting this interpretation of the ’231 patent is the
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`fact that the inventors did not include any examples where patients suffering from
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`any inflammatory autoimmune disease were actually given the claimed MTX
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`solutions, or any evidence that claimed concentrations of MTX solutions produce
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`results different from one another.
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`37. The ’231 patent also acknowledges that MTX solutions were
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`administered prior to July 2006 for the treatment of various inflammatory
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`autoimmune diseases, particularly RA, where “methotrexate has become the gold
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`standard in treatment . . . .” Ex. 1001 at 2:34-35. The ’231 patent also states that
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`MTX solutions were previously administered subcutaneously, but patients
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`previously showed a “disapproving attitude” due to “having to inject the required
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`relatively large amount of active substance solution (e.g. up to 3 ml in the case of a
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`certain dosage) under the skin every week, which was especially difficult to
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`convey to children, including the weekly doctor’s visit.” Id. at 2:37-51. Thus,
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`the ’231 patent indicates that the object of the invention is to provide a
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`“pharmaceutical formulation for the treatment of inflammatory autoimmune
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`diseases, in particular rheumatoid arthritis, which overcomes the disadvantages of
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`the prior art preparations described above,” allowing benefits including ease of
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`administration and reduction in pain. Id. at 2:53-65. The inventors apparently
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`achieved this goal by using the well-known technique of increasing the
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`concentration of MTX in solution, which allows for a smaller volume of liquid to
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`be administered to a patient while achieving the same dosage. See ¶¶ 52-54, infra.
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`38. The ’231 patent also discloses various devices for the subcutaneous
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`administration of the claimed highly concentrated MTX solutions. These include
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`injection devices, ready-made syringes, and pen injectors. See generally Ex. 1001
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`at cols. 4-7.
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`39. The ’231 patent concludes by providing two examples of how to
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`formulate a 50 mg/ml concentration of MTX in solution. Id. at 7:40-8:40.
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`40.
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`In my opinion, th