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