UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`FRONTIER THERAPEUTICS, LLC
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`
`
`Patent Owner
`
`____________________
`
`
`Inter Partes Review Case No. Unassigned
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`____________________
`
`
`
`DECLARATION OF DAVID C. GAMMON, BSPh
`
`
`
`
`
`
`
`____________________
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________________
`
`FRONTIER THERAPEUTICS, LLC
`
`Petitioner
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE
`SPEZIALPRÄPARATE MBH
`
`
`Patent Owner
`
`____________________
`
`
`Inter Partes Review Case No. Unassigned
`Patent No. 8,664,231
`Title: Concentrated Methotrexate Solutions
`
`____________________
`
`
`
`DECLARATION OF DAVID C. GAMMON, BSPh
`
`
`
`
`
`
`
`
`
`TABLE OF CONTENTS
`
`U.S. Patent No. 8,664,231
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`II. MY EXPERIENCE AND QUALIFICATIONS ............................................. 1
`
`III. MATERIALS REVIEWED ............................................................................ 3
`
`IV. THE ’231 PATENT ......................................................................................... 4
`
`V.
`
`PERSON OF ORDINARY SKILL IN THE ART .......................................... 6
`
`VI. CLAIM CONSTRUCTION ............................................................................ 6
`
`A.
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`Claims of the ‘231 Patent ...................................................................... 7
`
`“pharmaceutically acceptable solvent” ................................................. 7
`
`“injection device” .................................................................................. 8
`
`“ready-made syringe” ............................................................................ 9
`
`“pen injector” ...................................................................................... 10
`
`VII. BACKGROUND REGARDING MTX SOLUTIONS AND
`DEVICES FOR THEIR INJECTION ........................................................... 11
`
`VIII. CERTAIN REFERENCES DISCLOSE OR SUGGEST THE
`FEATURES RECITED IN THE ‘231 PATENT CLAIMS .......................... 14
`
`A. Grint .................................................................................................... 14
`
`B.
`
`C.
`
`Insulin Admin. ..................................................................................... 16
`
`The PDR .............................................................................................. 19
`
`D. Hospira ................................................................................................ 22
`
`IX. CONCLUSION ............................................................................................. 24
`
`
`
`ii
`
`
`
`
`
`I.
`
`INTRODUCTION
`
`U.S. Patent No. 8,664,231
`
`1.
`
`I, David C. Gammon, have been retained by Frontier Therapeutics,
`
`LLC (“Petitioner”) 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. MY EXPERIENCE AND 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.
`
`5.
`
`From 2010-2015, I practiced as a Clinical Pharmacy Specialist in the
`
`Women and Infants Hospital in Providence, Rhode Island.
`
`1
`
`
`
`
`
`6.
`
`My work included the preparation of chemotherapy and cytotoxic
`
`U.S. Patent No. 8,664,231
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`drugs for treating patients. As part of my work, I compounded these drugs for
`
`injection, which would include formulating varying concentrations of these active
`
`ingredients for injection. I have over twenty years of 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 was 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 with a Bachelor of Science in Pharmacy. I owned and operated a pharmacy in
`
`Douglasville, Georgia from 1982 to 1993. During this time, I compounded
`
`2
`
`
`
`
`
`pharmaceuticals (taking active and inactive ingredients and combining them into
`
`U.S. Patent No. 8,664,231
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`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 $300 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 35 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).
`
`4) Hoekstra et al. (2004) J. Rheumatol. 31(4): 645-648
`(“Hoekstra”) (Ex. 1004).
`
`3
`
`
`
`
`
`U.S. Patent No. 8,664,231
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`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) Mü ller-Ladner (2010) The Open Rheumatology Journal, 4:15-
`22. (“Mü ller-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
`
`4
`
`
`
`
`
`the prior art preparations described above.” Ex. 1001 at col. 2:53-65. These
`
`U.S. Patent No. 8,664,231
`
`disadvantages allegedly 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
`
`5
`
`
`
`
`
`graduating with a degree in pharmacy prior to 2006, would be able to make
`
`U.S. Patent No. 8,664,231
`
`varying concentrations of injectable products, including methotrexate.
`
`V.
`
`PERSON OF ORDINARY 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
`
`6
`
`
`
`U.S. Patent No. 8,664,231
`
`
`
`been informed by the prosecution history of the ’231 patent.
`
`A. Claims of the ‘231 Patent
`
`i. “pharmaceutically acceptable solvent”
`
`20.
`
`Independent claim 1 recites methotrexate in a “pharmaceutically
`
`acceptable solvent.” Ex. 1001 at 8:46.
`
`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
`
`7
`
`
`
`
`
`include water, in particular water for injection purposes, water comprising
`
`U.S. Patent No. 8,664,231
`
`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.
`
`ii. “injection device”
`
`24. Dependent claims 8, 9, 14, 19, 20 recite an “injection device.” Ex.
`
`1001 9:1-3, 4-5, 15-18; 10:8-11, 14-17.
`
`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 35 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
`
`8
`
`
`
`
`
`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.
`
`U.S. Patent No. 8,664,231
`
`iii. “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
`
`’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, lines 30 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
`
`9
`
`
`
`
`
`U.S. Patent No. 8,664,231
`
`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.
`
`
`iv. “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.”
`
`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, and column 7, lines 5-12, excerpted below:
`
`10
`
`
`
`
`
`U.S. Patent No. 8,664,231
`
`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
`
`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., PDR (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
`
`11
`
`
`
`
`
`(Ex. 1009) at § 2 “Qualitative and Quantitative Composition.” A pharmacist or
`
`other person experienced in formulating pharmaceutical solutions for injection
`
`U.S. Patent No. 8,664,231
`
`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 an
`
`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 “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 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 and my own experience with
`
`12
`
`
`
`
`
`MTX, there is nothing unique about the properties of MTX that would make it
`
`U.S. Patent No. 8,664,231
`
`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 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
`
`13
`
`
`
`
`
`known from the prior art” and “[s]uch injection devices are well known in the art
`
`U.S. Patent No. 8,664,231
`
`[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.
`
`VIII. CERTAIN REFERENCES DISCLOSE OR SUGGEST THE
`FEATURES RECITED IN THE ‘231 PATENT CLAIMS
`
`A. 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
`
`14
`
`
`
`
`
`autoimmune diseases. See e.g., Ex. 1003 at 2:23-24; 3:4-5; 5:64; 6:66-7:1
`
`U.S. Patent No. 8,664,231
`
`(“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
`
`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
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`a suitable pharmaceutically acceptable carrier in dosage unit form as hereintofore
`
`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 have
`
`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
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`ampule, or carpule, as recited in claim 13 of the ’231 patent.
`
`46. Grint further teaches that “[a] unit dosage form can, for example,
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`contain methotrexate in amounts ranging from about 0.1 to 400 mg.” Id. at 6:52-
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`66.
`
`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, propylene glycol, and liquid polyethylene glycol and the like), suitable
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`15
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`
`
`
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`mixtures thereof, and vegetable oils.” Ex. 1003 at 6:11-15. Grint further teaches
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`that in preparing MTX compositions, it may be advantageous to formulate such
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`U.S. Patent No. 8,664,231
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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.
`
`B.
`
`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, and based on that date, I am aware that it is prior art to the ’231 patent. I
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`have also been informed that it was not considered during prosecution of the ’231
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`patent.
`
`49.
`
`Before self-administering devices were available, patients receiving
`
`drugs by injection had to visit a clinic for the preparation and administration of
`
`medicaments by medical staff. I have 22 years of experience formulating drugs for
`
`injection in outpatient clinics. Thus, I recognize that the development of injection
`
`devices for self-administration, such as ready-made syringes and pen-injectors,
`
`alleviated the inconvenience and cost of injections administered at clinics by
`
`medical staff.
`
`16
`
`
`
`
`
`50.
`
`Self-administration of injectable medicaments has become a
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`U.S. Patent No. 8,664,231
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`preferred method for treating certain diseases, including those requiring chronic
`
`treatment. For example, Insulin Admin. states that “[w]henever possible, insulin
`
`should be self-administered by the patient.” Ex. 1015 at S124. Self-administration
`
`improves compliance, benefits the patient and clinic by saving time, and reduces
`
`the costs associated with travel and having to staff a healthcare professional at a
`
`clinic to administer injections. Insulin Admin. also teaches that “[t]he syringes may
`
`be prefilled periodically by a relative, friend, home health aide, or visiting nurse
`
`and the dose may be self-injected.” Id. A person of skill in the art, knowing the
`
`advantages of self-administration of insulin, would be motivated to formulate
`
`MTX for self-administration to aid with patient compliance and convenience,
`
`particularly because MTX is used chronically to treat diseases such as rheumatoid
`
`arthritis and psoriasis.
`
`51.
`
`Self-administration of injectables became even easier with the
`
`introduction of pen injectors and ready-made syringes. Ready-made syringes and
`
`pen injectors have been marketed at least since the late 1980s. For example, Insulin
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`Admin. discloses the self-administration of insulin by using an injection device
`
`such as a “penlike device” or a “prefilled syringe.” Id. at S123. Insulin Admin.
`
`further teaches that “[s]everal pen-like devices and insulin-containing cartridges
`
`are available that deliver insulin subcutaneously through a needle.” Id. And it
`
`17
`
`
`
`
`
`further states that for many patients, including “those using multiple daily injection
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`U.S. Patent No. 8,664,231
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`regimes[], these devices have been demonstrated to improve accuracy of insulin
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`administration and/or adherence.” Id. The “pen-like” device disclosed in Insulin
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`Admin. is an “injection device” and “pen injector” following the broadest
`
`reasonably construction for these terms discussed above in Section VI.A.ii. and iv.
`
`52.
`
`Insulin Admin. also discloses that some patients “may benefit from
`
`the use of prefilled syringes (e.g., the visually impaired, those dependent on others
`
`for drawing their insulin, or those traveling or eating in restaurants.)”. Id. The
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`prefilled syringe disclosed in Insulin Admin. is a “ready-made syringe” following
`
`the broadest reasonably construction for this term discussed above in Section
`
`VI.A.iii.
`
`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
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`devices such as a pen injector and ready-made syringes. Ex. 1001 at 2:26-36; 6:54-
`
`61 (“[r]eady-made syringes for parenteral administration containing methotrexate
`
`Solutions … are known from the prior art. …;” “[s]uch injection devices are well
`
`known in the art. Preferably, one such injection device is a so-called pen injector”).
`
`54.
`
`Based on my own experience, the disclosure of Insulin Admin., and
`
`the fact that the ’231 patent acknowledges that MTX solutions have been used with
`
`injection devices such as pen injectors and ready-made syringes, it is my opinion
`
`18
`
`
`
`
`
`that a person of skill in the art would want to use the higher concentration of MTX
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`U.S. Patent No. 8,664,231
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`solution, such as that disclosed in Grint, with an injection device such as the
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`prefilled syringe or “pen-like” injector disclosed in Insulin Admin., as it would
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`promote self-administration, improve patient compliance, and be more convenient
`
`for the patient, physician, and treating clinic.
`
`C. The PDR
`
`55.
`
`The PDR for Mexate® is from the 1985 edition of the Physician’s
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`Desk Reference (“PDR”)1, and based on this date, I have been informed that the
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`PDR 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
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`the product “Mexate® … (methotrexate sodium) FOR INJECTION.” Ex. 1007 at
`
`762, middle col. I have reviewed the PDR, and I am aware that Mexate® was a
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`lyophilized MTX product that is reconstituted for injection. I have been informed
`
`that the PDR was not considered by the Examiner during prosecution of the ’231
`
`patent.
`
`
`
`1 The PDR is an annually published reference compiling package inserts for
`prescription drugs. A person skilled in formulating pharmaceutical drugs would
`have been familiar with the PDR.
`
`19
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`
`
`56.
`
`The PDR discloses “parenteral” administration of the Mexate®
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`U.S. Patent No. 8,664,231
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`product, including by intramuscular injection to treat a variety of diseases,
`
`including psoriasis. Id. at 764, middle col. 57.
`
`57.
`
`The PDR further discloses that vials containing 20, 50, 100, or 250
`
`mg of MTX were available, and instructs reconstituting these vials with “2 to 10
`
`mls” of sterile water or sodium chloride. Id. at 762, right col.; 764, middle col. A
`
`skilled artisan would recognize that the PDR teaches MTX in vials or storage
`
`containers. A person skilled in the art of formulating pharmaceuticals for injection
`
`would have also known that reconstituting the available 20, 50, 100, or 250 mg
`
`vials with 2 mLs of diluent would result in a MTX solution having a concentration
`
`of 10, 25, 50, and 125 mg/ml, respectively. A skilled artisan would have further
`
`recognize that reconstituting the available 20, 50, 100, or 250 mg vials with 10
`
`mLs of diluent would result in a MTX solution having a concentration of 2, 5, 10,
`
`and 25 mg/ml, respectively. Therefore, it is my opinion that based on this
`
`disclosure, a person of skill in the art would understand that the PDR teaches MTX
`
`solutions having concentrations ranging between 2 and 125 mg/ml for treating
`
`psoriasis by intramuscular injection. Because the PDR reflects the FDA approved
`
`label for Mexate®, the manufacturer must have shown that using concentrations of
`
`between 2-125 mg/ml was safe and effective for treating the disclosed diseases in
`
`the test population.
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`20
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`58.
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`Th
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