UNITED STATES PATENT AND TRADEMARK OFFICE
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`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`KOIOS PHARMACEUTICALS LLC
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`Petitioner
`
`v.
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`MEDAC GESELLSCHAFT FUER KLINISCHE SPEZIALPRÄPARATE MBH
`
`Patent Owner
`____________
`
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
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`
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`Exhibit 1033
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`
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`Declaration of Dr. Donald Miller, Pharm.D
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`IPR2016-01370
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`Miller Declaration
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`Table of Contents
`I. INTRODUCTION ..................................................................................................... 1
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`II. QUALIFICATIONS ................................................................................................. 2
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`III. MATERIALS REVIEWED ........................................................................................ 5
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`IV. THE ’231 PATENT ................................................................................................ 7
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`V. LEVEL OF SKILL IN THE ART ................................................................................ 8
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`VI. CLAIM CONSTRUCTION ........................................................................................ 9
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`A. Claims of the ’231 patent ............................................................................. 9
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`1. “pharmaceutically acceptable solvent” ................................................ 10
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`2. “Injection device” ................................................................................ 11
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`3. “Ready-made syringe” ......................................................................... 12
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`4. “Pen injector” ....................................................................................... 13
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`VII. BACKGROUND REGARDING MTX SOLUTIONS AND DEVICES FOR THEIR
`INJECTION ................................................................................................................ 14
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`VIII. CERTAIN REFERENCES DISCLOSE OR SUGGEST THE FEATURES RECITED
`IN THE ’231 PATENT CLAIMS .................................................................................... 18
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`A. Grint ........................................................................................................... 18
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`B. Arthur ......................................................................................................... 22
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`C. Moitra ......................................................................................................... 24
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`D. Insulin Admin. ............................................................................................ 25
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`E. Wyeth .......................................................................................................... 28
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`F. Hoekstra and Jørgensen ............................................................................. 31
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`1. Hoekstra ............................................................................................... 31
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`2. Jørgensen ............................................................................................. 32
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`3. Hoekstra in combination with Jørgensen teaches the use of
`highly concentrated MTX solutions for subcutaneous administration ...... 32
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`IX. CONCLUSION ..................................................................................................... 34!
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`I, Dr. Donald Miller, declare the following:
`I.
`INTRODUCTION
`1.
`I have been retained by Koios Pharmaceuticals LLC
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`Miller Declaration
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`(“Petitioner”) as an independent expert consultant in this proceeding before
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`the United States Patent and Trademark Office.
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`2.
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`I understand that this proceeding involves U.S. Patent No.
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`8,664,231 (“the ’231 patent”) (Ex. 1001). I further understand that the ’231
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`patent claims priority to German Application No. DE 10 2006 033 837, filed
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`July 21, 2006. Ex. 1001 at Front Cover. I further understand that the ’231
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`patent is assigned to medac GmbH.
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`3.
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`I have been asked to provide information concerning the
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`formulation of pharmaceutical solutions containing methotrexate (“MTX”)
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`for injection by various routes of administration prior to July 2006. I have
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`also been asked to consider whether certain references disclose or suggest
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`features recited in the claims of the ’231 patent. My opinions are set forth
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`below.
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`4.
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`In forming my opinions, I have reviewed the previous
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`declaration submitted by Dr. David Gammon in support of another challenge
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`to the ’231 patent, as well as the materials cited therein, and have relied on
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`and incorporated those opinions into this declaration where appropriate. I
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`have applied my personal judgment, knowledge, and experience in
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`reviewing and incorporating those opinions, and all opinions set forth in this
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`declaration are my own. I have also reviewed and considered Medac’s
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`Preliminary Response to a challenge brought by Frontier Therapeutics, LLC,
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`and Dr. Elena Massarotti’s declaration in support of that document. I address
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`certain of the views expressed in those documents, and reserve the right to
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`address the arguments and opinions presented by Medac’s lawyers and
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`experts (and any other relevant information) further should the Board
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`institute this inter partes review.
`II. QUALIFICATIONS
`5. My curriculum vitae, which includes a detailed summary of my
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`background and experience and a list of my publications is attached as
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`Exhibit A to this Declaration.
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`6.
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`I am Professor of Pharmacy Practice at the North Dakota State
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`University School of Pharmacy, within the College of Health Professions.
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`Until 2015, I was Chairman of the Department of Pharmacy Practice at
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`NDSU. I am also Associate Faculty for the Master of Public Health program
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`at NDSU.
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`7.
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`I received my Pharm.D. from the University of Michigan and
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`my Certificate of Residency from University Hospital in Saskatoon,
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`Saskatchewan in 1978. I received a B.Sc. in Pharmacy from University of
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`Manitoba in 1976.
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`8.
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`I am member of the American College of Rheumatology, the
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`American Pharmacists Association, and the American College of Clinical
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`Pharmacy, as well as other professional institutions.
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`9.
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`Since 1995, I have been on the Editorial Advisory Board for
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`“Arthritis Today.” I am also a member of the FDA Arthritis Advisory
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`Committee. The FDA Arthritis Advisory Committee consists of twelve
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`members with expertise in arthritis, rheumatology, and related specialties.
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`The purpose of the Committee is to review and evaluate “data concerning
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`the safety and effectiveness of marketed and investigational human drug
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`products for use in the treatment of arthritis, rheumatism, and related
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`diseases,” and to make “appropriate recommendations to the Commissioner
`
`of Food and Drugs.” Ex. 1037 (FDA Arthritis Advisory Committee). More
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`specifically, as a member of the Arthritis Advisory Committee, I review the
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`efficacy and safety data submitted in support of New Drug Applications for
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`proposed arthritis medications. I also consider the appropriate safety
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`warnings and information that should be included in new arthritis drug
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`product labels, as well as appropriate changes to existing drug labels. Based
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`on this experience, I am aware that the FDA does not approve arthritis
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`medications for human administration unless it has deemed such
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`medications to be safe. I am also aware that if an FDA-approved product
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`label omits safety warnings or special administration instructions or
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`precautions, it is reasonable for one of skill in the art to assume that the FDA
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`determined that such warnings, instructions, or precautions were not
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`necessary.
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`10.
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`I have been familiar with the use of methotrexate to treat
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`rheumatoid arthritis since at least the 1980s. In 1985, I co-authored “The use
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`of methotrexate in rheumatoid arthritis” in Drug Intelligence and Clinical
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`Pharmacy, 1985;19:349-58. In 1986 I was the lead author of “Methotrexate
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`in rheumatoid arthritis: An update,” published in Pharmacotherapy, 1986;
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`4:170-78. I have also remained current regarding treatments for rheumatoid
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`arthritis throughout my career. For instance, in June 2015, I delivered a
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`lecture at the Sanford Health Rheumatology Conference titled “Drugs for
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`Managing Rheumatoid Arthritis. Efficient Medicine in Rheumatoid
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`Arthritis.” Furthermore, since November 2015 I have been a member of the
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`Committee on Rheumatologic Care of the American College of
`
`Rheumatology.
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`11. From 1983 to 2001, I worked as a clinical pharmacist, first at
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`Dakota Medical Center in Fargo and later at the VA Medical Center in
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`Fargo. This involved monitoring drug therapy and recommending or
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`implementing changes in drug orders under protocol with the medical staff.
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`From 1983 to 2001, I also participated as an investigator in several studies of
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`pharmaceutical agents for treatment of rheumatic diseases.
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`12. Although I am being compensated at my normal consulting rate
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`for the time I spend on this matter, no part of my compensation is dependent
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`on the outcome of this proceeding, and I have no other interest in this
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`proceeding.
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`13.
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`I am not an attorney and offer no legal opinions. Certain of my
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`opinions, however, are based on an understanding of the applicable legal
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`rules, and I have set forth my understanding of the law in relevant instances.
`III. MATERIALS REVIEWED
`14.
`In forming my opinions, I have relied on my nearly 40 years of
`
`experience, and reviewed the ’231 patent and the following exhibits to the
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`Petition.
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`1) U.S. 8,664,231 to Heiner Will, titled, “Concentrated
`Methotrexate Solutions,” filed on March 4, 2009, and
`issued on March 4, 2014 (“the’231 Patent”) (Ex. 1001).
`
`2) Excerpts from File History for U.S. Patent No. 8,664,231
`(Ex. 1002).
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`3) U.S. 6,544,504 to Paul Grint et al., titled, “Combined
`Use of Interleukin 10 and Methotrexate for Immuno-
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`modulatory Therapy,” filed on June 26, 2000, and issued
`on April 8, 2003 (“Grint”) (Ex. 1003).
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`4) Hoekstra et al. (2004) J. Rheumatol. 31(4):645-647
`(“Hoekstra”) (Ex. 1004).
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`5) Jørgensen et al. (1996) Ann. Pharmacother. 30:729-32
`(“Jørgensen”) (Ex. 1005).
`
`6) Declaration of Dr. Elena Massarotti, dated June 2, 2016,
`in support of Medac’s Preliminary Response in IPR2016-
`00649 (Ex. 1007).
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`7) Brooks et al. (1990) Arthritis and Rheum. 33(1):91-94
`(“Brooks”) (Ex. 1008).
`
`8) Medac’s Preliminary Response in IPR2016-00649, dated
`June 2, 2016 (Ex. 1009).
`
`9) Insulin Administration Position Statement (2003),
`Diabetes Care, 26(1) S121-S124 (“Insulin Admin.”) (Ex.
`1015).
`10) Product Label for the “Methotrexate Sodium for
`Injection” product by Wyeth, Inc., Date of First
`Authorization August 10, 1959, Date of Supplement
`Approval January 27, 2004, Obtained from Archive.org
`as of April 29, 2005 (“Wyeth”) (Ex. 1021).
`11) 2003 Ed. of Physician’s Desk Reference for
`“Methotrexate Sodium for Injection” by Wyeth
`Pharmacal, Inc. (“the PDR for Wyeth”) (Ex. 1022).
`
`12) Arthur et al. (2002) A Study of Parenteral Use of
`Methotrexate in Rheumatic Conditions, J. Clin. Nursing
`2002;11:256-263 (“Arthur”) (Ex. 1023).
`
`13) Arthur et al. (2001) Self-Injection of Gold and
`Methotrexate, J. Rheumatol. 2001;28:212 (“Arthur
`2001”) (Ex. 1024).
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`14) Moitra et al. (2005) Caveats to the use of parenteral
`methotrexate in the treatment of rheumatic disease,
`Rheumatology 2005;44:256-57 (“Moitra”) (Ex. 1025).
`IV. THE ’231 PATENT
`15. The ’231 patent is related to a method of treating inflammatory
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`autoimmune diseases by subcutaneous administration of MTX at a
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`concentration of more than 30 mg/ml.
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`16. The ’231 patent indicates that the object of the invention is to
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`provide a “pharmaceutical formulation for the treatment of inflammatory
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`autoimmune diseases, in particular rheumatoid arthritis, which overcomes
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`the disadvantages of the prior art preparations described above.” Ex. 1001 at
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`col. 2:53-65. These disadvantages include patients showing a “disapproving
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`attitude” toward subcutaneous injections of MTX due to “having to inject
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`the required relatively large amount [volume] of active substance solution
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`(e.g. up to 3 ml in the case of a certain dosage) under the skin every week,
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`which was especially difficult to convey to children, including the weekly
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`doctor’s visit.” Id. at col. 2:37-52. The inventors apparently resolved this
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`issue by using the well-known technique of increasing the concentration of
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`MTX in solution, which allows for smaller volume of liquid to be
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`administered to a patient.
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`17. The ’231 patent discloses the use of injection devices, ready-
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`made syringes, and pen injectors for the subcutaneous administration of
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`MTX. See generally Ex. 1001 at cols. 4-7. I agree with the specification of
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`the ’231 patent that injection devices, storage containers, ready-made
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`syringes and pen injectors were well known prior to July 2006. See Ex. 1001
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`at col. 4:55-65; col. 5:28-32, 54-63; col. 6:32-38, 55-64.
`
`18. The ’231 patent concludes by providing two examples of how
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`to formulate a 50 mg/ml concentration of MTX in solutions. Id. at col. 7:40
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`– col. 8:40. I have reviewed these examples and they recite nothing more
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`than well-known techniques for making concentrated solutions of
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`injectables. Anyone graduating with a degree in pharmacy would have been
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`able to make varying concentrations of injectable products, including
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`methotrexate.
`V.
`LEVEL OF SKILL IN THE ART
`19.
`In my opinion, based on my experience, a person having
`
`ordinary skill in the art with respect to the ’231 patent would have either a
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`Pharm.D. or a Ph.D. in pharmaceutical sciences, pharmacology, or a related
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`discipline; an M.D. or D.O. with experience in using oral and injectable
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`MTX to treat inflammatory autoimmune diseases; or person with a lesser
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`degree with several years of experience in formulating and/or administering
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`methotrexate for injection, such as a nurse or pharmacy technician. A person
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`of ordinary skill in the art would collaborate with others having expertise in,
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`for example, methods of treating disease and administering medicines. I
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`understand that Dr. Massarotti’s opinions on this topic are largely consistent
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`with my own.
`VI. CLAIM CONSTRUCTION
`20.
`I have been informed that the construction of a patent claim
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`applied during this proceeding may differ from that in a district court
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`proceeding.
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`21. Specifically, I have been advised that in inter partes review
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`proceedings before the U.S. Patent and Trademark Office, a patent claim
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`receives the broadest reasonable interpretation in light of the specification of
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`the patent in which it appears. I have also been advised that, at the same
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`time, claim terms are given their ordinary and accustomed meaning as would
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`be understood by one of ordinary skill in the art.
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`22.
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`I have followed these claim-construction principles in my
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`analysis set forth below. In some cases, and where so stated, my opinions
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`have additionally been informed by the prosecution history of the ’231
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`patent.
`A. Claims of the ’231 patent
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`1.
`“pharmaceutically acceptable solvent”
`Independent claim 1 recites methotrexate in a
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`23.
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`“pharmaceutically acceptable solvent.” Ex. 1001 at 8:46.
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`24. My opinion is that the broadest reasonable construction of
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`“pharmaceutically acceptable solvent” is “a solvent that is safe for
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`administration to patients, including humans, that will not interfere with the
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`active pharmaceutical substance or other component in the solution.”
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`25. My interpretation of “pharmaceutically acceptable solvent” is
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`based, in part, on my years of experience and the well-known understanding
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`that for administration of a solvent into a patient, the solvent being used
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`must be safe for administration and not adversely impact the active
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`ingredient.
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`26.
`
` This construction is consistent with the disclosure of the ’231
`
`patent, which states, “[a]ll solvents which are pharmaceutically acceptable
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`and are not incompatible with the active substance or other possible
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`components of the medicament or the pharmaceutical solution formulation
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`can be used as the pharmaceutically acceptable solvent.” Ex. 1001 at 3:28-
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`32. The ’231 patent further states that “[a]ccording to the present invention,
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`especially suitable solvents include water, in particular water for injection
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`purposes, water comprising isotonization additives and sodium chloride
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`solution, in particular isotonic sodium chloride solution.” Id. at 3:32-36. The
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`examples of suitable solvents provided in the ’231 patent are all safe for
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`administration to patients.
`2.
`“Injection device”
`27. Dependent claims 8, 9, 14, 19, 20 recite an “injection device.”
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`Ex. 1001 at 9:1-3, 4-5, 15-18; 10:8-11, 14-17.
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`28. My opinion is that the broadest reasonable construction of
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`injection device is “a device that permits a medicament to be injected into a
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`patient.”
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`29. My construction is based, in part, on my 40 years of experience
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`studying and teaching pharmaceutical solutions for injection, including all
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`types of devices for injecting pharmaceutical solutions into a patient.
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`30. Further, my construction of the term “injection device” is
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`supported by the disclosure of the ’231 patent, which states for example, at
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`column 4, lines 19 to 27:
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`In a preferred embodiment of the present invention, the
`medicament according to the present invention is
`contained in an injection device for a single application,
`in particular a ready-made syringe. According to the
`present invention, an injection device for a single
`application is a device which in addition to a vessel
`containing the pharmaceutical solution formulation
`according to the present invention comprises an injection
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`needle (hypodermic needle) through which the
`medicament can be administered to the patient.
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`See also, Ex. 1001 at 4:27-29.
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`“Ready-made syringe”
`3.
`31. Dependent claim 10, recites a “ready-made syringe.” Ex. 1001
`
`at 9:6-7.
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`32. My opinion is that the broadest reasonable construction of
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`ready-made syringe is “a device containing a medicament that permits the
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`medicament to be injected into a patient.”
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`33. This construction is based, in part, on my experience studying
`
`and teaching the use of pharmaceutical solutions for injection. Further, as the
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`’231 patent states, ready-made syringes have been known and used by
`
`skilled artisans, such as myself, since prior to at least 2006.
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`34. The ’231 patent further supports my constructions, for example,
`
`at column 4, lines 55 to 59 and column 5, paragraph 28 to 40, respectively:
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`An especially preferred example of an injection device
`for a single application according to the present invention
`is a ready-made syringe. Ready-made syringes are well-
`known in the pharmaceutical field, in particular also in
`the treatment of rheumatoid arthritis with methotrexate.
`
`Ready-made syringes are well known in the
`pharmaceutical field and are not restricted in any way in
`the present invention. Ready-made syringes according to
`the present invention for example also encompass
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`disposable injection systems such as the Uniject®
`injection system. In one embodiment, the ready-made
`syringe can already be provided with a suitable
`hypodermic needle for intravenous, intramuscular or
`subcutaneous injection; in an alternative embodiment, the
`ready-made syringe is at first provided with a rubber tip
`or the like which prior to application is replaced with a
`separately packaged sterile hypodermic needle by the
`physician, the medical staff, or, in case of self-
`application, by the patient himself.
`
`4.
`“Pen injector”
`35. Dependent claims 15 and 20 recite a “pen injector.” Ex. 1001 at
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`9:19-21; 10:12-13.
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`36. My opinion is that the broadest reasonable construction of pen
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`injector is “a device that injects a dose of medicament into a patient via a
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`powered or manually inserted hypodermic needle, wherein the device may
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`be for single use or multiple uses, and may be disposable or reusable.”
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`37. This construction is supported by my experience as a person of
`
`skill in the art, having familiarity with the literature and state of the art
`
`regarding solutions for administration via injection devices such as pen
`
`injectors. As the ’231 patent also discloses, pen injectors, such as those used
`
`by diabetic patients for insulin administration have been known in the art
`
`since prior to at least 2006. Additionally, the EpiPen® has been available for
`
`self-administration since at least the late 1980s.
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`38.
`In my opinion, the meaning of the term “pen injector” is further
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`supported by the disclosure of the ’231 patent at, for example, column 6,
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`lines 60-67, column 7, lines 5-12, excerpted below:
`
`Preferably, one such injection device is a so-called pen
`injector, into which the carpule can be inserted. Pen
`injectors usually look like large fountain pens and are in
`particular commonly used by diabetics for comfortably
`injecting the insulin dose they require. After the inserted
`carpule has been emptied, a new carpule can easily be
`inserted in the pen injector (comparable to the
`replacement of an ink cartridge in the fountain pen
`mentioned above as a comparison).
`
`
`
` …
`
` A
`
` pen injector according to the present invention is
`preferably designed such that it is suitable for the
`subcutaneous application of the active substance which
`can in particular be achieved by the provision of a
`hypodermic needle suitable for subcutaneous injection.
`Furthermore, a pen injector according to the present
`invention and the carpule contained therein are preferably
`designed such that multiple applications of single
`dosages can be carried out.
`
`VII. BACKGROUND REGARDING MTX SOLUTIONS AND DEVICES FOR
`THEIR INJECTION
`39. MTX is administered orally and in parenteral forms including
`
`intravenously, intramuscularly, and subcutaneously.
`
`40. MTX has long been available in a variety of different forms,
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`including lyophilized preparations that require reconstitution and ready-to-
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`use solutions. See e.g., Wyeth (Ex. 1021) at 24. A pharmacist or other person
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`experienced in formulating pharmaceutical solutions for injection would
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`understand, including prior to July 2006, how to formulate different
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`concentrations of drugs by varying the weight of the lyophilized drug
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`powder (i.e. in milligrams) and the volume of solvent (i.e. in milliliters).
`
`Thus, to make a more concentrated solution, such an experienced person
`
`would understand, including prior to July 2006, either to increase the amount
`
`of the drug or decrease the volume of the solvent. See Wyeth (Ex. 1021) at
`
`24 (instructing that the 1 gram vial of methotrexate “should be
`
`reconstituted with 19.4 mL to a concentration of 50 mg/mL.”) (emphasis
`
`original). This relationship is governed by a simple mathematical formula:
`
`dosage (in mg)/concentration (in mg/ml) = solution volume (in ml). The
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`making of varying concentrations of solutions for injection is taught as part
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`of all programs in pharmacy and is a common activity of pharmacists.
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`41. Based on my experience as a Professor of Pharmacy Practice, I
`
`know of nothing unique or unusual about the properties of MTX that would
`
`make it challenging to prepare a concentrated MTX solution or dissuade a
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`person of ordinary skill in the art from making a concentrated MTX solution
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`for injection. Indeed, the Wyeth product insert, which was approved by the
`
`FDA, specifically instructs those of skill in the art to formulate a
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`concentrated 50 mg/ml MTX solution for intramuscular injection by
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`reconstituting 1 mg of methotrexate with 19.4 ml of an “appropriate sterile,
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`preservative free medium.” Ex. 1021 at 24.
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`42.
`
`Injection devices, such as those used to inject MTX solutions,
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`have also been known in the art and used to administer parenteral drug
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`formulations. Injection devices, such as ready-made syringes and pen
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`injectors, are used, and have been used since before July 2006, because they
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`provide advantages to physicians, clinics, and patients. For example, the use
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`of injection devices allows patients to self-administer injectables. This
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`reduces the time a patient might have needed to take out of their daily lives
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`visiting a clinic to receive an injection. It also allows physicians and clinics
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`to devote more time to patients as they do not need to take time from their
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`practice to administer drugs. Self-administration can also aid in patient
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`compliance, as the injection devices are easy to use, and prefilled or ready-
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`made syringes ensure that a patient receives the proper dose.
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`43.
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`Indeed, patients have specifically self-administered
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`methotrexate via subcutaneous injection using pre-filled syringes and pen-
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`type injection devices since prior to 2006. See Arthur (Ex. 1023) at 259
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`(“Three pre-filled syringes in a lockable box, needles, alcohol swabs and a
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`sharps disposal box were provided and participants were discharged for a
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`month . . . [p]articipants self-administered their MTX by the SC route at
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`Miller Declaration
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`home for 3 consecutive weeks.”); id. (noting that, as of 2002, “the pen-type
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`syringe” was “commonly used for SC injections.”); Moitra (Ex. 1025) at 256
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`(“We analysed the notes of 102 of the 115 patients receiving parenteral
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`MTX for a variety of conditions in the 3 months leading up to and including
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`June 2002. Ninety-one patients were using the subcutaneous as opposed to
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`the i.m. route and of these, 77 had successfully been taught to self-inject.”).
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`And patients have long been self-administering insulin via subcutaneous
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`injection using syringes, prefilled syringes, and pen injectors. See Insulin.
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`Admin. (Ex. 1015) at S123. Accordingly, as the ’231 patent itself recognizes,
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`there was nothing novel about the use of self-injection devices to administer
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`methotrexate subcutaneously as of July 2006. Ex. 1001 at 2:26-36; 6:54-61
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`(stating “[r]eady-made syringes for parenteral administration containing
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`methotrexate solutions . . . are known from the prior art” and “[s]uch
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`injection devices are well known in the art . . . [where] one such injection
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`device is a so-called pen injector.”).
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`44. Due to the experience and success with subcutaneous self-
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`administration of methotrexate and insulin with various injection devices
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`discussed in the previous paragraph, a person of ordinary skill in the art prior
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`to 2006 had the incentive and technical ability to formulate a highly
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`concentrated MTX solution and also formulate or package that solution so
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`Miller Declaration
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`that it could be self-administered subcutaneously by an injection device such
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`as a ready-made syringe or pen injector. As noted in the previous paragraph,
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`the literature demonstrates that methotrexate was already being
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`subcutaneously self-administered using various injection devices prior to
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`2006. And Wyeth demonstrates the FDA had approved a highly concentrated
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`MTX solution for parenteral administration via injection devices prior to
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`July 2006. Ex. 1021. I have not seen anything in the ’231 patent, its
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`prosecution history, or in the literature indicating that there was a technical
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`hurdle to placing the highly concentrated MTX solutions disclosed in Grint
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`(discussed in the next paragraph) or Wyeth into the subcutaneous self-
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`administration devices taught by Arthur, Moitra, and Insulin Admin. Based
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`on my experience and the literature, no such technical hurdle existed.
`VIII. CERTAIN REFERENCES DISCLOSE OR SUGGEST THE FEATURES
`RECITED IN THE ’231 PATENT CLAIMS
`A. Grint
`45. Grint is U.S. Patent No. 6,544,504 entitled “Combined Use of
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`Interleukin 10 and Methotrexate for Immunomodulatory Therapy.” Grint
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`issued on April 8, 2003 (Ex. 1003, Front page), and based on this date, I
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`have been informed that Grint is prior art to the ’231 patent.
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`46. Grint teaches the subcutaneous administration of MTX at
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`Miller Declaration
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`concentrations greater than 30 mg/ml for the treatment of inflammatory
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`autoimmune diseases. See e.g., Ex. 1003 at 2:23-24; 3:4-5; 5:64; 6:66-7:1
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`(“Expressed in proportions, methotrexate is generally present in from about
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`0.1 to about 40 mg/ml of carrier.”); 7:56-57 (“The dose of MTX was 12.5-25
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`mg/week (oral, subcutaneous or intramuscular)[.]”). Grint also teaches that
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`“methotrexate in amounts ranging from . . . 1 to 35 mg [is] preferred, and 10
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`to 25 [mg is] most preferred.” Id. at 6:64-66. And Grint clarifies that
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`methotrexate should be “compounded for convenient and effective
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`administration in effective amounts with a pharmaceutically acceptable
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`carrier . . . .” Id. at 6:60-62. Based on these disclosures, a skilled artisan with
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`experience formulating MTX for injection would have understood, prior to
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`July 2006, how to pair a MTX concentration within the range disclosed by
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`Grint with a desired and appropriate dosage in order to yield a solution
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`volume that is “convenient” and “effective” for administration. For instance,
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`a skilled artisan would have understood that the 35 mg/ml concentration
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`disclosed in Grint allows the administration of a 35 mg dose of MTX
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`(within the “preferred” dosage range disclosed by Grint) using 1 ml of
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`solution, which would be both convenient and effective. By contrast, a
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`skilled artisan would have further understood that it would be inconvenient
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`and ineffective to use a 40 mg/ml concentration to administer 1 mg of MTX,
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`Miller Declaration
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`as this would require a 0.025 ml solution, which cannot be accurately drawn
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`and administered. Accordingly, I disagree with Dr. Massarotti’s reasoning
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`and conclusions that the skilled artisan would not have understood Grint to
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`disclose the subcutaneous administration of MTX in concentrations of 30
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`mg/ml or more. See Ex. 1007 ¶¶ 28-41. Although a high concentration might
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`be unsuitable in terms of convenience for a small dose such as 1 mg, it is
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`well suited to larger, more typical doses such as Grint’s 10-25 mg range. As
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`noted earlier, a skilled artisan would understand and manage the basic
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`mathematical relationship that dosage (in mg)/concentration (in mg/ml) =
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`solution volume (in ml). I also disagree with the arguments made by
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`Medac’s lawyers that Grint’s teaching regarding MTX concentrations is
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`limited to the “conventional practice,” which Medac describes as a
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`concentration of no more than 25 mg/ml. Ex. 1009 at 28. The reference to
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`“conventional practice” in Grint relates to dosage administration forms (such
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`as oral tablets and gel caps), and not MTX concentrations. Compare Ex.
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`1003 at 5:21-42 and 6:60-7:1. Moreover, prior to July 2006 the FDA had
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`approved an injectable methotrexate product in a 50 mg/ml MTX
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`concentration, see Wyeth (Ex. 1021) and the PDR for Wyeth (Ex. 1022).
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`47. Grint discloses that it may be beneficial to formulate parenteral
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`Miller Declaration
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`MTX compositions “in dosage unit form for case [sic, ease] of
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`administration and uniformity of dosage.” Grint (Ex. 1003) at 6:52-54. Grint
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`also discloses “[m]ethotrexate is compounded . .