`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`___________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`___________________________________
`
`FRONTIER THERAPEUTICS, LLC
`
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`
`
`Patent Owner
`
`___________________________________
`
`Inter Partes Review Case No. IPR2016-00649
`Patent Number 8,664,231
`
`
`
`EXPERT DECLARATION OF ELENA MASSAROTTI, M.D.
`June 2, 2016
`
`
`
`Medac Exhibit 2018
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`I, Dr. Elena Massarotti, have been retained as an expert by counsel for
`
`medac Gesellschaft Für Klinische Spezialpräparate Mbh, Inc. (“Medac”) in the
`
`above-captioned Inter Partes Review (“IPR”).
`
`I.
`
`QUALIFICATIONS
`1.
`
`I am a medical doctor specializing
`
`in rheumatology, which
`
`encompasses inflammatory autoimmune diseases. I have a particular interest in
`
`inflammatory arthritis, lupus, and vasculitis. My professional time is divided
`
`between patient care, education, and clinical research. I routinely
`
`treat
`
`inflammatory autoimmune disease patients with methotrexate, including oral,
`
`intramuscular, and subcutaneous administration, and have done so throughout my
`
`more than twenty-five years of clinical experience.
`
`2.
`
`I graduated from Tufts University School of Medicine in 1984. I
`
`completed my internship and residency in internal medicine at New England
`
`Medical Center (now known as Tufts Medical Center) between 1984 and 1987. I
`
`completed a fellowship in Rheumatology/Immunology at New England Medical
`
`Center from 1988 to 1990. I was then the Chief Medical Resident at the New
`
`England Medical Center from 1990 to 1991.
`
`3.
`
`I am board certified in Internal Medicine and in Rheumatology. I am
`
`a member of the American College of Rheumatology.
`
`
`
`
`
`
`Page 2
`
`Page 00002
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`4.
`
`Between 1990 and 2007, I had clinical academic positions at two
`
`different hospitals. From 1991 to 1993, I was the director of house staff training at
`
`the Mt. Auburn Hospital in Cambridge, Massachusetts (a Harvard Medical School
`
`affiliate). From 1993 to 2002, I was the director of clinical rheumatology training
`
`at Tufts Medical Center. From 2001 to 2002, I was the acting division chief of
`
`rheumatology at Tufts Medical Center. From 2002 to 2007, I was the clinical
`
`director of rheumatology at Tufts Medical Center.
`
`5.
`
`Since 2007, I have been an Associate Professor at Harvard Medical
`
`School and an Associate Physician at the Brigham and Women’s Hospital
`
`(“BWH”) in Boston. I am Director of Clinical Trials at the Lupus Center at BWH
`
`and Co-Director of the Clinical Trials Center in the BWH Division of
`
`Rheumatology. Over the course of my career, I have held a number of major
`
`committee assignments and appointments at BWH and Tufts-New England
`
`Medical Center. I have also received a number of professional and teaching
`
`honors and awards, including recognition by Boston Magazine and U.S. News and
`
`World Report.
`
`6.
`
`I have been or currently serve as an ad hoc reviewer for a number of
`
`medical journals including the New England Journal of Medicine, Infectious
`
`Diseases in Clinical Practice, Lupus, Annals of the Rheumatic Diseases, Arthritis
`
`and Rheumatism, and the Journal of the American Medical Association. I was a
`
`
`
`
`
`
`Page 3
`
`Page 00003
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`member of the Editorial Board of Arthritis Care and Research from 2012-2015. I
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`am on the Executive Committee of the Lupus Nephritis Trials Network. I am a
`
`member of the Harvard Medical School admissions committee and the Harvard
`
`Catalyst research committee. I have been an invited speaker at dozens of
`
`conferences and courses and have authored or co-authored over ninety
`
`peer-reviewed articles, review articles, book chapters, and abstracts. In addition, I
`
`have been or am currently an investigator on at least thirty-six clinical trials and
`
`studies. These publications include reports of clinical trials, epidemiologic studies
`
`and clinical observations in the areas of autoimmune disease.
`
`7. My educational background, work experience and a list of my
`
`publications are set forth in my curriculum vitae, which is attached as Tab A to this
`
`report. A list of the cases in which I have testified as an expert at trial or by
`
`deposition over the previous 4 years is attached at Tab B.
`
`II.
`
`SCOPE OF ASSIGNMENT AND SUMMARY OF MY OPINIONS
`8.
`
`I am informed and understand that Frontier Therapeutics, LLC
`
`(“Frontier”) has petitioned for an IPR of Medac’s U.S. Patent 8,664,231 (Ex. 1001,
`
`“the ‘231 Patent”) and has requested the cancellation of claims 1-22 of the ‘231
`
`Patent. I am informed and understand that in the IPR, Frontier has relied upon,
`
`among other things, U.S. Patent 6,544,504 (Ex. 1003, “Grint”); the Mexate
`
`Product Information in the 1985 Physicians’ Desk Reference (Ex. 1007, “Mexate”)
`
`
`
`
`
`
`Page 4
`
`Page 00004
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`and a Hospira Product Summary for Mexthotrexate 100 mg/ml Injection
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`(“Hospira”) (Ex. 1009).
`
`9.
`
`I am informed and understand that the claims of the ‘231 Patent have
`
`a date of July 21, 2006. I have been asked to assess the knowledge of the skilled
`
`artisan at that July 21, 2006 date and to consider what the skilled artisan at that
`
`date would have understood from Grint, Mexate, and Hospira.
`
`10.
`
`In forming my opinions, I have relied upon my education, experience,
`
`and various written materials. A list of the written materials that I considered in
`
`rendering my opinions is attached to this declaration as Tab C. Each of these
`
`materials is a type of document that experts in my field would reasonably rely
`
`upon when forming their opinions.
`
`11.
`
`I hereby declare that all statements made herein of my own
`
`knowledge are true and that all statements made on information and belief are
`
`believed to be true; and further that these statements were made with the
`
`knowledge that willful false statements and the like so made are punishable by fine
`
`or imprisonment, or both, under 18 U.S.C. 1001. If called to testify as to the truth
`
`of the matters stated herein, I could and would testify competently.
`
`
`
`
`
`
`Page 5
`
`Page 00005
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`III. LEVEL OF SKILL IN THE ART
`12.
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`I have been instructed for, the purposes of this Declaration, to opine
`
`on the knowledge and understanding of a person having ordinary skill in the art as
`
`of July 21, 2006.
`
`13.
`
`I understand that the factors considered in determining the ordinary
`
`level of skill in the art include: (i) the levels of education and experience of persons
`
`working in the field; (ii) the types of problems encountered in the field; and (iii)
`
`the sophistication of the technology. I understand that a person having ordinary
`
`skill in the art is not a specific real individual, but rather a hypothetical individual
`
`having the qualities reflected by the factors above.
`
`14.
`
`In my opinion, based on my over 25 years of experience in treating
`
`inflammatory autoimmune diseases, often using oral, intramuscular and
`
`subcutaneous administration of methotrexate, a person having ordinary skill in the
`
`art with respect to the ‘231 Patent as of July 21, 2006 would have the
`
`understanding of: a) a person with an M.D. and experience using methotrexate to
`
`treat inflammatory autoimmune diseases; or b) a person with a Ph.D. or Pharm.D.
`
`in pharmacology, pharmaceutics, or chemistry; or c) a person with a lesser degree
`
`but with at least several years of additional experience in methotrexate preparation
`
`(e.g., a pharmacy technician or nurse) in either an academic or industrial setting. I
`
`understand that Petitioner has taken the position that a person having ordinary skill
`
`
`
`
`
`
`Page 6
`
`Page 00006
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`in the art would have either a Pharm. D. or a Ph.D. in pharmacy, pharmacology, or
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`a related discipline; an M.D. or D.O. with experience in using methotrexate; or a
`
`BS in pharmacy with at least two years of experience formulating active
`
`pharmaceutical ingredients for injection. A person of ordinary skill in the art would
`
`collaborate with others having expertise in, for example, methods of treating
`
`disease and administering medicines. My opinions are the same regardless of
`
`which of these levels of skill in the art I apply.
`
`IV. THERAPEUTIC ISSUES WITH ORAL, SUBCUTANEOUS AND
`INTRAMUSCULAR METHOTREXATE
`15. Methotrexate via oral administration has been used to treat
`
`rheumatoid arthritis and other inflammatory autoimmune diseases since the 1950s.
`
`The ‘231 Patent (Ex. 1001) at 2. I have often prescribed oral methotrexate, usually
`
`in tablet form, to patients with rheumatoid arthritis and other inflammatory
`
`autoimmune diseases.
`
`16. There are several challenges with oral administration of methotrexate.
`
`The bioavailability of the orally administered methotrexate decreases as the
`
`methotrexate dose increases to greater than 15-20 mg per week. Pavy (Ex. 2029)
`
`at 4. This decreases the therapeutically effective dose that can be administered
`
`orally. Furthermore, some patients experience gastrointestinal symptoms related to
`
`
`
`
`
`
`Page 7
`
`Page 00007
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`oral methotrexate administration. These symptoms often decrease after patients
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`switch from oral to parenteral administration. Id.
`
`17.
`
`In my experience and to the best of my knowledge, the highest
`
`concentration used by me and other clinicians in the field prior to July 21, 2006 for
`
`subcutaneous or intramuscular administration of methotrexate was 25 mg/ml. See,
`
`e.g., Zackheim (Ex. 1010) at 1.
`
`18. To administer subcutaneous or intramuscular doses of methotrexate
`
`greater than 25 mg, clinicians faced the dilemma of administering the drug in a
`
`volume greater than 1 ml. Volumes of greater than 1 ml were likely to cause
`
`greater discomfort to the patient. Moreover, it is important to note that these
`
`injections are usually given weekly as a treatment for chronic illness, and high
`
`volumes are accordingly impractical because of the continuous burden it places on
`
`the patients receiving such injections every week and the negative effect that
`
`multiple injections given on a weekly basis in perpetuity have on their quality of
`
`life. Alternatively, clinicians could use multiple doses of 25 mg/ml methotrexate
`
`to deliver more (or even less) than 25 mg. This is what I would typically do.
`
`Zackheim (Ex. 1010) at 1; see also, paragraph 24, infra. In my experience,
`
`however, patients generally prefer as few injections as possible.
`
`
`
`
`
`
`Page 8
`
`Page 00008
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`19. The methods of the ‘231 Patent mitigate these problems associated in
`
`prescribing oral methotrexate and injectable methotrexate products at
`
`concentrations of 25 mg/ml or less.
`
`V.
`
`GRINT DOES NOT DISCLOSE SUBCUTANEOUS
`ADMINISTRATION OF METHOTREXATE AT A
`CONCENTRATION OF MORE THAN 30 MG/ML
`A. Grint Does Not Explicitly Disclose The Administration Of
`Subcutaneous Methotrexate At A Concentration Of More Than 30
`mg/ml
`20. Claim 1 of the ‘231 Patent recites “[a] method for the treatment of
`
`inflammatory autoimmune diseases in a patient in need thereof, comprising
`
`subcutaneously administering to said patient a medicament comprising
`
`methotrexate in a pharmaceutically acceptable solvent at a concentration of more
`
`than 30 mg/ml.”
`
`21. Grint does not disclose subcutaneous administration of a medicament
`
`comprising methotrexate
`
`in a pharmaceutically acceptable solvent at a
`
`concentration of more than 30 mg/ml. Grint refers to the administration of
`
`methotrexate at col. 5, line 22 to col. 7, line 4. The word “subcutaneous” does not
`
`appear in that section of Grint (the term appears along with oral and intramuscular
`
`only in Example 1 (7:57 and 8:1-2), which does not recite any methotrexate
`
`concentration). Rather, in that section Grint reports that methotrexate can be
`
`administered “orally” (col. 5, line 25), “parenterally or intraperitoneally” (col. 5,
`
`
`
`
`
`
`Page 9
`
`Page 00009
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`lines 65-66) or as “[a] single intravenous dose” (col. 7, line 5). Grint also recites in
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`that section that “methotrexate is generally present in from about 0.1 to about 40
`
`mg/ml” in the medicament (col. 6, lines 66-67). Grint does not correlate any
`
`concentration or amount of methotrexate with any mode of administration.
`
`22. Parenteral administration refers to a mode of drug administration that
`
`avoids or circumvents the gastrointestinal tract. See, e.g., Aschenbrenner (Ex.
`
`2024) at 13. Parenteral administration includes at least eighteen different modes of
`
`administration, including intravenous, intra-arterial, intraosseous, intramuscular,
`
`intradermal, subcutaneous, intracardiac, intrathecal, intraperitoneal, intravesical,
`
`intravitreal, intracavernous, epidural, intracerebral, intracerebroventricular,
`
`intrapleural, inhalational, and transdermal. Baird (Ex. 2025) at 19; and
`
`Aschenbrenner (Ex. 2024) at 13 and 16-21.
`
`23. As of July 21, 2006, it was known by me and others in the field that
`
`different modes of parenteral administration were used clinically with different
`
`concentrations of methotrexate.
`
` For example, for
`
`intrathecal
`
`injection,
`
`methotrexate concentrations should be between 1 mg/ml and 2.5 mg/ml. See, e.g.,
`
`Mexate (Ex. 1007) at 5. Higher concentrations should not be used. By way of
`
`another example, Hospira describes
`
`the administration of methotrexate
`
`intravenously at a concentration of 100 mg/ml using Onco-Vials in a Faulding
`
`administration device. Hospira (Ex. 1009) at 13. As yet another example,
`
`
`
`
`
`
`Page 10
`
`Page 00010
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`subcutaneous administration of methotrexate has been reported at “50 mg/2ml”
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`i.e., 25 mg/ml. Kurnik (Ex. 2028) at 2.
`
`24. To the extent that more than 25 mg of methotrexate was to be
`
`administered subcutaneously, it was standard practice in the art, and in my
`
`practice, to give more than one injection at concentrations of 25 mg/ml
`
`methotrexate or less. For example, Zackheim reports that “[p]atients should be
`
`instructed to use only 1 ml syringes so that gross errors in dosage are less likely to
`
`occur. Thus doses greater than 25 mg require the use of at least two syringes.”
`
`Zackheim (Ex. 1010) at 1.
`
`25. To my knowledge, no document published prior to July 21, 2006
`
`reports the actual subcutaneous administration of methotrexate at a concentration
`
`greater than 25 mg/ml. Certainly, Grint – and for that matter, Mexate and
`
`Hospira– do not report this administration. There is similarly no report of such an
`
`administration or the preparation of a pharmaceutical formulation for such an
`
`administration in the expert declarations submitted on behalf of Frontier by M. Eric
`
`Gershwin, M.D. or David C. Gammon. BSPh. My experience in the subcutaneous
`
`administration of methotrexate prior to July 21, 2006 is similar to the published
`
`reports in that I had never administered methotrexate subcutaneously, for any
`
`condition, let alone for an inflammatory autoimmune disease, at a concentration
`
`greater than 25 mg/ml. Further, I am not aware of any others who have
`
`
`
`
`
`
`Page 11
`
`Page 00011
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`administered methotrexate subcutaneously for an inflammatory autoimmune
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`disease or any other condition at a concentration greater than 25 mg/ml prior to
`
`July 21, 2006 or indeed for several years thereafter.
`
`26. Moreover, a skilled artisan reading Grint as of July 21, 2006 would
`
`have understood the recitation in Example 1 of Grint – dosing methotrexate at
`
`“12.5-25 mg/week (oral, subcutaneous or intramuscular)” – as consistent with what
`
`was conventional practice in the art of administering subcutaneous methotrexate
`
`prior to July 21, 2006. Grint (Ex. 1003) at col. 7, lines 57-59. As I explained
`
`above, the standard practice in the field at that time, and in my own experience,
`
`was to administer subcutaneous methotrexate at concentrations of 25 mg/ml or
`
`less. Thus, to administer the 25 mg maximum methotrexate dose of Example 1, an
`
`appropriate number of tablets or a 1 ml intramuscular or subcutaneous injection
`
`would have been used.
`
`B. Grint Recites Methotrexate Concentrations That Require Drug
`Volumes That Are Unsuitable For Subcutaneous Administration
`27. As explained above, Grint does not explicitly correlate subcutaneous
`
`administration with any concentration of methotrexate. Moreover, the skilled
`
`artisan would have not correlated the recitation in Grint of a parenteral
`
`administration of methotrexate “from about 0.1 to about 40 mg/ml” with
`
`subcutaneous or intramuscular administration. This is because, as I explain below,
`
`
`
`
`
`
`Page 12
`
`Page 00012
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`the range of methotrexate concentrations “from about 0.1 to about 40 mg/ml”
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`captures volumes that are totally unsuitable for subcutaneous or intramuscular
`
`administration in the treatment of inflammatory autoimmune illnesses.
`
`1.
`
`Administration Of Methotrexate At The Concentrations
`Recited In Grint Requires Drug Volumes That Are Too
`Large For Subcutaneous Administration
`28. Grint recites that the effective doses for methotrexate for autoimmune
`
`illness (e.g., rheumatoid arthritis and psoriasis) “typically range from about 1-100
`
`mg/week, more preferably from about 5-35 mg/week, and most preferably from
`
`about 10-25 mg/week.” Grint (Ex. 1003) at col. 7, lines 32-35.
`
`29. Administering the lowest “most preferable” effective dose recited in
`
`Grint – i.e., 10 mg/week – in a methotrexate concentration of about 2 mg/ml
`
`(within the range of the methotrexate concentrations recited in Grint) would
`
`require the administration of 5 ml of drug solution.
`
`30. Likewise, administering the lowest “more preferable” effective dose
`
`recited in Grint –i.e., 5 mg/week – in a methotrexate concentration of about 1
`
`mg/ml (within the range of the methotrexate concentrations recited in Grint)
`
`would also require the administration of 5 ml of solution.
`
`31. Administering the lowest effective dose recited in Grint – i.e., 1
`
`mg/week – in a methotrexate concentration of about 0.1 mg/ml (the lowest
`
`
`
`
`
`
`Page 13
`
`Page 00013
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`methotrexate concentration of the range recited in Grint) would require the
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`administration of 10 ml of solution.
`
`32. A skilled artisan as of July 21, 2006, would have understood (as I
`
`would have) that the administration of 5 ml or 10 ml of methotrexate solution was
`
`not appropriate for weekly subcutaneous injections. As I explained above in
`
`Paragraph 18, these injections are given weekly as a treatment for chronic illness,
`
`and high volumes are accordingly impractical because of the continuous burden it
`
`places on the patients receiving such injections every week and the negative effect
`
`it has on their quality of life. Ideally, subcutaneous injection volume should not
`
`exceed 1.0 ml because larger volumes were likely to cause greater discomfort to
`
`the patient.
`
`33. As I explained above in Paragraph 25, prior to July 21, 2006 and even
`
`through today, I have never, and I know of no one else who has, administered
`
`subcutaneous methotrexate to treat rheumatoid arthritis and other inflammatory
`
`autoimmune diseases in concentrations above 25 mg/ml.
`
`34. Accordingly, the only concentration range (0.1 to 40 mg/ml) provided
`
`by Grint, when combined with the methotrexate doses disclosed therein for
`
`treating inflammatory autoimmune diseases, includes concentrations that are
`
`inappropriate for subcutaneous administration because they require drug volumes
`
`that are too large. The skilled artisan therefore would not (as I would not) consider
`
`
`
`
`
`
`Page 14
`
`Page 00014
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`that entire recited concentration range as one appropriate for subcutaneous
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`administration.
`
`2.
`
`Administration Of Methotrexate At The Concentrations
`Recited In Grint Requires Drug Volumes That Are Too
`Small And Too Risky For Subcutaneous Administration
`35. As explained above (Paragraph 21), Grint recites the parenteral
`
`administration of methotrexate at a concentration “from about 0.1 to about 40
`
`mg/ml”. Grint also recites that the effective doses for methotrexate “typically
`
`range from about 1-100 mg/week, more preferably from about 5-35 mg/week, and
`
`most preferably from about 10-25 mg/week.” Grint (Ex. 1003) at col. 7, lines 32-
`
`35.
`
`36. Administering the lowest effective dose recited in Grint – i.e., 1
`
`mg/week – in a methotrexate concentration of about 40 mg/ml (the highest
`
`methotrexate concentration of the range recited in Grint) would require the
`
`administration of 0.025 ml of solution
`
`37. Administering the lowest effective dose recited in Grint – i.e., 1
`
`mg/week – in a methotrexate concentration of about 20 mg/ml (within the range of
`
`methotrexate concentration recited in Grint) would require the administration of
`
`0.05 ml of solution.
`
`38. A skilled artisan would have found, as I have in my own experience,
`
`that these drug volumes of 0.05 ml and 0.025 ml are too small to reliably and
`
`
`
`
`
`
`Page 15
`
`Page 00015
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`practicably draw into syringes and inject or self-inject for subcutaneous
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`administration. The risk of a misdraw and resulting in an inaccurate dose, such as
`
`an overdose, would be high.
`
`39. For example, as described above in Paragraph 36, patients receiving 1
`
`mg/week in a methotrexate concentration of about 40 mg/ml would require 0.025
`
`ml of methotrexate weekly. But an overdraw of only 0.025 ml for that patient
`
`would result in administering twice as much weekly methotrexate as intended.
`
`That, in turn, would likely result in unacceptable side effects for patients, including
`
`gastrointestinal side effects (nausea, diarrhea, vomiting), bone marrow
`
`suppression, hair loss and central nervous system side effects.
`
`40. Accordingly, the only concentration range (0.1 to 40 mg/ml) provided
`
`by Grint, when combined with the methotrexate dosing ranges disclosed therein
`
`for treating inflammatory autoimmune diseases, includes concentrations that are
`
`inappropriate for subcutaneous administration because they require drug volumes
`
`that are too small to reliably and practicably draw into syringes and inject or self-
`
`inject for subcutaneous administration. The skilled artisan would not consider (as I
`
`would not) the entire recited concentration range as one appropriate for
`
`subcutaneous administration.
`
`41.
`
`In sum, the skilled artisan reading Grint as of July 21, 2006 would not
`
`have understood the recitation in Grint of methotrexate administered “parenterally”
`
`
`
`
`
`
`Page 16
`
`Page 00016
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`at “from about 0.1 to about 40 mg/ml” to indicate that methotrexate could be
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`administered subcutaneously or intramuscularly at concentrations greater than 30
`
`mg/ml. Rather, the skilled artisan, similar to myself, would have understood from
`
`Grint that the parenteral mode of administration utilizing methotrexate at
`
`concentrations greater than 30 mg/ml would have been intravenous and not
`
`subcutaneous or intramuscular.
`
`VI. THE SKILLED ARTISAN WOULD NOT UNDERSTAND MEXATE
`AS TEACHING OR SUGGESTING THE SUBCUTANEOUS OR
`INTRAMUSCULAR ADMINISTRATION OF METHOTREXATE AT
`A CONCENTRATION OF MORE THAN 30 MG/ML FOR THE
`TREATMENT OF INFLAMMATORY AUTOIMMUNE DISEASE
`A. The Skilled Artisan Would Have Chosen A Single-Dose Vial Of
`Mexate® That Most Closely Matched The Dose Needed For The
`Disease State To Be Treated
`42. The skilled artisan as of July 21, 2006 would not understand Mexate
`
`(Ex. 1007) as an à la carte menu of disease states, modes of administration,
`
`dosages, and drug concentrations to be mixed and matched at will. Rather, the
`
`skilled artisan would consider those disease states, modes of administration,
`
`dosages, and drug concentrations and then identify reasonable combinations in
`
`view of the knowledge and practice in the art.
`
`43. For example, Mexate indicates that the product is Mexate® “FOR
`
`INJECTION”. Mexate also explains, however, that the dosage schedule for
`
`psoriasis chemotherapy using Mexate® “FOR INJECTION” includes “weekly
`
`
`
`
`
`
`Page 17
`
`Page 00017
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`oral,” “divided dose intermittent oral schedule over a 36-hour period,” and “daily
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`oral with a rest period.” Mexate (Ex. 1007) at 3, 5. Notwithstanding these
`
`instructions, the skilled artisan based on his or her experience would not use
`
`Mexate® “FOR INJECTION” for oral administration.
`
`44. Similarly, it was known as of July 21, 2006 that high doses of
`
`methotrexate were used to treat cancer and low doses of methotrexate were used to
`
`treat inflammatory autoimmune diseases, such as psoriasis or rheumatoid arthritis.
`
`The ‘231 Patent (Ex. 1001) at col. 1, lines 24-32 and 56-60; Weinblatt (1993) (Ex.
`
`1018) at 3.
`
` Mexate itself notes that “METHOTREXATE HAS BEEN
`
`ADMINISTERED IN VERY HIGH DOSAGE … IN EXPERIMENTAL
`
`TREATMENT OF CERTAIN NEOPLASTIC DISEASES.” Mexate (Ex. 1007)
`
`at 3.
`
`45. Consistent with that knowledge, Mexate indicates that methotrexate
`
`should be used to treat lymphomas in doses of 0.625 to 2.5 mg/kg per day. Mexate
`
`(Ex. 1007) at 5. Accordingly, this would translate to an average 70 kg adult
`
`receiving between 43.75 and 175 mg of methotrexate daily. Similarly, Mexate
`
`recites that methotrexate should be administered twice weekly at a dose of 30
`
`mg/M2 for treating leukemia. Id. The average adult body surface area is 1.7 M2.
`
`See, e.g., Aschenbrenner (Ex. 2024) at 24. Accordingly, this would translate to the
`
`
`
`
`
`
`Page 18
`
`Page 00018
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`average adult leukemia patient receiving about 51 mg of methotrexate twice
`
`Attorney Docket No.
`110670-0010-651
`
`
`
`
`weekly.
`
`46. By contrast, Mexate indicates that the average 70 kg adult should
`
`receive 10 to 25 mg per week of methotrexate for psoriasis chemotherapy – i.e., far
`
`less than for cancers like lymphomas and leukemias. Mexate (Ex. 1007) at 5. It
`
`further indicates that 50 mg per week should ordinarily not be exceeded for the
`
`treatment of psoriasis, psoriasis being the only inflammatory autoimmune disease
`
`listed in Mexate. Id. In my experience, however, 50 mg per week methotrexate
`
`doses are never used for the treatment of psoriasis.
`
`47. Accordingly, the skilled artisan would have recognized that the 50,
`
`100 and 250 mg single-dose vials would be used for the treatment of lymphoma,
`
`which according to Mexate requires administration of 43.75 to 175 mg
`
`methotrexate daily. Similarly, the skilled artisan would select the 50 mg or 100 mg
`
`single-dose vial for the treatment of leukemia (51 mg of methotrexate twice
`
`weekly). And, the skilled artisan would have selected (as I would have) the 20 mg
`
`or 50 mg single-dose vial for the treatment of psoriasis (10 to 25 mg per week of
`
`methotrexate, not to exceed 50 mg per week).
`
`
`
`
`
`
`Page 19
`
`Page 00019
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`B.
`
`The Skilled Artisan Would Have Understood That Not All Single-
`Dose Vials Of Mexate® Could Be Reconstituted At Volumes
`Required For Subcutaneous Or Intramuscular Injection
`48. Even with the selection of a 20 mg or 50 mg single-dose vial of
`
`Mexate® for the treatment of psoriasis, the skilled artisan as of July 21, 2006 would
`
`recognize (as I do) that these single-dose vials were not appropriate at all levels of
`
`reconstitution for preparing doses for subcutaneous or intramuscular injection for
`
`the treatment of psoriasis or other inflammatory autoimmune diseases.
`
`49. For example, Mexate recites reconstituting the single-dose vial with
`
`from 2 to 10 ml of Sterile Water Sterile Water for Injection, USP, 0.9% Sodium
`
`Chloride Injection, USP, or Bacteriostatic Water for Injection, USP with Parabens
`
`or Benzyl Alcohol.
`
`50. Using 10 ml to reconstitute the 20 mg or 50 mg single-dose vial of
`
`Mexate® would result in concentrations of 2 mg/ml and 5 mg/ml, respectively. To
`
`administer the 10-25 mg per week dose for psoriasis, the skilled artisan would have
`
`had to administer 5 to 12.5 ml of the 2 mg/ml solution or 2 to 5 ml of the 5 mg/ml
`
`solution. Further, in my experience, subcutaneous and intramuscular injection
`
`volume should not exceed 1.0 ml because larger volumes are likely to cause
`
`greater discomfort to the patient.
`
`
`
`
`
`
`Page 20
`
`Page 00020
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`C. The Skilled Artisan Would Have Chosen A Single-Dose Vial Of
`Mexate® To Minimize Waste
`51. Mexate indicates that Mexate® is available in 20, 50, 100, and 250 mg
`
`single-dose vials. Mexate (Ex. 1007) at 3. A skilled artisan would understand that
`
`single-dose vials should not be administered to multiple patients or saved for later
`
`use. See, e.g., 2007 CDC Guidelines (Ex. 2020) at 84. In other words, any unused
`
`drug in a single-dose vial should be discarded. Accordingly, the skilled artisan, as
`
`I would, would have chosen a single-dose vial that most closely matched the dose
`
`needed for the patient’s disease state.
`
`52. The skilled artisan would also have wanted, as I do in my practice, to
`
`minimize wasting drug to avoid paying for drug that is never administered to a
`
`patient. Based on the psoriasis dosages in Mexate, the use of one or two 20 mg
`
`single-dose vials to administer the 10-25 mg Mexate® dosage for psoriasis would
`
`generate 10-15 mg of wasted drug; use of a 50 mg single-dose vial would generate
`
`25-40 mg of wasted drug; use of a 100 mg single-dose vial would generate 75-90
`
`mg of wasted drug (more than three times the amount that was administered); and
`
`use of a 250 mg single-dose vial would generate 225-240 mg of wasted drug (at
`
`least nine times, and as much as twenty-four times, the amount that was
`
`administered).
`
`
`
`
`
`
`Page 21
`
`Page 00021
`
`
`
`IPR2016-00649
`U.S. Patent No. 8,664,231
`
`
`
`
`
`Attorney Docket No.
`110670-0010-651
`
`53. For this reason, given the choice of a 20 mg vial, a 50 mg vial, a 100
`
`mg vial and a 250 mg vial, the skilled artisan would select (as I would have in my
`
`practice) either the 20 mg vial or the 50 mg vial for administration of 10 to 25 mg
`
`of Mexate® for the treatment of psoriasis to avoid excessive waste associated with
`
`selection of the larger vials.
`
`D. The Skilled Artisan Would Have Used The Lowest Available
`Concentration Of A Single-Dose Vial Of Methotrexate To Reduce
`Risk Of An Inaccurate Dose, Such As An Overdose
`54. As of July 21, 2006, the skilled artisan would (as I would) also have
`
`selected the lowest available concentration of a single-dose vial to minimize the
`
`risk of any inaccurate dose, such as an overdose, that could occur. By increasing
`
`the concentration of drug reconstituted from a single-dose vial, a clinician or a self-
`
`administering patient could run the risk of extracting too much drug and
`
`inadvertently overdosing the patient or extracting too little drug and inadvertently
`
`underdosing the patient. The skilled artisan would have recognized, as I do, that
`
`this risk is minimized if the concentration of methotrexate in the single-dose vial is
`
`at or under the