Frontier Therapeutics Exhibit 1012
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`

`
`U.S. Patent No. 8,664,231
`
`TABLE OF CONTENTS
`
`I.
`
`INTRODUCTION ........................................................................................ .. I
`
`MY EXPERIENCE AND QUALIFICATIONS ........................................... ..1
`
`III.
`
`MATERIALS REVIEWED .......................................................................... ..6
`
`IV.
`
`BACKGROUND OF METHOTREXATE ................................................... ..9
`
`PERSON OF ORDINARY SKILL IN THE ART ...................................... .. 15
`
`VI.
`
`2 VII.
`
`THE ’23l PATENT ..........
`
`....................................................... .; ............... ..l5
`
`CLAIM CONSTRUCTION ........................................................................ .. 17
`
`A.
`
`Claims of the ‘23l Patent ................................................................. ..18
`
`i.
`
`“subcutaneously” .............................................................................. .. 18
`
`VIII.
`
`CERTAIN REFERENCES DISCLOSE OR SUGGEST THE
`
`FEATURES RECITED IN THE ‘231 PATENT CLAIMS ........................ .. 19
`
`A.
`
`Grint discloses all elements of claims 1, 2, 4, 5, 6, I7, and 22 ......... .. 19
`
`l.
`
`2.
`
`Grint discloses “a method for treating inflammatory
`autoimmune diseases in a patient in need thereof” (Claim
`1) ............................................................................................. ..20
`
`Grint discloses “subcutaneously administering to said
`patient a medicament comprising methotrexate” (Claim
`1) ............................................................................................. ..20
`
`3.
`
`Grint discloses that the methotrexate is “in a
`
`4.
`
`5.
`
`pharmaceutically acceptable solvent at a concentration of
`more than 30 mg/ml” (Claim 1) ............................................. ..2l
`
`Grint discloses that the methotrexate is “present at a
`concentration of more than 30 mg/ml to 100 mg/ml”
`(Claim 2) ................................................................................. ..2]
`
`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
`
`6.
`
`G-rint discloses “the inflammatory autoimmune disease is
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`

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`U.S. Patent No. 8,664,23 l.
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`selected from rheumatoid arthritis, juvenile arthritides,
`vasculitides, collagenoses, Crohn’s disease, colitis
`ulcerosa, bronchiai 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) ......... ..23
`
`B.
`
`C.
`
`7.
`
`Grint discloses that “the sodium chloride solution is
`
`isotonic sodium chloride solution” (Claim l7) ...................... ..24
`
`8.
`
`Grint discloses methotrexate “present at a concentration
`of from 40 mg/ml to 80.mg/mi” (Claim 22) ........................... ..24
`
`Grint In View OfA1sufyani Teaches Every Element of Claim
`18 ...................................................................................................... ..24
`
`The PDR (Ex. l007)_ or Hospira (Ex. 1009) in view of Brooks
`(EX. 1008) teach each element of Claims l~5, l7, and 22 ofthe
`’23i patent ........................................................................................ ..26
`
`l.
`
`2.
`
`3.
`
`PDR (Ex. 1007) ...................................................................... ..26
`
`Hospira (Ex. 1009) ................................................................. ..28
`
`Brooks (Ex. I008) .................................................................. ..29
`
`IX.
`
`Secondary Considerations ........................................................................... ..32
`
`A.
`
`B.
`
`C.
`
`A. Any toxicity associated with MTX after subcutaneous
`injection is dose, not concentration dependent ................................. ..32
`
`The bioavailability of MTX after subcutaneous injection is
`dose, not concentration dependent .................................................... ..35
`
`Applicants’ evidence of unexpected results is not based on a
`comparison of the claimed invention to the closest prior art ............ ..36
`
`D.
`
`Zackheim does not teach away from the claimed invention ............. ..39
`
`X.
`
`CONCLUSION ........................................................................................... ..40
`
`iii
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`

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`U.S. Patent No. 8,664,231
`
`I.
`
`INTRODUCTION
`
`1.
`I, Dr. M. Eric Gershwin, M.D., have been retained by Frontier
`Therapeutics, LLC (“Petitioner’I) as an independent expert consultant in this
`
`proceeding before the United States Patent and Trademark Office.
`
`2.
`
`I understand that this proceeding invoives 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 033 837.5, filed July 21, 2006.
`
`Ex.1001 at Front Cover. 1 further understand that the ’23l patent is assigned to
`
`medac GmbH.
`
`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 ’23l patent. My opinions are set
`
`forth below.
`
`II. MY EXPERIENCE AND QUALIFICATIONS
`
`4.
`
`My curriculum vitae, which includes a detailed summaiy of my
`
`background and experience and a list of my publications and patents is attached as
`
`Exhibit 1031.
`
`5.
`
`I am a Distinguished Professor of Medicine, and Chief of
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`

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`US. Patent No. 8,664,231
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`Rheumatoiogy, Allergy and Clinical Immunology in the School of Medicine at the
`
`University Of California, Davis. My official title is Distinguished Professor of
`
`Medicine.
`
`6.
`
`I received my A.B. degree (summa cum laude) in Zoology from
`
`Syracuse University in 1966. In 1975, I graduated with an M.D. from Stanford
`
`University School of Medicine in Palo Alto, California.
`
`I was an intern and
`
`medical resident from 19714973 at Tufts-New England Medical Center, Boston,
`
`MA. From 1973 to 1977, I was a Clinical Associate, Immunology, National
`
`Institute of Health, Bethesda, MD.
`
`7.
`
`From 197 5— 1977, I was an Assistant Professor of Medicine
`
`(Rheumatology and Clinical immunol.), University of California, Davis.
`
`8.
`
`From 1976-1979, I was the Director of the Tissue Typing Laboratory
`
`at the University of California, Davis.
`
`9.
`
`From 1977-1981, I was an Associate Professor of Medicine in the
`
`Division of Rheumatology/Allergy and Clinical immunology at the University of
`
`California, Davis.
`
`10.
`
`From 1981 to the present time, I have been a Professor of Medicine,
`
`Division of Rheumatology/Allergy and Clinical Immunology, University of
`
`California, Davis.
`
`ll.
`
`From 1982 to the present time, I have been the Chief of the Division
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`U.S. Patent No. 8,664,231
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`of Rheumatology/Allergy and Clinical Immunology, University of California,
`
`Davis.
`
`12.
`
`From 1985~l986, I was a Visiting Scientist at the Walter and Eiiza
`
`Hall Institute of Medical. Research, Melbourne, Australia, supported by a
`
`fellowship from the Guggenheim Foundation.
`
`13.
`
`From 2003 to the present time, I have been a Distinguished Professor
`
`of Medicine, University of California, Davis.
`
`14.
`
`I have received. a large number of awards and have been offered
`
`memberships in a large number of organizations in recognition of my work as
`
`listed below: Phi Beta Kappa, 1966; Pi Mu Epsilon, 1966; Witco Chem. Award in
`
`Organic Chem., Syracuse University, 1964, 1965, 1966; Stanford Award for
`
`Outstanding Student Research, 1968; Associate of American Colleges Recognition
`
`in Trop. Med., 1970; Rbt. Shelton Alumni Scholar Award, Stanford Univ., 1971;
`
`Alpha Omega Alpha, 1971; University of California Faculty Award for Biomedical
`
`Research, 1979; Chair, Division of Comp. Imrnunol. 1984-1986 (ASZ); ASCI,
`
`1984; UC Award for Biomedical Research, 1985; Guggenheim Fellowship, 1985-
`
`1986; Oettinger Award, 1988; NIH General Medicine Study Section (A) 1990-
`
`1992; Chairperson, 1992-1994; American Association of Physicians (AAP), 1994;
`
`Jack and Donald Chia Professor of Medicine, 1994; Consultant, Center for
`
`Excellence, Japan Ministry of Education, 2004; Medal of the University of Milan,
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`

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`U.S. Patent No. 8,664,231 -
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`2005.
`
`15.
`
`I am the Editor-in-Chief of the Journal of Autoimmunity.
`
`I am also
`
`the Editor-in—Chief of Clinicai Reviews in Allergy and immunology.
`
`I have also
`
`served on the editorial boards and/or reviewed peer reviewed medical literature for
`
`more than 50 Scientific journals, including Annals of Rheumatic Diseases, Nature
`
`Clinical Rheumatology, Arthritis and Rheumatism, Year Book of Rheumatology,
`
`the Journal of Rheumatology the Annals of Internal Medicine, Annals of
`
`Rheumatic Diseases, Arthritis , and Rheumatism, , Scandinavian Journal of
`
`Rheumatology, and the New England Journal of Medicine.
`
`16.
`
`In addition to my academic teaching experience, I have been an
`
`invited speaker for more than 500 named and major lectures on topics relating to
`
`rheuinatology and immunology. For example, I have been an invited speaker for
`
`the plenary session in the last five Congresses of Autoimmunity.
`
`I have also been
`
`an invited speaker to provide a keynote address for multiple symposia sponsored
`
`by the Falk Foundation, the Japanese Ministry, the Chinese Science Foundation,
`
`and many American universities, including the Cleveland Clinic, Tufts University,
`
`University of Washington, University of Oregon, University of Caiifornia,
`
`University of Arizona, University of Texas, amongst others.
`
`17.
`
`I have also served on the scientific advisory/medical boards of
`
`several companies, including Phannakea, UCB Pharrna, Galmead, Pfizer, Hoffman
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`

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`U.S. Patent No. 8,664,231
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`LaR0che, and Genentech.
`
`18.
`
`l have authored or coauthored more than 1000 peer review scientific
`
`articles reporting on original research, the vast majority for issues relating to
`
`immunology.
`
`1 have also couauthored or edited more than 50 books related to
`
`immunology and rheumatology. My peer review publications began in 1967 and
`
`continue through the present and are noted on my Curriculum Vitae. I am triple
`
`board certified including Internal Medicine, Allergy—Clinica1 Immunology and
`
`Rheumatology.
`
`19.
`
`Over the course of my professional career my entire research
`
`program has essentially been directed toward increasing our knowledge about
`
`immunology and rheumatology.
`
`I have studied new treatments for Complex
`
`diseases, including rheumatoid arthritis, for over 25 years. I have been involved in
`
`the development of new drugs for the treatment of autoimmune diseases. Most
`
`notably, I have published on the use of MTX to treat autoimmune diseases such as
`
`rheumatoid arthritis. I have served as the Principal Investigator on many rnulti~
`
`center therapeutic and/or diagnostic studies in immunology and rheumatology.
`
`20.
`
`Currently, a great deal of my time is involved in direct patient care. I
`
`am a full—time clinician at the University of California, Davis.
`
`I have a
`
`consultative and continuity practice in immunology and rheumatology. My major
`
`clinical interest is in autoimmunity, including rheumatoid arthritis. While the vast
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`

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`U.S. Patent No. 8,664,231
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`majority of my practice is by referral from physicians, primarily in the western
`
`United States, I also have a fairly large national and international practice. Over
`
`the course of my career‘, I have prescribed and treated patients suffering from
`
`autoimmune diseases such as rheumatoid arthritis with MTX, including the
`
`administration of MTX subcutaneously and intrarnuscularly.
`
`21.
`
`Although I am being compensated at my rate of $625 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.
`
`22.
`
`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.
`
`III. MATERIALS REVIEWED
`
`23.
`
`in forming my opinions, i have relied on my 40 years of experience,
`
`and I have 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 ’23i Patent”) (Ex. 1001).
`
`2) Excerpts from File History for U .S. Patent No. 8,664,231. (Ex.
`1002).
`
`3) US. 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
`
`6
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`

`
`US. Patent No. 8,664,231
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`( (“Grint”) (Ex. 1003).
`
`4) Hoekstra et al. (2004) J. Rheumarol 31(4): 645-648
`(“Hoekstra”) (Ex. 1004).
`
`5) Jsargensen et al. (1996) Ann Pharmacorher 30:729—32
`(“iyargensen”) (Ex. 1005).
`
`6) Alsufyani et a1. (2003) J Rheumatol 312179-82 (“Alsufyani”)
`(Ex.1006).
`
`7) 1985 Ed. I-’hysioian’s Desk Reference for MeX.ate® (“the PDR”)
`(Ex. 1007).
`
`' 8) Brooks et a1. (1990) Arthritis and Rheum. 33(1): 91-94
`(“Brooks”) (Ex. 1008).
`
`9) Hospira (“Hospira”) (Ex. 1009).
`
`10) Zackheim (1992) J Am. Acad. 0fDerm. 23(6) p. 1008.
`(“zackheini”) (Ex. 1010).
`
`11) Miil1e1'—Ladne1" (201.0) The Open Rheumarology Journal 4:15-
`22. (“Mii11er—Ladner”) (Ex. 1011).
`
`12) Pincus et a1. (2003) Methotrexate as the “anchor drug” for the
`treatment of early rheumatoid arthritis 21 :S179—S185
`(“Pincus”) (Ex. 1014).
`
`13) Insulin Administration Position Statement (2003), Diabetes
`Care, 26(1) 5121~5124 (“insulin Admin”) (Ex. 1015).
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`

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`U.S. Patent No. 8,664,231
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`14) Weinblatt (1.993) “M.ethotrexate,” in Textbook of
`Rheumatoiogy, 4th Edition, Chapter 47, (Kelley et a1., eds.
`1993) (“Weinblatt 1993”) (Ex. 1018).
`
`15) Hoffmeister (1993) Methotrexate therapy in rheumatoid
`arthritis: 15 years experience. Am. J. Med. 7'5:69~73
`(“Hoffmeister 1993”) (Ex. 1019).
`-
`
`16) Weinbiatt (1995) Efficacy of1VI.ethotrexate in Rheumatoid
`Arthritis, Br. J. Rheum. 34(supp1. 2):43—48 (“Weinblatt 1995”)
`(Ex. 1020).
`
`17) Weinbiatt et al. (1985) “Efficacy of Low—Dose Methotrexate in
`Rheumatoid Arthritis,” N. Engl. J. Med. 3i2:818—822
`(“weinbiatt 1985”) (Ex. 1021).
`
`18) Hoffmeister (1972) Methotrexate in rheumatoid arthritis. Arth.
`Rheum. 15 (Suppl.): S3114 (abstract) (“Hoffmeister 1972”) (Ex.
`1022).
`
`19) Weinbiatt et a1. (1994) Methotrexate in Rheumatoid Arthritis:
`a 5 Year Prospective Muiticenter Study, Arth. Rheum.
`37(i0):1492—i498 (“Weinblatt 1994”) (Ex. 1023).
`
`20) Weinbiatt 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 a1. (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 a1. (1964) Methotrexate therapy in psoriatic arthritis.
`
`8
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`

`
`U.S. Patent No. 8,664,231
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`Double-blind study on 21 patients. J. Am. Med. Assoc. l89:743—
`7 (“Biack”) (Ex. 1026).
`
`23) Feagan et al. (1995) Methotrexate for the Treatment of Crohn’s
`Disease, N. Engl. 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. ].6(3):313—20 (“Furst”) (Ex. 1028).
`
`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. J. Med. 326:1043
`(“Giannini”) (Ex. 1029).
`
`26) Michaeis, 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
`
`24.
`
`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.
`
`25.
`
`Arninopterin, 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 arninopterin in patients with psoriasis, RA,
`
`and psoriatic arthritis was reported. Gubner (Ex. 1025); Weinblatt 1995 (Ex. 1020)
`
`9
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`

`
`U.S. Patent No. 8,664,231
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`at 43. Refinement of the aminopterin compound lead to the development of MTX.
`
`Weinblatt 1995 (Ex. 1020) at 43.
`
`26.
`
`I 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. 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.
`
`27.
`
`_ In 1972, Hoffmeister reported the beneficial effect of low dose
`
`intramuscular administration of MTX. Ex. 1022 at Abstract.
`
`28. 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, rheumatoiogists had over two decades of safety and efficacy experience
`
`using MTX for the treatment of RA.
`
`I
`
`29.
`
`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 “Results.” For example, a study published by Hoffmeister in
`
`10
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`

`
`U.S. Patent No. 8,664,231
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`1983 reported the results of 15 years of treating patients with up to 15 mg/ml of
`
`MTX given intramuscularly or orally. Hoffrneister 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.
`
`30.
`
`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 £049; see also Alsufyani (Ex. 1006). The study
`
`also reported an acceptable short-terrn safety profile. Giannini (Ex. 1029) at 1049.
`
`31.
`
`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.
`
`32.
`
`MTX may be administered orally or parenteraily (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
`
`11
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`U.S. 13ater1tNo. 8,664,231
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`indicated. However, doses greater than 20 mg/week used to treat inflammatory
`
`autoimmune diseases are generally administered intramuscuiarly 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.
`
`33.
`
`There are several advantages to subcutaneous administration over
`
`intramuscular administration. First, from my clinical 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; Zackheirn (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.
`
`34.
`
`In addition, the bioavailability of subcutaneous MTX compared to
`
`intramuscular MTX is the same. Weinblatt 1993 (Ex. 1018) at 769 (“The
`
`pharinacokinetics of subcutaneous MTX is the same as intramuscular MTX in
`
`12
`
`

`
`U.S. Patent No. 8,664,231
`
`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 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 for approximately 20 years.
`
`35.
`
`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/mg, and 10 mg/In?‘ oral weekly MTX. Furst (Ex. 1 028) at 313. The study
`
`dernonstrated “a dose related ilnproveinent 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 states that
`
`the toxicity of MTX “is usually dose—related.”l The PDR (Ex. 1007) at 763. I am
`
`aware of no study Concluding that drug concentration affects drug toxicity.
`
`I 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.
`
`13
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`U.S. Patent No. 8,664,231
`
`36.
`
`Further, MTX has a “we1i—def1ned toxicity profile” shown to be
`
`effective over long periods “with considerably lower toxicity than previously
`
`available DMARDS [disease—modifying anti-rheumatic drugs],” and further have
`
`shown to “have very few clinically significant side effects.” Pincus (Ex. 1014) at
`
`S-180-181.
`
`37.
`
`Although generally safe, dose-related effects were reported for MTX.
`
`However, physicians, such as myself, knew to monitor patients receiving MTX for
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`gastrointestinal, hepatic, and pulmonary toxicity, as weli as bone marrow
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`suppression and stornatitis and monitoring was and is a routine aspect of MTX
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`therapy. Pincus (Ex. 1014) at S-181; Weinblatt 1993 (Ex. 1018) at 776. And when
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`adverse events were noted, the physician’s response was to reduce the dose (in mg)
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`or to stop therapy, not to reduce the concentration. Weinblatt 1993 (Ex. 1018) at
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`774 (“In most patients, this toxicity is generally mild and generally occurs shortly
`
`after drug administration [and] may improve with dose reduction or cycled oral or
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`parenteral therapy”); see also the PDR (Ex. 1007) at 764 (“Once optimal clinical
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`response has been achieved, the dosage schedule should be reduced to the lowest
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`possible amount of drug and to the longest possible rest period”). Further, it was
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`and is the common practice to supplement MTX with folic acid to reduce or
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`eliminate potentially toxic side effects. Pincus (Ex. 1014) at S-181. Thus, any toxic
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`U.S. Patent No. 8,664,23l
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`effect was known to be dose rather than concentration dependent, and was
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`monitored and addressed by the treating physicians.
`
`38.
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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-~r'.e., not a substance that stimulates the production 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.
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`V.
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`PERSON OF ORDINARY SKILL IN THE ART
`
`39.
`
`In my opinion, based on my experience, a person having ordinary
`
`skill in the art with respect to the ’23l patent would have either a Pharm. D. or a
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`Ph.D. in pharmacy, pharmacology, or a related discipline; an MD. or D.O. with
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`experience in using MTX; or a BS in pharmacy or an equivalent degree with at
`
`least two years’ experience formulating active pharmaceutical ingredients for
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`injection. A person of ordinary skill in the art would collaborate with others having
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`ex ertise in, for exam le methods oftreatin disease and administerin medicines.
`P
`9
`8
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`VI.
`
`THE ’23l PATENT
`
`40.
`
`The ’23l 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 states that the term “inflammatory
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`autoimmune disease” encompasses “all inflammatory autoimmune diseases which
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`can reasonably be treated with methotrexate,” and lists inflammatory specific
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`U.S. Patent No. 8,664,231
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`diseases, including “rheumatoid arthritis and others ” 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
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`inflammatory autoimmune disease, then the claimed higher MTX concentrations
`
`would be similarly safe and effective for those same diseases. Further supporting
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`this interpretation of the ’23l patent is the fact that the inventors did not include
`
`any examples where patients suffering from any inflammatory autoimmune disease
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`were actually given the claimed. higher MTX solutions.
`
`41.
`
`The ’23i patent also acknowledges that MTX solutions were
`
`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
`
`standard in treatment. ...” Ex. 1001 at 2:33-35. The ’23l 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
`
`certain dosage) under the skin every week, which was especiaily difficult to
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`convey to children, including the weekly doctor’s visit.” Id. at 2:37-5 i. Thus, the
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`’23i patent indicates that the object of the invention is to provide a
`
`“pharmaceutical formulation for the treatment of inflammatory autoimmune
`
`diseases, in particular rheumatoid arthritis, which overcomes the disadvantages of
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`U.S. Patent No. 8,664,231
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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
`
`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.
`
`42.
`
`The ’231 patent also discloses various devices for the subcutaneous
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`I 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
`
`at cols. 4~7.
`
`43.
`
`The ’23l 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.
`
`44.
`
`In my opinion, the methods claimed in the ’23l patent were known
`
`and employed by physicians in the art prior to the July 2007 filing date of the PCT
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`Application and the July 2006 filing date of the German Application.
`
`VII. CLAIM CONSTRUCTION
`
`45.
`
`I have been informed that the construction of a patent claim applied
`
`during this proceeding may differ from that in a district court proceeding.
`
`46.
`
`Specifically, I have been advised that in inter partes review
`
`proceedings before the US. Patent and Trademark Office, a patent claim receives
`
`the broadest reasonable interpretation in light of the specification of the patent in
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`U.S. Patent No. 8,664,233
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`which it appears. 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.
`
`47.
`
`I have followed these clai1n—construction principles in my analysis set
`
`forth below. In some cases, and. where so stated, my opinions have additionally
`
`been informed by the prosecution history of the ’23l patent.
`
`A.
`
`Claims of the ‘Z31 Patent
`
`i. “subcutaneously”
`
`48.
`
`Independent claim 1 recites administering MTX “subcutaneously."
`
`Ex. 1001 at 9:44-45.
`
`49. My opinion is that the broadest reasonable construction of
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`“subcutaneously” is: under the skin.
`
`50.
`
`My interpretation of “subcutaneously” is based, in part, on my years
`
`of experience prescribing and administering injectable drugs, and the well-known
`
`common understanding of the term. More specifically, “subcutaneously” can be
`
`contrasted with “intrainuscuiar” injections, where the drug is administered into a
`
`patient’s muscle, and “intravenous” injections, where the drug is administered
`
`directly into a patient’s vein.
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`18
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`U.S. Patent No. 8,664,231
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`51.
`
`Additionally, the following excerpts from the 231 patent support my
`
`construction of “subcutaneously” at Ex. 1001 at 2:37~52 and 4:65—5:5,
`
`respectively:
`
`However‘, it has been found that a subcutaneous
`
`administration in particular has its difficulties. When treated
`with the preparations known from the prior art, patients
`showed a disapproving attitude. This was due to the problem
`of having to inject the required relatively large amount of
`active substance solution (e.g. up to 3 ml in the case of a
`certain dosage) under the skin every week, which was
`especially difficult to convey to children, including the
`weekly doctor’s visit.
`
`Although the provision of methotrexate solutions in
`readymade syringes, some for self—application, have had a
`positive impact on patient compliance, the prior art
`preparations that are approved for subcutaneous application
`have the disadvantage that, depending on the amount of
`active substance to be administered in each week, relatively
`large amounts of liquid have to be injected under the
`patient’s skin.
`
`52.
`
`The above passage from the ’231 patent supports my construction
`
`that “subcutaneous” means “under the skin.”
`
`VIII. CERTAIN REFERENCES DISCLOSE OR SUGGEST THE
`
`FEATURES RECITED IN THE ‘Z31 PATENT CLAIMS
`
`A.
`
`Grint discloses all elements of claims 1, 2, 4, 5, 6, 17, and 22
`
`53.
`
`Grint is U.S. Patent No. 6,544,504 entitled “Combined Use of
`
`Interleukin 10 and Methotrexate for lmrnunomodulatory Therapy.” Grint issued on
`
`April 8, 2003 (Ex. 1003, Front Cover), and based on this date, I have been
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`U.S. Patent No. 8,664,231
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`informed that Grint is prior art to the ’231 patent. I am also aware that the PTO did
`
`not consider Grint during prosecution. of the ’23l patent.
`
`54.
`
`Grint teaches the subcutaneous administration of MTX at
`
`concentrations greater than 30 mg/mi for the treatment of inflammatory
`
`autoimmune diseases including RA. See, e.g., id. at 2:23-24; 3:4-5; 5:64; 6:66~7:l;
`
`7:56-57. Grint describes administering interleukin 10 (IL—l0) and MTX, stating
`
`that IL-10 and MTX “may be administered together in a single pharmaceutical
`
`composition or separately” and may be administered “at different times during the
`
`course of a common treatment schedule.” Id. at 3:l3—21. Further, Grint discioses
`
`that the MTX may be administered “parenterally,” which means the drug can be
`
`administered via injection. And in some of the examples in Grint, the patients
`
`received IVITX subcutaneously. Id. at 5:65-66; 7:54-57.
`
`55.
`
`For the following reasons, I believe that Grint teaches all elements of
`
`claims 1, 2, 4, 5, 6, i7, and 22 ofthe ’23l patent.
`
`1.
`
`Grint discloses “a method for treating inflammatory
`autoimmune diseases in a patient in need thereof” (Claim
`1)
`
`56.
`
`Grint expressly teaches that “the methods of the invention can be
`
`used
`
`for treatment of established autoimmune disease,” including RA. Ex. 1003
`
`at 3:4—i 1; 2:23-24.
`
`2.
`
`Grint discloses “subcutaneously administering to said
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`U.S. Patent No. 8,664,231
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`patient a medicament comprising methotrexa