`
`
`
`Paper No. __
`Filed: July 1, 2014
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`ANTARES PHARMA, INC., LEO PHARMA A/S and LEO PHARMA INC.,
`
`
`Petitioners
`
`v.
`
`MEDAC GESELLSCHAFT FUER KLINISCHE SPEZIALPRÄPARATE MBH
`
`Patent Owner
`
`____________
`
`Case No.: Not yet assigned
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`
`DECLARATION OF DR. MICHAEL E. WEINBLATT
`
`
`
`ANTARES Exhibit 1012
`
`Page 1 of 48
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`Patent No. 8,664,231
`
`Table of Contents
`
`I. 
`
`Introduction .................................................................................................................... 1 
`
`II.  Qualifications ................................................................................................................. 1 
`
`III.  Materials Reviewed ........................................................................................................ 6 
`
`IV.  Background of Methotrexate ....................................................................................... 8 
`
`V. 
`
`Level of Skill In the Art .............................................................................................. 13 
`
`VI.  The ’231 Patent ............................................................................................................ 14 
`
`VII.  Claim Construction ..................................................................................................... 16 
`
`A. 
`
`Claims of the ’231 patent ................................................................................ 17 
`
`1. 
`
`“subcutaneously” .................................................................................. 17 
`
`VIII.  Certain References Disclose or Suggest All Claims of the ’231 Patent ............... 18 
`Grint discloses all elements of claims 1, 2, 4, 5, 6, 17, and 22 ................... 18 
`
`A. 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`5. 
`
`Grint discloses “a method for treating inflammatory
`autoimmune diseases in a patient in need thereof” (Claim
`1) ............................................................................................................. 19 
`
`Grint discloses “subcutaneously administering to said
`patient a medicament comprising methotrexate” (Claim 1) .......... 19 
`
`Grint discloses that the methotrexate is “in a
`pharmaceutically acceptable solvent at a concentration of
`more than 30 mg/ml” (Claim 1) ........................................................ 19 
`
`Grint discloses that the methotrexate is “present at a
`concentration of more than 30 mg/ml to 100 mg/ml”
`(Claim 2) ................................................................................................ 20 
`
`Grint discloses the “[p]harmaceutically acceptable solvent []
`selected from water, water for injection purposes, water
`comprising isotonization additives and sodium chloride
`solution” (Claim 4) ............................................................................... 22 
`
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`Patent No. 8,664,231
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`6. 
`
`7. 
`
`8. 
`
`Grint discloses “the inflammatory autoimmune disease is
`selected from rheumatoid arthritis, juvenile arthritides,
`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) .......................................................... 22 
`
`Grint discloses that “the sodium chloride solution is
`isotonic sodium chloride solution” (Claim 17) ................................ 23 
`
`Grint discloses methotrexate “present at a concentration of
`from 40 mg/ml to 80 mg/ml” (Claim 22) ....................................... 23 
`
`B. 
`
`C. 
`
`Grint In View Of Alsufyani Teaches Every Element of Claim 18 ............. 23 
`
`The PDR for Mexate® (Ex. 1007) or Hospira (Ex. 1009) in view of
`Brooks (Ex. 1008) teach each element of Claims 1-5, 17, and 22 of
`the ’231 patent .................................................................................................. 25 
`
`1. 
`
`2. 
`
`3. 
`
`The PDR for Mexate® (Ex. 1007) ........................................................ 25 
`
`Hospira (Ex. 1009) ................................................................................ 27 
`
`Brooks (Ex. 1008) .................................................................................. 28 
`
`D.  Hoekstra (Ex. 1004) and Jørgensen (Ex. 1005) Teach Every Element
`of Claims 1-6, 17, and 22 ................................................................................ 31 
`
`1. 
`
`2. 
`
`3. 
`
`Hoekstra (Ex. 1004) .............................................................................. 31 
`
`Jørgensen (Ex. 1005) ............................................................................... 32 
`
`Hoekstra (Ex. 1004) and Jørgensen (Ex. 1005), in view of
`secondary reference Alsufyani (Ex. 1006) Teach Every
`Element of Claim 18 ............................................................................ 34 
`
`IX. 
`
`Secondary Considerations .......................................................................................... 35 
`
`A. 
`
`B. 
`
`Any toxicity associated with MTX after subcutaneous injection is
`dose, not concentration dependent ............................................................... 35 
`
`The bioavailability of MTX after subcutaneous injection is dose,
`not concentration dependent ......................................................................... 37 
`
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`Patent No. 8,664,231
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`C. 
`
`Applicant’s evidence of unexpected results is not based on a
`comparison of the claimed invention to the closest prior art ................... 38 
`
`D. 
`
`Zackheim does not teach away from the claimed invention ....................... 42 
`
`X. 
`
`Conclusion .................................................................................................................... 44 
`
`
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`Patent No. 8,664,231
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`I, Dr. Michael E. Weinblatt, declare the following:
`I.
`
`Introduction
`1.
`
`I have been retained by Antares Pharma, Inc., Leo Pharma A/S and Leo
`
`Pharma Inc. (“Petitioners”) as an independent expert consultant in this proceeding
`
`before the United States Patent and Trademark Office.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 8,664,231
`
`(“the ’231 patent”) (Ex. 1001). I further understand that the ’231 patent claims
`
`priority to German Application No. DE 10 2006 033 837, filed July 21, 2006. Ex.
`
`1001 at Front Cover.
`
`3.
`
`I have been asked to provide information regarding the use of
`
`methotrexate (“MTX”) to treat inflammatory autoimmune diseases, particularly
`
`rheumatoid arthritis, and the various routes of administration used for MTX prior to
`
`July 2006. I have also been asked to consider whether certain references disclose or
`
`suggest the features recited in the claims of the ’231 patent. My opinions are set forth
`
`below.
`
`II. Qualifications
`4. My curriculum vitae, which includes a detailed summary of my
`
`background and experience and a list of my publications and patents is attached as
`
`Exhibit 1031.
`
`
`
`1
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`Patent No. 8,664,231
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`5.
`
`I am a Senior Physician in the Department of Medicine, Rheumatology,
`
`and Immunology of Brigham and Women’s Hospital in Boston, Massachusetts.
`
`6.
`
`I received my B.A. degree in chemistry from McDaniel College (formerly
`
`Western Maryland College) in 1971. In 1975, I graduated magna cum laude with an
`
`M.D. from the University of Maryland School of Medicine. I was an intern and
`
`medical resident from 1976-1978 at the University of Maryland Hospital. During
`
`1978-1980, I was a clinical fellow in medicine at Harvard Medical School and a clinical
`
`fellow in rheumatology at Robert B. Brigham Hospital.
`
`7.
`
`I have been affiliated with Harvard Medical School since 1981, when I
`
`was an Instructor of Medicine. I was an Assistant Professor of Medicine from 1982-
`
`1989, and an Associate Professor of Medicine from 1989-1998. From 1998 through
`
`the present I have been a Professor of Medicine at Harvard Medical School. Since
`
`2007 I have been the John R. and Eileen K. Riedman Professor of Medicine.
`
`8.
`
`I have held and continue to hold appointments at a number of hospitals,
`
`including Brigham and Women’s Hospital in Boston. For example, I was an
`
`Associate Rheumatologist/Immunologist at Brigham and Women’s Hospital from
`
`1982-1990, and held the position of Rheumatologist/Immunologist at that hospital
`
`from 1990-1997. I have been a Senior Physician in the Department of Medicine,
`
`Rheumatology, and Immunology at the Hospital from 1997 to the present date. In
`
`2012, I was named the inaugural incumbent of the R. Bruce and Joan M. Mickey
`
`Distinguished Chair in Rheumatology.
`
`
`
`2
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`Patent No. 8,664,231
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`9.
`
`From 1985-1999 I served as Director of the Robert E. Brigham Arthritis
`
`Center. From 1985 through 2014 I have served as Director of the Therapeutic Unit,
`
`Division of Rheumatology and Immunology at Brigham and Women’s Hospital.
`
`From 1990 to 1995, I held the position of Vice Chairman of Clinical Affairs in the
`
`Department of Rheumatology and Immunology at Brigham and Women’s Hospital.
`
`From 1995 to the present, I have served as Co-Director of Clinical Rheumatology at
`
`Brigham and Women’s Hospital.
`
`10.
`
`I am a member of the American College of Rheumatology. I served on
`
`the Board of Directors of the College from 1995-1998, as Vice President in 1998-
`
`1999, President-Elect in 1999-2000, and President in 2000-2001.
`
`11.
`
`I have served on the editorial boards of a number of scientific journals,
`
`including Annals of Rheumatic Diseases, Nature Clinical Rheumatology, Arthritis and
`
`Rheumatism, Year Book of Rheumatology, and Journal of Rheumatology. I have
`
`been an invited reviewer for Annals of Internal Medicine, Annals of Rheumatic
`
`Diseases, Arthritis and Rheumatism, British Journal of Rheumatology, Journal of
`
`Rheumatology, Scandinavian Journal of Rheumatology, and the New England Journal
`
`of Medicine.
`
`12.
`
`I have received a number of awards and honors in recognition of my
`
`research, including the 1997 National Arthritis Foundation Virginia P. Engalitcheff
`
`Award for Impact on Quality of Life (for work on MTX), the 2002 Arthritis
`
`Foundation (Massachusetts Chapter) James H. Fairclough Jr. Memorial Award, the
`
`
`
`3
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`Patent No. 8,664,231
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`2005 Carol Nachman Award for Rheumatology (for work on MTX), and the 2008
`
`American College of Rheumatology Distinguished Clinical Investigator Award.
`
`13.
`
`In addition to my academic teaching experience, I have been an invited
`
`speaker for more than 50 named and major lectures on topics relating to rheumatoid
`
`arthritis and its treatment. For example, in 2010, I was invited to give the State of the
`
`Art Lecture on Methotrexate in Rheumatoid Arthritis at the national meeting of the
`
`American College of Rheumatology.
`
`14.
`
`I have also served on the scientific advisory boards of several companies,
`
`including for example Antares, Amgen, AbbVie, BMS, Janssen, Eli Lilly and
`
`Company, Merck, Pfizer, Roche, and Crescendo Bioscience.
`
`15.
`
`I have authored or coauthored more than 162 scientific articles reporting
`
`on original research the majority for issues relating to rheumatoid arthritis (“RA”) or
`
`its treatment, edited or co-edited 13 books pertaining to rheumatoid arthritis,
`
`published 60 review articles, book chapters, or books on rheumatoid arthritis, and
`
`published over 200 abstracts for presentations at scientific meetings.
`
`16. Over the course of my professional career my entire research program
`
`has essentially been directed toward increasing our knowledge about RA and
`
`developing new treatments that can reduce the burden of this disease. I have studied
`
`new treatments for this complex disease for over 25 years. Most notably I have been
`
`involved in the development of MTX as a treatment for RA. I have authored and/or
`
`co-authored numerous papers on the use of MTX for the treatment of RA including
`
`
`
`4
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`Patent No. 8,664,231
`
`Weinblatt et al. (1985) “Efficacy of Low-Dose Methotrexate in Rheumatoid Arthritis,”
`
`New England J. Med. 312:818-822. MTX has become the most widely used drug for
`
`the treatment of this disease. I have served as the Principal Investigator on many
`
`multi-center therapeutic studies on rheumatoid arthritis.
`
`17. Approximately 50% of my time is involved in direct patient care. I have
`
`a consultative and continuity practice in rheumatology. My major clinical interest is in
`
`RA and other complicated systemic rheumatic illnesses. While the vast majority of
`
`my practice is by referral from physicians, primarily rheumatologists in the Northeast
`
`United States, I also have a fairly large national and international practice.
`
`18.
`
`I have previously served as a technical expert for AbbVie (formerly
`
`Abbott Laboratories) in litigations against Centocor Ortho Biotech, Inc. and The
`
`Mathilda and Terence Kennedy Institute of Rheumatology Trust.
`
`19. Although I am being compensated at my rate of $700 per hour for the
`
`time I spend on this matter, no part of my compensation is dependent on the
`
`outcome of this proceeding, and I have no other interest in this proceeding.
`
`20.
`
`I am not an attorney and offer no legal opinions, but in the course of my
`
`work, I have had experience studying and analyzing patents and patent claims from
`
`the perspective of a person skilled in the art.
`
`
`
`5
`
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`Patent No. 8,664,231
`
`III. Materials Reviewed
`21.
`In forming my opinions, I have relied on my 35 years of experience, and
`
`reviewed the ’231 patent, its prosecution history, and particularly the following
`
`exhibits to the Petition.
`
`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):645-648 (“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) 1985 Ed. Physician’s Desk Reference for Mexate® (“the PDR for
`Mexate®”) (Ex. 1007).
`8) Brooks et al. (1990) Arthritis and Rheum. 33(1):91-94 (“Brooks”)
`(Ex. 1008).
`9) Hospira (“the Hospira reference”) (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) Pincus et al. (2003) Methotrexate as the “anchor drug” for the
`treatment of early rheumatoid arthritis 21:S179-S185 (“Pincus”)
`(Ex. 1014).
`
`
`
`6
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`Patent No. 8,664,231
`
`13) Insulin Administration Position Statement (2003), Diabetes Care,
`26(1) 5121-5124 (“Insulin Admin.”) (Ex. 1015).
`14) Weinblatt (1993) “Methotrexate,” in Textbook of Rheumatology,
`4th Edition, Chapter 47, (Kelley et al., eds. 1993) (“Weinblatt
`1993”) (Ex. 1018).
`15) Hoffmeister (1983) Methotrexate therapy in rheumatoid arthritis:
`15 years experience. Am J Med 75:69-73 (“Hoffmeister 1983”) (Ex.
`1019).
`16) Weinblatt (1995) Efficacy of Methotrexate in Rheumatoid
`Arthritis, Br. J. Rheum. 34(suppl. 2):43-48 (“Weinblatt 1995”) (Ex.
`1020).
`17) Weinblatt et al. (1985) “Efficacy of Low-Dose Methotrexate in
`Rheumatoid Arthritis,” New England J. Med. 312:818-822
`(“Weinblatt 1985”) (Ex. 1021).
`18) Hoffmeister (1972) Methotrexate in rheumatoid arthritis. Arthritis
`rheum. 15 (Suppl.): S114 (abstract) (“Hoffmeister 1972”) (Ex. 1022).
`19) Weinblatt et al. (1994) Methotrexate in Rheumatoid Arthritis: a 5
`Year Prospective Multicenter Study, Arth. Rheum. 37(10):1492-
`1498 (“Weinblatt 1994”) (Ex. 1023).
`20) Weinblatt et al. (1992) Long-Term Prospective Study of
`Methotrexate the Treatment of Rheumatoid Arthritis: 84-Month
`Update, Arth. Rheum. 35(2):129-137 (“Weinblatt 1992”) (Ex.
`1024).
`21) Gubner et al. (1951) Therapeutic suppression of tissue reactivity.
`II. Effect of aminopterin in rheumatoid arthritis and psoriasis.
`Am J Med Sci., 22:176-82 (“Gubner”) (Ex. 1025).
`22) Black et al. (1964) Methotrexate therapy in psoriatic arthritis.
`Double-blind study on 21 patients. J Am Med Assoc 189:743-7
`(“Black”) (Ex. 1026).
`23) Feagan et al. (1995) Methotrexate for the Treatment of Crohn’s
`Disease, New England J. Med. 332(5):292-297 (“Feagan”) (Ex.
`1027).
`24) 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).
`
`
`
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`Patent No. 8,664,231
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`25) 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.. Med. 326:1043 (“Giannini”) (Ex.
`1029).
`26) Michaels, et al. (1992) Weekly Intravenous Methotrexate in the
`Treatment of Rheumatoid Arthritis, Arthritis and Rheumatism
`25(3):339-341 (“Michaels”) (Ex. 1030).
`
`IV. Background of Methotrexate
`22. The use of MTX for the treatment of inflammatory diseases dates back
`
`to the 1950s. Its long-term safety and efficacy for the treatment of inflammatory
`
`diseases such as rheumatoid arthritis (“RA”) and psoriasis is well documented. Pincus
`
`(Ex. 1014) at S180.
`
`23. Aminopterin, a folic acid antagonist, is the parent compound of MTX.
`
`Aminopterin was initially developed in the 1940s for the treatment of acute childhood
`
`leukemia. In 1951, a study of aminopterin in patients with psoriasis, RA, and psoriatic
`
`arthritis was reported. Gubner (Ex. 1025); Weinblatt 1995 (Ex. 1020) at 43. Refinement
`
`of the aminopterin compound lead to the development of MTX. Weinblatt 1995 (Ex.
`
`1020) at 43.
`
`24.
`
`Since the 1951 study, MTX has been studied as a therapy for
`
`inflammatory diseases such as psoriasis, psoriatic arthritis and rheumatoid arthritis.
`
`Pincus (Ex. 1014) at S180. For example, in 1964, Black et al. reported a double-blind
`
`study of MTX verses placebo in patients with active psoriatic arthritis. Black (Ex.
`
`1026) at 141. MTX or placebo was administered intravenously or intramuscularly. Id.
`
`
`
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`Patent No. 8,664,231
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`An improvement in both the psoriasis and arthritis occurred in the treatment group.
`
`Id. at 143. Positive responses were noted within a few weeks of drug administration.
`
`Id.
`
`25.
`
`In 1972, Hoffmeister reported the beneficial effect of low dose
`
`intramuscular administration of MTX. Ex. 1022 at Abstract.
`
`26.
`
`In 1985, I organized one of the first randomized, placebo-controlled
`
`trials of short-term MTX in patients with RA. This trial was designed as a 24-week
`
`crossover study. Patients received an initial MTX dose of 7.5 mg/week taken in a
`
`cycled oral regimen, which was increased to 15.0 mg/week if a clinical response was
`
`not noted after 6 weeks. Weinblatt 1985 (Ex. 1021) at 819. By 12 weeks (or 24 weeks
`
`for the crossover from placebo to MTX group), patients had significant
`
`improvements in the number of tender joints, duration of morning stiffness, and
`
`disease activity. Id. at Abstract. This clinical study “clearly documented the efficacy
`
`and safety of methotrexate for the treatment of RA.” Pincus (Ex. 1014) at S180.
`
`27. MTX was approved by the FDA in 1988 as a weekly therapy for treating
`
`rheumatoid arthritis. Weinblatt 1993 (Ex. 1018) at 767. By the time of its approval,
`
`rheumatologists had over two decades of safety and efficacy experience using MTX
`
`for the treatment of RA.
`
`28.
`
`Subsequent long-term, controlled trials established that MTX remained
`
`effective for treating RA over many years of therapy with acceptable toxicity levels.
`
`Weinblatt 1994 (Ex. 1023) at 1492 “Conclusion;” Weinblatt 1992 (Ex. 1024) at 129
`
`
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`Patent No. 8,664,231
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`“Results.” For example, a study published by Hoffmeister in 1983, reported the
`
`results of 15 years of treating patients with up to 15 mg/ml of MTX given
`
`intramuscularly or orally. Hoffmeister 1983 (Ex. 1019) at 70. The report concluded that
`
`low dose MTX for rheumatoid arthritis is effective with few serious side effects. Id. at
`
`Abstract.
`
`29. By 1994, MTX was a well-established therapy for treating patients with
`
`RA. Weinblatt 1995 (Ex. 1020) at 43, 47. It has also been shown to be an effective
`
`treatment for treating juvenile rheumatoid arthritis. For example, Giannini et al.
`
`reported in 1992 clinical effectiveness in children with resistant juvenile rheumatoid
`
`arthritis. Ex. 1029 at 1049; see also Alsufyani (Ex. 1006). The study also reported an
`
`acceptable short-term safety profile. Giannini (Ex. 1029) at 1049.
`
`30. MTX has also been shown to be effective in treating chronically active
`
`Crohn’s disease, another inflammatory autoimmune disease. Feagan (Ex. 1027) at
`
`Abstract. In a double-blind placebo-controlled study, MTX was administered
`
`intramuscularly at doses of 25 mg. Id. at 293. It was reported that MTX “improved
`
`symptoms rapidly and reduced the requirement for prednisone in patients with
`
`chronically active Crohn’s disease. Id. at 296.
`
`31. MTX may be administered orally or parenterally (e.g., by intravenous,
`
`intramuscular, or subcutaneous routes of administration). The historical initial dose
`
`was generally 7.5 mg/week administered orally. Weinblatt 1995 (Ex. 1020) at 46. The
`
`initial dose may be increased if a positive result is not indicated. However, doses
`
`
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`Patent No. 8,664,231
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`greater than 20 mg/week used to treat inflammatory autoimmune diseases are
`
`generally administered intramuscularly or subcutaneously because of decreased oral
`
`bioavailability. Id.; Weinblatt 1993 (Ex. 1018) at 769. Therefore, for patients not
`
`responding to oral administration of MTX, intramuscular or subcutaneous routes are
`
`preferred due to the completeness of absorption compared to oral administration.
`
`Brooks (Ex. 1008) at 91; Weinblatt 1993 (Ex. 1018) at 769.
`
`32. There are several advantages to subcutaneous administration over
`
`intramuscular administration. First, from my experience treating patients and as
`
`evident in the literature, intramuscular injections are reported to be more painful than
`
`subcutaneous injections. Brooks (Ex. 1008) at 93; Zackheim (Ex. 1010) at 1008
`
`(“Subcutaneous injections were well tolerated and less painful than intramuscular
`
`ones.”) (citing Brooks). In addition, subcutaneous injections may be self-administered
`
`by the patient, further increasing patient compliance. Brooks (Ex. 1008) at 91;
`
`Zackheim (Ex. 1010) at 1008. Intramuscular injections, on the other hand, are most
`
`often performed by a medical provider in a hospital or clinical setting.
`
`33.
`
`In addition, the bioavailability of subcutaneous MTX compared to
`
`intramuscular MTX is the same. Weinblatt 1993 (Ex. 1018) at 769 (“The
`
`pharmacokinetics of subcutaneous MTX is the same as intramuscular MTX in
`
`rheumatoid arthritis.”). In the 1990s, Brooks and others reported that “IM
`
`[intramuscular] and SQ [subcutaneous] are interchangeable routes of administration.”
`
`Brooks (Ex. 1008) at Abstract. Brooks has been well known in the field since its
`
`
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`Patent No. 8,664,231
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`publication in 1990, and clinicians have thus considered subcutaneous administration
`
`to be a valid and effective method of administering MTX. I have been treating
`
`patients with RA using a subcutaneous injection of MTX since at least 1995.
`
`34.
`
`Since at least 1989, it has been known in the field and reported in the
`
`literature that any toxicity effects of MTX are related to dose, not concentration. In
`
`1989 Furst et al. reported a linear dose-response study comparing placebo, 5 mg/m2,
`
`and 10 mg/m2 oral weekly MTX. Furst (Ex.1028) at 313. The study demonstrated “a
`
`dose related improvement in efficacy and a trend toward a dose to toxicity
`
`relationship for MTX in the treatment of resistant RA.” Id. Moreover, product
`
`inserts for MTX products further confirm this point. The PDR for Mexate® states
`
`that the toxicity of MTX “is usually dose-related.”1 The PDR for Mexate (Ex. 1007) at
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`763. I am aware of no study concluding that drug concentration affects drug toxicity.
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`35.
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`Further MTX has a “well-defined toxicity profile” shown to be effective
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`over long periods “with considerably lower toxicity than previously available
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`DMARDs [disease-modifying anti-rheumatic drugs],” and further have shown to
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`“have very few clinically significant side effects.” Pincus (Ex. 1014) at S-180-181.
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`36. Although generally safe, dose-related effects were reported for MTX.
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`However, physicians, such as myself, knew to monitor patients receiving MTX for
`
`
`1 The PDR (Physician’s Desk Reference) is a book published annually and compiles
`package inserts for FDA approved drugs. Physicians use the PDR as a reference to
`obtain prescribing and warning information about approved prescription drugs.
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`gastrointestinal, hepatic, and pulmonary toxicity, as well as bone marrow suppression
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`and stomatitis and monitoring was and is a routine aspect of MTX therapy. Pincus
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`(Ex. 1014) at S-181; Weinblatt 1993 (Ex. 1018) at 776. And when adverse events were
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`noted, the physician’s response was to reduce the dose (in mg) or to stop therapy, not
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`to reduce the 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 [and]
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`may improve with dose reduction or cycled oral or parenteral therapy.”); see the PDR
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`for Mexate® (Ex. 1007) at 764 (“Once optimal clinical response has been achieved, the
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`dosage schedule should be reduced to the lowest possible amount of drug and to the
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`longest possible rest period.”). Further, it was and is the common practice to
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`supplement MTX with folic acid to reduce or eliminate potentially toxic side-effects.
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`Pincus (Ex. 1014) at S-181. Thus any toxic effect was known to be dose, rather than
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`concentration dependent, and was monitored and addressed by the treating
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`physicians.
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`37.
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`In addition, it has been known in the art prior to at least 2006 that MTX
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`is not antigenic—i.e., not a substance that stimulates the production of an antibody
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`when introduced into the body. MTX is not an irritant and generally does not cause
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`skin reactions or concerns with local toxicity.
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`V.
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`Level of Skill In the Art
`38.
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`In my opinion, based on my experience, a person having ordinary skill in
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`the art with respect to the ’231 patent would have either a Pharm. D. or a Ph.D. in
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`pharmacy, pharmacology, or a related discipline; an M.D. or D.O. with experience in
`
`using MTX; or a BS in pharmacy or an equivalent degree with at least two years’
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`experience formulating active pharmaceutical ingredients for injection. A person of
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`ordinary skill in the art would collaborate with others having expertise in, for example,
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`methods of treating disease and administering medicines.
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`VI. The ’231 Patent
`39. 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 of
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`more than 30 mg/ml. The specification states that the term “inflammatory
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`autoimmune 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, Bechterew’s
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`disease, joint arthroses or psoriasis, as well as psoriasis arthritis and in particular
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`plaque-type psoriasis vulgaris.” Ex. 1001 at 3:57-67. Based on this disclosure, one of
`
`ordinary skill in the art would conclude that if MTX at lower concentrations was safe
`
`and effective for the treatment of a particular inflammatory autoimmune disease, then
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`the claimed higher MTX concentrations would be similarly safe and effective for
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`those same diseases. Further supporting this interpretation of the ’231 patent is the
`
`fact that the inventors did not include any examples where patients suffering from any
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`Patent No. 8,664,231
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`inflammatory autoimmune disease were actually given the claimed higher MTX
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`solutions.
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`40. 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 2:33-35. The ’231 patent also states that
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`MTX solutions were previously administered subcutaneously, but patients previously
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`showed a “disapproving attitude” due to “having to inject the required relatively large
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`amount of active substance solution (e.g. up to 3 ml in the case of a certain dosage)
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`under the skin every week, which was especially difficult to convey to children,
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`including the weekly doctor’s visit.” Id. at 2:37-51. Thus, the ’231 patent indicates
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`that the object of the invention is to provide a “pharmaceutical formulation for the
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`treatment of inflammatory autoimmune diseases, in particular rheumatoid arthritis,
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`which overcomes the disadvantages of the prior art preparations described above,”
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`allowing benefits including ease of administration and reduction in pain. Id. at 2:53-
`
`65. The inventors apparently achieved this goal by using the well-known technique of
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`increasing the concentration of MTX in solution, which allows for a smaller volume
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`of liquid to be administered to a patient.
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`41. 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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`Patent No. 8,664,231
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`injection devices, ready-made syringes, and pen injectors. See generally Ex. 1001 at cols.
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`4-7.
`
`42. 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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`43.
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`In my opinion, the methods claimed in the ’231 patent were known and
`
`employed by physicians in the art prior to the July 2007 filing date of the PCT
`
`Application and the July 2006 filing date of the German Application.
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`VII. Claim Construction
`44.
`I have been informed that the construction of a patent claim applied
`
`during this proceeding may differ from that in a district court proceeding.
`
`45.
`
`Specifically, I have been advised that in inter partes review proceedings
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`before the U.S. Patent and Trademark Office, a patent claim receives the broadest
`
`reasonable interpretation in light of the specification of the patent in which it appears.
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`I have also been advised that, at the same time, claim terms are given their ordinary
`
`and accustomed meaning as would be understood by one of ordinary skill in the art.
`
`46.
`
`I have followed these claim-construction principles in my analysis set
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`forth below. In some cases, and where so stated, my opinions have additionally been
`
`informed by the prosecution history of the ’231 patent.
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`Patent No. 8,664,231
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`A.
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`47.
`
`Claims of the ’231 patent
`1.
`Independent claim 1 recites administering MTX “subcutaneously.” Ex.
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`“subcutaneously”
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`1001 at 9:44-45.
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`48. My opinion is that the broadest reasonable construction of
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`“subcutaneously” is: under the skin.
`
`49. My interpretation of “subcutaneously” is based, in part, on my years of
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`experience prescribing and administering injectable drugs, and the well-known
`
`common understanding of the term. More specifically, “subcutaneously” can be
`
`contrasted with “intramuscular” injections, where the drug is administered into a
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`patient’s muscle, and “intravenous” injections, where the drug is administered directly
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`into a patient’s vein.
`
`50. Additionally, the following excerpts from the ’231 paten