Paper No. __
`Filed: July 1, 2014
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`
`
`
`ANTARES PHARMA, INC., LEO PHARMA A/S and LEO PHARMA INC.,
`
`
`Petitioners
`
`v.
`
`MEDAC GESELLSCHAFT FUER KLINISCHE SPEZIALPRÄPARATE MBH
`
`Patent Owner
`
`____________
`
`Case No.: Not yet assigned
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`
`DECLARATION OF DAVID C. GAMMON, BSPh
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`Page 1 of 29
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`KOIOS Exhibit 1013
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`

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`Patent No. 8,664,231
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`Table of Contents
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`I. 
`
`Introduction .................................................................................................................... 3 
`
`II.  Qualifications ................................................................................................................. 3 
`
`III.  Materials Reviewed ........................................................................................................ 5 
`
`IV.  The ’231 Patent .............................................................................................................. 6 
`
`V. 
`
`Level of Skill in the Art ................................................................................................. 8 
`
`VI.  Claim Construction ....................................................................................................... 8 
`
`A. 
`
`Claims of the ’231 Patent .................................................................................. 8 
`
`1. 
`
`2. 
`
`3. 
`
`4. 
`
`“pharmaceutically acceptable solvent”................................................ 8 
`
`“Injection device” .................................................................................. 9 
`
`“Ready-made syringe” ......................................................................... 10 
`
`“Pen injector” ....................................................................................... 11 
`
`VII.  Background Regarding MTX Solutions and Devices for Their Injection .......... 13 
`
`VIII.  Certain References Disclose or Suggest the Features Recited in the ’231
`Patent Claims ................................................................................................................ 16 
`
`B. 
`
`C. 
`
`D. 
`
`Grint .................................................................................................................... 16 
`
`Insulin Admin. .................................................................................................... 17 
`
`The PDR for Mexate® ......................................................................................... 20 
`
`E.  Hospira ................................................................................................................ 23 
`
`F. 
`
`Hoekstra and Jørgensen ........................................................................................ 25 
`
`1. 
`
`2. 
`
`Hoekstra .................................................................................................. 25 
`
`Jørgensen ................................................................................................... 26 
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`Patent No. 8,664,231
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`3. 
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`Hoekstra in combination with Jørgensen teaches the use of
`highly concentrated MTX solutions for subcutaneous
`administration ....................................................................................... 26 
`
`IX.  Conclusion .................................................................................................................... 28 
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`Patent No. 8,664,231
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` I, David C. Gammon, declare the following:
`
`I.
`
`Introduction
`1.
`
`I have been retained by Antares Pharma, Inc., Leo Pharma A/S and Leo
`
`Pharma Inc. (“Petitioners”) as an independent expert consultant in this proceeding
`
`before the United States Patent and Trademark Office.
`
`2.
`
`I understand that this proceeding involves U.S. Patent No. 8,664,231
`
`(“the ’231 patent”) (Ex. 1001). I further understand that the ’231 patent claims
`
`priority to German Application No. DE 10 2006 033 837.5, filed July 21, 2006. Ex.
`
`1001 at Front Cover. I further understand that the ’231 patent is assigned to medac
`
`GmbH.
`
`3.
`
`I have been asked to provide information concerning the formulation of
`
`pharmaceutical solutions containing methotrexate (“MTX”) for injection by various
`
`routes of administration prior to July 2006. I have also been asked to consider
`
`whether certain references disclose or suggest the features recited in the claims of the
`
`’231 patent. My opinions are set forth below.
`
`II. Qualifications
`4. My curriculum vitae, which includes a detailed summary of my
`
`background and experience and a list of my publications and patents is attached as
`
`Exhibit 1032.
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`3
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`Patent No. 8,664,231
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`5.
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`Since 2010, I have been a Clinical Pharmacy Specialist in the Woman
`
`and Infants Hospital in Providence, Rhode Island.
`
`6.
`
`In my current position, my work includes the preparation of
`
`chemotherapy and cytotoxic drugs for treating patients. As part of my work, I
`
`compound these drugs for injection, which would include formulating varying
`
`concentrations of these active ingredients for injection. I have over twenty years’
`
`experience in the preparation and oversight of chemotherapy agents such as
`
`methotrexate (with respect to methotrexate, I have compounded the active ingredient
`
`from lyophilized powder for injection), mitomycin, and monoclonal antibodies for
`
`oncology, rheumatology, ophthalmology, and dermatology in both inpatient and
`
`outpatient clinics. I have been preparing and dispensing pharmaceutical solutions for
`
`administration by injection since 1982. Further, I have been dispensing injection
`
`devices, for instance the EpiPen®, since at least the late 1980s.
`
`7.
`
`Prior to joining the Woman and Infants Hospital, I worked as a
`
`consultant pharmacist at the University of Massachusetts Medical School from 2009
`
`to 2010 and a pharmacology instructor there from 2005 to 2011. I was a clinical
`
`pharmacist at UMass Memorial Hospital from 1999 to 2009 where I also served as a
`
`Pharmacist Investigator and a member of the Children’s Oncology Group, a national
`
`cooperative organization.
`
`8.
`
`I graduated from the University of Georgia School of Pharmacy in 1981
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`with a Bachelor of Science in Pharmacy. I owned and operated a pharmacy in
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`
`
`4
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`Patent No. 8,664,231
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`Douglasville, Georgia from 1982 to 1993. During this time, I compounded
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`pharmaceuticals (taking active and inactive ingredients and combining them into
`
`pharmaceutically elegant final dosage forms acceptable to patients). For example, I
`
`formulated varying concentrations of oral solutions, suppositories, ointments, and
`
`capsules.
`
`9.
`
`Although I am being compensated at my rate of $400 per hour for the
`
`time I spend on this matter, no part of my compensation is dependent on the
`
`outcome of this proceeding, and I have no other interest in this proceeding.
`
`10.
`
`I am not an attorney and offer no legal opinions, but in the course of my
`
`work, I have had experience studying and analyzing patents and patent claims from
`
`the perspective of a person skilled in the art.
`
`III. Materials Reviewed
`11.
`In forming my opinions, I have relied on my 33 years of experience, and
`
`I have reviewed the ’231 patent, its prosecution history, and particularly the following
`
`exhibits to the Petition.
`
`1) U.S. 8,664,231 to Heiner WILL, titled, “Concentrated
`Methotrexate Solutions,” filed on March 4, 2009, and issued on
`March 4, 2014 (“the ’231 Patent”) (Ex. 1001).
`2) Excerpts from File History for U.S. Patent No. 8,664,231. (Ex.
`1002).
`3) U.S. 6,544,504 to Paul GRINT et al., titled, “Combined Use of
`Interleukin 10 and Methotrexate for Immunomodulatory
`Therapy,” filed on Jun. 26, 2000, and issued on April 8, 2003
`(“Grint”) (Ex. 1003).
`
`
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`5
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`Patent No. 8,664,231
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`4) Hoekstra et al. (2004) J. Rheumatol 31(4):645-648 (“Hoekstra”)
`(Ex. 1004).
`5) Jørgensen et al. (1996) Ann Pharmacother 30:729-32 (“Jørgensen”)
`(Ex. 1005).
`6) 1985 Ed. Physician’s Desk Reference for Mexate® (“the PDR for
`Mexate®”) (Ex. 1007).
`7) Brooks et al. (1990) Arthritis and Rheum. 33(1):91-94 (“Brooks”)
`(Ex. 1008).
`8) Hospira (“Hospira”) (Ex. 1009).
`9) Zackheim (1992) J. Am. Acad. of Derm. 23(6) p. 1008.
`(“Zackheim”) (Ex. 1010).
`10) Müller-Ladner (2010) The Open Rheumatology Journal 4:15-22.
`(“Müller-Ladner”) (Ex. 1011).
`11) Pincus et al. (2003) Methotrexate as the “anchor drug” for the
`treatment of early rheumatoid arthritis 21:S179-S185 (“Pincus”)
`(Ex. 1014).
`12) Insulin Administration Position Statement(2003), Diabetes Care,
`26(1) 5121-5124 (“Insulin Admin.”) (Ex. 1015).
`13) Weinblatt (1993) “Methotrexate,” in Textbook of Rheumatology,
`4th Edition, Chapter 47, (Kelley et al., eds. 1993) (“Weinblatt
`1993”) (Ex. 1018).
`14) Hoffmeister (1993) Methotrexate therapy in rheumatoid arthritis:
`15 years experience. Am J Med 75:69-73 (“Hoffmeister 1993”) (Ex.
`1019).
`IV. The ’231 Patent
`12. The ’231 patent is related to a method of treating inflammatory
`
`autoimmune diseases by subcutaneous administration of MTX at a concentration of
`
`more than 30 mg/ml.
`
`13. The ’231 patent indicates that the object of the invention is to provide a
`
`“pharmaceutical formulation for the treatment of inflammatory autoimmune diseases,
`
`in particular rheumatoid arthritis, which overcomes the disadvantages of the prior art
`
`
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`Patent No. 8,664,231
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`preparations described above.” Ex. 1001 at col. 2:53-65. These disadvantages include
`
`patients showing a “disapproving attitude” toward subcutaneous injections of MTX
`
`due to “having to inject the required relatively large amount [volume] of active
`
`substance solution (e.g. up to 3 ml in the case of a certain dosage) under the skin
`
`every week, which was especially difficult to convey to children, including the weekly
`
`doctor’s visit.” Id. at col. 2:37-51. The inventors apparently resolved this issue by
`
`using the well-known technique of increasing the concentration of MTX in solution,
`
`which allows for a smaller volume of liquid to be administered to a patient.
`
`14. The ’231 patent discloses the use of injection devices, ready-made
`
`syringes, and pen injectors for the subcutaneous administration of MTX. See generally
`
`Ex. 1001 at cols. 4-7. I agree with the specification of the ’231 patent that injection
`
`devices, storage containers, ready-made syringes and pen injectors were well known
`
`prior to July 2006. See Ex. 1001 at col. 4:55-65; col. 5:28-32, 54-63; col. 6:32-38, 55-
`
`64.
`
`15. The ’231 patent concludes by providing two examples of how to
`
`formulate a 50 mg/ml concentration of MTX in solution. Id. at col. 7:40 - col. 8:40. I
`
`have reviewed these examples and they recite nothing more than well-known
`
`techniques for making concentrated solutions of injectables. In fact, anyone
`
`graduating with a degree in pharmacy prior to 2006, would be able to make varying
`
`concentrations of injectable products, including methotrexate.
`
`
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`Patent No. 8,664,231
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`V.
`
`Level of Skill in the Art
`16.
`
`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 Pharm. D. or a Ph.D. in
`
`pharmacy, pharmacology, or a related discipline; an M.D. or D.O. with experience in
`
`using MTX; or a BS in pharmacy or an equivalent degree with at least two years’
`
`experience formulating active pharmaceutical ingredients for injection.
`
`VI. Claim Construction
`17.
`I have been informed that the construction of a patent claim applied
`
`during this proceeding may differ from that in a district court proceeding.
`
`18.
`
`Specifically, I have been advised that in inter partes review proceedings
`
`before the U.S. Patent and Trademark Office, a patent claim receives the broadest
`
`reasonable interpretation in light of the specification of the patent in which it appears.
`
`I have also been advised that, at the same time, claim terms are given their ordinary
`
`and accustomed meaning as would be understood by one of ordinary skill in the art.
`
`19.
`
`I have followed these claim-construction principles in my analysis set
`
`forth below. In some cases, and where so stated, my opinions have additionally been
`
`informed by the prosecution history of the ’231 patent.
`
`A.
`
`20.
`
`Claims of the ’231 Patent
`1.
`Independent claim 1 recites methotrexate in a “pharmaceutically
`
`“pharmaceutically acceptable solvent”
`
`acceptable solvent.” Ex. 1001 at 8:46.
`
`
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`21. My opinion is that the broadest reasonable construction of
`
`“pharmaceutically acceptable solvent” is “a solvent that is safe for administration to
`
`patients, including humans, that will not interfere with the active pharmaceutical
`
`substance or other component in the solution.”
`
`22. My interpretation of “pharmaceutically acceptable solvent” is based, in
`
`part, on my years of experience formulating injectable drugs, and the well-known
`
`understanding that for administration of a solvent into a patient, the solvent being
`
`used must be safe for administration and not adversely impact the active ingredient.
`
`23. This construction is consistent with the disclosure of the ’231 patent,
`
`which states, “[a]ll solvents which are pharmaceutically acceptable and are not
`
`incompatible with the active substance or other possible components of the
`
`medicament or the pharmaceutical solution formulation can be used as the
`
`pharmaceutically acceptable solvent.” Ex. 1001 at 3:28-32. The ’231 patent further
`
`states that “[a]ccording to the present invention, especially suitable solvents include
`
`water, in particular water for injection purposes, water comprising isotonization
`
`additives and sodium chloride solution, in particular isotonic sodium chloride
`
`solution.” Id. at 3:32-36. The examples of suitable solvents provided in the ’231
`
`patent are all safe for administration to patients.
`
`2.
`“Injection device”
`24. Dependent claims 8, 9, 14, 19, 20 recite an “injection device.” Ex. 1001
`
`at 9:1-3, 4-5, 15-18; 10:8-11, 14-17.
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`25. My opinion is that the broadest reasonable construction of injection
`
`device is “a device that permits a medicament to be injected into a patient.”
`
`26. My construction is based, in part, on my 33 years of experience
`
`formulating and dispensing pharmaceutical solutions for injection, including all types
`
`of devices for injecting pharmaceutical solutions into a patient.
`
`27.
`
`Further, my construction of the term “injection device” is supported by
`
`the disclosure of the ’231 patent, which states for example, at column 4, lines 19 to 27:
`
`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 needle
`(hypodermic needle) through which the medicament can be
`administered to the patient.
`
`See also, Ex. 1001 at 4:27-29.
`3.
`“Ready-made syringe”
`28. Dependent claim 10, recites a “ready-made syringe.” Ex. 1001 at 9:6-7.
`
`29. My opinion is that the broadest reasonable construction of ready-made
`
`syringe is “a device containing a medicament that permits the medicament to be
`
`injected into a patient.”
`
`30. This construction is also based, in part, on my extensive experience
`
`formulating and dispensing pharmaceutical solutions for injection. Further, as the
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`
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`Patent No. 8,664,231
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`’231 patent states, ready-made syringes have been known and used by skilled artisans,
`
`such as myself, since at least 2006.
`
`31. The ’231 patent further supports my constructions for example, at
`
`column 4, lines 55 to 59 and column 5, paragraph 28 to 40, respectively:
`
`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 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”
`32. Dependent claims 15 and 20 recite a “pen injector.” Ex. 1001 at 9:19-
`
`21; 10:12-13.
`
`33. My opinion is that the broadest reasonable construction of pen injector
`
`is “a device that injects a dose of medicament into a patient via a powered or manually
`
`inserted hypodermic needle, wherein the device may be for single use or multiple uses,
`
`and may be disposable or reusable.”
`
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`34. This construction is supported by my experience as a person of skill in
`
`the art, having formulated and dispensed 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 at least 2006. Additionally, as discussed above at ¶ 6, the EpiPen® has been
`
`available for self-administration since at least the late 1980s.
`
`35.
`
`In my opinion, the meaning of the term “pen injector” is further
`
`supported by the disclosure of the ’231 patent, at for example column 6, 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.
`
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`Patent No. 8,664,231
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`VII. Background Regarding MTX Solutions and Devices for Their Injection
`36. MTX is administered orally and parenterally (intravenously,
`
`intramuscularly, and subcutaneously). I have compounded or manipulated MTX in
`
`various concentrations for use in various diseases, including cancer, RA, and psoriasis
`
`since before 2006.
`
`37. MTX is available in a variety of different forms, including lyophilized
`
`preparations that require reconstitution and MTX ready-to-use solutions. See e.g., the
`
`PDR for Mexate (Ex. 1007) at 762, right col. (“Mexate [MTX] for Injection is available
`
`in 20, 50, 100, and 250 mg single dose vials of lyophilized sterile powder, containing
`
`no preservatives, to be administered parenterally.”); Hospira (Ex. 1009) at § 2
`
`“Qualitative and Quantitative Composition.” A pharmacist or other person
`
`experienced in formulating pharmaceutical solutions for injection would understand
`
`how to formulate different concentrations of drugs by varying the weight of the
`
`lyophilized drug powder (i.e. in milligrams) and volume of solvent (i.e. in milliliters).
`
`Thus to make a more concentrated solution, such experienced person would
`
`understand to either increase the weight of the drug or decrease the volume of the
`
`solvent. Making varying concentrations of solutions for injection is taught as part of
`
`all programs in Pharmacy, and is a common activity of pharmacists.
`
`38.
`
`In fact, lyophilized MTX products available before 2006 specifically
`
`teach a person of ordinary skill in the art that the concentration of the MTX solution
`
`can be varied. The PDR for Mexate® indicates that the MTX for intramuscular injection
`
`
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`Patent No. 8,664,231
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`can be “reconstituted with 2 to 10 ml of Sterile Water for Injection, USP, 0.9%
`
`Sodium Chloride Injection, USP, or Bacteriostatic Water for Injection, USP with
`
`Paraben or Benzyl Alcohol.” Ex. 1007 at 764, middle col. Using different volumes of
`
`solution to reconstitute the lyophilized MTX would result in different concentrations
`
`of the MTX solution.
`
`39. Moreover, MTX solutions are stable. Here again, the PDR for Mexate®,
`
`teaches that “mexate for injection is stable for four weeks at room temperature (25 C)
`
`at concentrations of 2 to 125 mg/ml in Sterile Water for Injection.” Ex. 1007 at 764,
`
`middle col. In my opinion, based on at least the PDR for Mexate® and my own
`
`experience with MTX, there is nothing unique about the properties of MTX that
`
`would make it challenging to formulate a highly concentrated MTX solution or
`
`dissuade a person of ordinary skill in the art from making a highly concentrated MTX
`
`solution for injection.
`
`40.
`
`Injection devices, such as those used to inject MTX solutions, have also
`
`been known in the art and used to administer parenteral drug formulations. Injection
`
`devices, such as ready-made syringes and pen injectors, are used because they provide
`
`advantages to physicians, clinics and patients. For example, the use of injection
`
`devices allows patients to self-administer injectables. This reduces the time a patient
`
`might have needed to take out of their daily lives visiting a clinic to receive an
`
`injection. It also allows physicians and clinics to devote more time to patients as they
`
`do not need to take time from their practice to administer drugs. Self-administration
`
`
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`Patent No. 8,664,231
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`can also aid in patient compliance, as the injection devices are easy to use, and
`
`prefilled or ready-made syringes ensure that a patient receives the proper dose.
`
`41. An example of the benefits of using injection devices for the self-
`
`administration of injectable drugs can be seen from the use of insulin to treat diabetes.
`
`Patients have been self-administering insulin via subcutaneous injection using
`
`syringes, prefilled, syringes, and pen injectors since prior to 2006. See Insulin. Admin.
`
`(Ex. 1015) at S123. Indeed, the ’231 patent states “[r]eady-made syringes for
`
`parenteral administration containing methotrexate solutions…are known from the
`
`prior art” and “[s]uch injection devices are well known in the art [where] one such
`
`injection device is a so-called pen injector”. Ex. 1001 at 2:26-36; 6:54-61.
`
`42. Due to the experience and success with self-administration of insulin
`
`with injection devices, a person of ordinary skill in the art prior to 2006 had the
`
`incentive and technical ability to formulate a highly concentrated MTX solution and
`
`also formulate or package that solution so that it could be administered by an
`
`injection device such as a ready-made syringe or pen injector. Moreover, I have not
`
`seen anything in the ’231 patent, its prosecution history, or in the literature indicating
`
`that there was a technical hurdle in formulating a highly concentrated MTX solution
`
`or using such a solution in an injection device.
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`Patent No. 8,664,231
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`VIII. Certain References Disclose or Suggest the Features Recited in the ’231
`Patent Claims
`B. Grint
`43. Grint is U.S. Patent No. 6,544,504 entitled “Combined Use of
`
`Interleukin 10 and Methotrexate for Immunomodulatory Therapy.” Grint issued on
`
`April 8, 2003 (Ex. 1003, Front Cover), and based on this date, I have been informed
`
`that Grint is prior art to the ’231 patent. I am also aware that the PTO did not
`
`consider Grint during prosecution of the ’231 patent.
`
`44. Grint teaches the subcutaneous administration of MTX at concentrations
`
`greater than 30 mg/ml for the treatment of inflammatory autoimmune diseases. See
`
`e.g., Ex. 1003 at 2:23-24; 3:4-5; 5:64; 6:66-7:1 (“Expressed in proportions,
`
`methotrexate is generally present in from about 0.1 to about 40 mg/ml of carrier.”);
`
`7:56-57 (“The dose of MTX was 12.5-25 mg/week (oral, subcutaneous, or
`
`intramuscular)[.]”).
`
`45. Grint discloses that it may be beneficial to formulate parenteral MTX
`
`compositions “in dosage unit form for case [sic, ease] of administration and
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`uniformity in dosage.” Id. at 6:52-54. Grint also discloses “[m]ethotrexate is
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`compounded for convenient and effective administration in effective amounts with a
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`suitable pharmaceutically acceptable carrier in dosage unit form as hereintofore
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`disclosed.” Id. at 6:60-64. Grint discloses that the “carrier” can be a solvent. Id. at
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`6:42-43. Based on this disclosure, a person of ordinary skill in the art would
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`Patent No. 8,664,231
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`understand that the concentrated MTX solution of Grint would be stored in a
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`container, which could include for example, an injection bottle, vial, bag, glass ampule,
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`or carpule, as recited in claim 13 of the ’231 patent.
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`46. Grint further teaches that “[a] unit dosage form can, for example, contain
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`methotrexate in amounts ranging from about 0.1 to 400 mg.” Id. at 6:52-66.
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`47. Grint discloses that MTX may be formulated with “a solvent or
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`dispersion medium containing… water, ethyl alcohol, polyol (for example, glycerol,
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`propylene glycol, and liquid polyethylene glycol and the like), suitable mixtures
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`thereof, and vegetable oils.” Ex. 1003 at 6:11-15. Grint further teaches that in
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`preparing MTX compositions, it may be advantageous to formulate such
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`compositions with “isotonic agents, for example, sugars or sodium chloride.” Ex.
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`1003 at 6:22-24. Thus a person of skill in the art would read Grint as teaching a
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`solution of methotrexate in a pharmaceutically acceptable solvent than can include
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`water or sodium chloride and further that the sodium chloride may be an isotonic
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`sodium chloride solution as recited in claims 1, 4, and 17.
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`C. Insulin Admin.
`48.
`Insulin Administration (“Insulin Admin.”) (Ex. 1015 ) is a Position
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`Statement published by the American Diabetes Association. It was published in 2003,
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`and based on that date, I am aware that it is prior art to the ’231 patent. I have also
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`been informed that it was not considered during prosecution of the ’231 patent.
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`49. Before self-administering devices were available, patients receiving drugs
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`by injection had to visit a clinic for the preparation and administration of
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`medicaments by medical staff. I have 21 years of experience formulating drugs for
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`injection in outpatient clinics. Thus, I recognize that the development of injection
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`devices for self-administration, such as ready-made syringes and pen-injectors,
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`alleviated the inconvenience and cost of injections administered at clinics by medical
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`staff.
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`50.
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`Self-administration of injectable medicaments has become a preferred
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`method for treating certain diseases, including those requiring chronic treatment. For
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`example, Insulin Admin. states that “[w]henever possible, insulin should be self-
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`administered by the patient.” Ex. 1015 at S124. Self-administration improves
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`compliance, benefits the patient and clinic by saving time, and reduces the costs
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`associated with travel and having to staff a healthcare professional at a clinic to
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`administer injections. Insulin Admin. also teaches that “[t]he syringes may be prefilled
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`periodically by a relative, friend, home health aide, or visiting nurse and the dose may
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`be self-injected.” Id. A person of skill in the art, knowing the advantages of self-
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`administration of insulin, would be motivated to formulate MTX for self-
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`administration to aid with patient compliance and convenience, particularly because
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`MTX is used chronically to treat diseases such as rheumatoid arthritis and psoriasis.
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`51.
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`Self-administration of injectables became even easier with the
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`introduction of pen injectors and ready-made syringes. Ready-made syringes and pen
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`injectors have been marketed at least since the late 1980s. For example, Insulin Admin.
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`discloses the self-administration of insulin by using an injection device such as a “pen-
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`like device” or a “prefilled syringe.” Id. at S123. Insulin Admin. further teaches that
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`“[s]everal pen-like devices and insulin-containing cartridges are available that deliver
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`insulin subcutaneously through a needle.” Id. And it further states that for many
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`patients, including “those using multiple daily injection regimes[],these devices have
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`been demonstrated to improve accuracy of insulin administration and/or adherence.”
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`Id. The “pen-like” device disclosed in Insulin Admin. is an “injection device” and “pen
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`injector” following the broadest reasonably construction for these terms discussed
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`above in Section VI.A.2 and 4.
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`52.
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`Insulin Admin. also discloses that some patients “may benefit from the
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`use of prefilled syringes (e.g., the visually impaired, those dependent on others for
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`drawing their insulin, or those traveling or eating in restaurants.)”. Id. The prefilled
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`syringe disclosed in Insulin Admin. is a “ready-made syringe” following the broadest
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`reasonably construction for this term discussed above in Section VI.A.3.
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`53. The ’231 patent itself discloses that it was well known in the art that
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`MTX solutions for parenteral administration may be formulated into injection devices
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`such as a pen injector and ready-made syringes. Ex. 1001 at 2:26-36; 6:54-61
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`(“[r]eady-made syringes for parenteral administration containing methotrexate
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`solutions…are known from the prior art….;” “[s]uch injection devices are well known
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`in the art. Preferably, one such injection device is a so-called pen injector”).
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`54. Based on my own experience, the disclosure of Insulin Admin., and the
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`fact that the ’231 patent acknowledges that MTX solutions have been used with
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`injection devices such as pen injectors and ready-made syringes, it is my opinion that a
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`person of skill in the art would want to use the higher concentration of MTX
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`solution, such as that disclosed in Grint, with an injection device such as the prefilled
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`syringe or “pen-like” injector disclosed in Insulin Admin., as it would promote self-
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`administration, improve patient compliance, and be more convenient for the patient,
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`physician, and treating clinic.
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`D. The PDR for Mexate®
`55. The PDR for Mexate® is from the 1985 edition of the Physician’s Desk
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`Reference (“PDR”)1, and based on this date, I have been informed that the PDR for
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`Mexate® is prior art to the ’231 patent. The provided PDR pages 762-764 comprise a
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`reprint of the “full text of the latest Official Package Circular dated July 1984” for the
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`product “Mexate®…(methotrexate sodium) FOR INJECTION.” Ex. 1007 at 762,
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`middle col. I have reviewed the PDR for Mexate®, and I am aware that Mexate® was a
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`lyophilized MTX product that is reconstituted for injection. I have been informed
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`that the PDR for Mexate® was not considered by the Examiner during prosecution of
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