Trials@uspto.gov
`571-272-7822
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`Paper 7
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` Entered: January 6, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`ANTARES PHARMA, INC., LEO PHARMA A/S AND
`LEO PHARMA INC.,
`Petitioner,
`
`v.
`
`MEDAC GESELLSCHAFT FÜER KLINISCHE
`SPEZIALPRÄPARATE MBH.,
`Patent Owner.
`____________
`
`Case IPR2014-01091
`Patent 8,664,231 B2
`____________
`
`Before TONI R. SCHEINER, ERICA A. FRANKLIN, and
`JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.
`
`FRANKLIN, Administrative Patent Judge.
`
`DECISION
`Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`

`

`
`
`IPR22014-010991
`
`
`Patennt 8,664,2331 B2
`
`
`
`TRODUC
`
`II.
`TION
`IN
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`
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`Antares Pharma, Innc., Leo Phharma A/SS and Leo PPharma Incc.
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`(colllectively, ““Petitioner””) filed a PPetition reqquesting ann inter parttes review
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`of cllaims 1–222 of U.S. Paatent No. 88,664,231 BB2 (Ex. 10001, “the ’2231
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`patennt”). Papeer 1 (“Pet.””). Medac Gesellschaaft für klinnische
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`Spezzialpräparaate mbH (“Patent Owwner”) filedd a Prelimi
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`Petittion. Paperr 6 (“Prelimm. Resp.”)).
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`We havee jurisdiction under 335 U.S.C. §§ 314, whi
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`ch providees that an
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`interr partes revview may nnot be instituted “unlless . . . theere is a reaasonable
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`likellihood that the petitiooner wouldd prevail wwith respectt to at leastt 1 of the
`35 U.S.C.
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`claimms challengged in the petition.”
` § 314(a).
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` Upon connsidering
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`the PPetition andd Preliminnary Response, we deetermine thhat Petitionner has
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`showwn a reasonnable likeliihood that it would pprevail in shhowing thee
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`unpaatentabilityy of claims 1–22. Acccordingly,, we instituute an interr partes
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`revieew of thosee claims.
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`nary Respoonse to thee
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`invoolving the ’231 patentt, titled meedac Pharmma, Inc. v. AAntares Phharma, Incc,
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`A.
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`Relaated Proceeedings
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`Petitionner and Pateent Ownerr identify oone district
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`court actioon
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`No. 1:14-cv-011498-JBS-KKMW (D.NN.J.). Pet.. 1; Paper 55, 2.
`B.
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`The ’2331 Patent ((Ex. 1001)
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`The ’231 patent relates to a mmethod forr treating innflammatoory
`auto
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`immune diiseases, such as rheummatoid arthhritis, juveenile rheummatoid
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`arthrritis, or psooriasis, commprising addministerinng subcutaaneously a
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`an 30 mg/mml of
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`conccentrated mmethotrexatte solutionn comprisinng more th
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`methhotrexate. Ex. 1001, Abstract. Methotrexxate is an eeffective cyytostatic
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`ell known for treatin
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`agennt that is w
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`2
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`g breast caancer, leukkemia in chhildren, andd
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`psoriasis. Id. at 1:24–30. “Over the years, methotrexate has become the
`gold standard in the treatment of rheumatoid arthritis.” Id. at 2:34–36. As a
`basic therapeutic for rheumatoid arthritis, methotrexate is administered once
`a week, orally or parenterally. Id. at 64–67.
`The invention is also directed to a ready-made syringe and carpule
`containing the methotrexate solution, as well as a pen-injector comprising
`the ready-made syringe and/or carpule. Id. at 1:10–13. Preparing
`methotrexate, including drawing it up in a syringe from a bottle, is subject to
`strict restrictions, such as requiring the preparation to occur within a suitable
`venting system. Id. at 2:7–17.
`Previously, ready-made syringes were developed to avoid the step of
`preparing a methotrexate solution for injection. Id. at 2:18–19.) The ’231
`patent states, “[f]or the first time, the applicant in the present invention was
`able to have such ready-made syringes for subcutaneous application
`approved throughout Europe.” Id. at 2:19–22. These ready-made syringes
`may be administered by the physician, medical staff, or by the patient as a
`self-application, without requiring any preparation of the injection. Id. at
`22–25.
`According to the Specification, the claimed invention provides a
`concentrated methotrexate solution for subcutaneous administration that
`allows a smaller volume of the solution to be injected, thereby overcoming
`the pain associated with subcutaneously injecting larger amounts of solution,
`e.g., up to 3 ml. Id. at 2:44–60.
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`3
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`
`Illustrative Claim
`C.
`Claim 1 of the ’231 patent, the only independent claim, is illustrative
`and is reproduced below:
`1. A method for the treatment of inflammatory autoimmune
`diseases in a patient in need thereof, comprising subcutaneously
`administering
`to said patient a medicament comprising
`methotrexate in a pharmaceutically acceptable solvent at a
`concentration of more than 30 mg/ml.
`
`
`
`The Prior Art
`D.
`Petitioner relies upon the following prior art references:
`US 6,544,504 B1, issued Apr. 8, 2003
`
`Grint
`
`Ex. 1003
`
`Ex. 1015
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`
`
`Ex. 1006
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`
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`Ex. 1007
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`Ex. 1009
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`Ex. 1008
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`
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`Insulin Admin.
`
`Alsufyani
`
`The PDR
`
`Hospira
`
`Brooks
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`American Diabetes Assn., Insulin Admin.,
`26 DIABETES CARE Supp. 1, S121–S124
`(2003).
`
`Alsufyani et al., The Role of Subcutaneous
`Adm. of Methotrexate in Children with
`Juvenile Idiopathic Arthritis Who Have
`Failed Oral Methotrexate,
`31:1 J. RHEUMATOLOGY 179–82 (2003).
`
`Edward R. Barnhart, Physicians’ Desk
`Reference (39th ed. 1985).
`
`Hospira UK Ltd, Product Summary for
`Methotrexate 100mg/ml Injection (Rev.
`2005)
`
`Brooks et al., Pharmacokinetics of
`Methotrexate Adm. by Intramuscular and
`Subcutaneous Injections in patients with
`Rheumatoid Arthritis, 33 ARTHRITIS AND
`RHEUMATOLOGY 91–94 (1990).
`
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`4
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`

`IPR2014-01091
`Patent 8,664,231 B2
`
`Hoekstra
`
`Jorgensen
`
`Hoekstra et al., Bioavailability of Higher
`Dose Methotrexate Comparing Oral and
`Subcutaneous Admin. in Patients with
`Rheumatoid Arthritis, 31:4 J.
`RHEUMATOLOGY 645–648 (2004).
`
`Jorgensen et al., Pain Assessment of
`Subcutaneous Injections, 30 ANN.
`PHARMACOTHERAPY 729–32 (1996).
`
`Ex. 1004
`
`
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`Ex. 1005
`
`
`Petitioner also relies upon the declarations of Dr. Michael E.
`Weinblatt (Ex. 1012) and Dr. David C. Gammon (Ex. 1013).
`E.
`The Asserted Grounds of Unpatentability
`Petitioner challenges the patentability of claims 1–22 of the ’231
`patent on the following grounds:
`
`References
`Grint
`
`Basis
`§ 102(b)
`
`Claims Challenged
`1, 2, 4–6, 11–13, 17, and 22
`
`Grint and Insulin Admin.
`
`§ 103(a)
`
`7–10, 14–16, and 19–21
`
`Grint and Alsufyani
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`§ 103(a)
`
`18
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`§ 103(a)
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`1–5, 11–13, 17, and 22
`
`§ 103(a)
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`7–10, 14–16, and 19–21
`
`§ 103(a)
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`1–6, 11–13, 17, and 22
`
`§ 103(a)
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`7–10, 14–16, and 19–21
`
`§ 103(a)
`
`18
`
`The PDR or Hospira and
`Brooks
`The PDR or Hospira, Brooks,
`and Insulin Admin.
`Hoekstra and Jorgensen
`
`Hoekstra, Jorgensen, and
`Insulin Admin.
`Hoekstra, Jorgensen, and
`Alsufyani
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`5
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`

`

`
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`IPR22014-010991
`
`
`Patennt 8,664,2331 B2
`
`
`
`ANALYSSIS
`II.
`
`A.
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`Claaim Constrruction
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`In an intter partes rreview, thee Board intterprets claaim terms iin an
`n in light
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`constructioasonable cbroadest reang to the bent accordinunexxpired pate
`37 C.F.R.
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`of thhe specificaation of thee patent in which theey appear.
`
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`§ 42.100(b). UUnder that standard, aand absent
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`any speciaal definitioons, we
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`give
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`claim termms their orddinary andd customaryy meaningg, as wouldd be
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`undeerstood by one of orddinary skilll in the art
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`at the timee of the invvention.
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`
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`In ree Translogiic Tech., Innc., 504 F.3d 1249, 11257 (Fed.
`
`Cir. 2007)). Any
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`speccial definitiions for claaim terms mmust be seet forth withh reasonabble clarity,
`
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`delibberateness,, and precission. In ree Paulsen,
`(Fed.
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`
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`30 F.3d 14475, 1480
`
`Cir. 1994).
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`Petitioneer discussees the meanning of fivee claim terrms, explaiining that
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`thesee terms aree “presumeed to take oon their orddinary andd customaryy meaning
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`that they wouldd have to oone of ordi
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`nary skill iin the art.”” Pet. 9–100. For
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`exammple, Petitiioner asserrts that “suubcutaneouusly” meanns “under thhe skin.”
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`Id. aat 9. Patentt Owner dooes not proopose any ddifferent c
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`onstructionns for the
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`claimms terms, bbut clarifies that “subbcutaneoussly,” i.e., “uunder the sskin,” is
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`distinct from “intramuscuular” or “inntravenouss.” Prelim.. Resp. 20.. We agreee
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`withh Patent Owwner, as “inntramuscullar” is not
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`simply un
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`der the skiin, but in a
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`musccle, and “inntravenouss” is in a veein.
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`In view of our analysis, we ddetermine tthat construuction of thhe
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`remaaining claimm terms is not necesssary for puurposes of tthis Decisiion.
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`6
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`
`B. Anticipation by Grint (Ex. 1003)
`Petitioner asserts that Grint anticipates claims 1, 2, 4–6, 11–13, 17,
`and 22of the ’231 patent. Pet. 15. Patent Owner opposes Petitioner’s
`assertion. Prelim. Resp. 20.
`
`1.
`
`Grint
`
`Grint discloses a method for controlling autoimmune diseases,
`including rheumatoid arthritis and psoriasis, by administering a combination
`of methotrexate and interleukin 10. Ex. 1003, 1:14–18. This combination
`therapy causes a synergistic suppression of T cell proliferation, such that
`methotrexate can be used in lower amounts, “thereby avoiding or reducing
`the serious side effects normally associated with the use of this drug.” Id. at
`2:44–65. According to Grint, methotrexate and interleukin 10 may be
`administered either at the same time, or at different times during the course
`of a common treatment schedule. Id. at 3:14–22. Methotrexate may be
`administered orally, intraperitoneally, or parenterally, e.g. subcutaneously or
`intramuscularly. Id. at 3:25, 64–65, 5:54–59. Grint teaches that it is
`especially advantageous to formulate parenteral compositions in dosage unit
`form, i.e., physically discrete units suited as unitary dosages. Id. at 6:52–55.
`For example, a unit dosage form can contain methotrexate from 0.1 to about
`40 mg/ml of carrier. Id. at 6:60–7:1.
`2. Analysis
`
`Patent Owner asserts that “Grint does not disclose each and every
`
`element of the ’231 patent’s method claims ‘arranged as in the claim.’”
`Prelim. Resp. 22. Specifically, Patent Owner asserts that Grint does not
`“correlate treating a specific disease with a specific route of administration,
`
`
`
`
`7
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`a specific concentration of medicament, and a specific dose.” Id. at 23.
`According to Patent Owner, Grint discloses treating patients with the
`conventional 12.5 to 25 mg of methotrexate weekly by oral, subcutaneous,
`and intramuscular routes of administration, but contains no description
`regarding the methotrexate concentration that is used in these diverse routes
`of administration. Id.
`Most relevant to Patent Owner’s contentions, independent claim 1
`recites “subcutaneously administering . . . a medicament comprising
`methotrexate . . . at a concentration of more than 30 mg/ml.” Claim 2,
`which depends from claim 1, recites that the methotrexate concentration is
`“more than 30 mg/ml to 100 mg/ml.” Claim 12, which depends from claims
`1 and 11, recites that the medicament is contained in a storage container,
`which “contains a total dosage amount of 5 to 5,000 mg.” Claim 22, which
`depends from claim 1, recites that the methotrexate concentration is “from
`40 mg/ml to 80 mg/ml.” Other claims challenged in the anticipation ground
`relate to acceptable solvents, diseases to be treated, and the storage
`container.
`To the extent that combining disclosures in Grint may be involved in
`meeting the claim limitations, such disclosures are related directly to each
`other by the teachings of that reference. Petitioner points us to where Grint
`discloses a method for treating inflammatory autoimmune diseases in a
`patient, including rheumatoid arthritis, comprising administering a
`medication comprising methotrexate in a pharmaceutically acceptable
`solvent. Pet. 15; Ex. 1003, 1:14–18. In particular, Petitioner points us to
`where Grint discloses a treatment method that involves administering
`methotrexate parenterally, including subcutaneously, from a unit dosage
`
`
`
`
`8
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`form containing methotrexate at a concentration of more than 30 mg/ml, i.e.,
`0.1 to about 40 mg/ml of carrier. Pet. 15–16; Ex. 1003, 3:25, 64–65, 5:54–
`59, 6:60–7:1. Based on such descriptions, contrary to Patent Owner’s
`assertion, we are persuaded that Petitioner reasonably establishes that Grint
`correlates treatment of a specific disease with a specific route of
`administration (subcutaneous) and use of a specific concentration range of a
`methotrexate solution.
`With respect to dosage, the claims at issue for this anticipation ground
`do not recite administering “a specific dose.” Rather, for example,
`dependent claim 12 recites that “the storage container contains a total dosage
`amount of 5 to 5,000 mg.” Petitioner has shown that Grint discloses a unit
`dosage form containing a total dosage amount overlapping this range, i.e.,
`“0.1-400 mg, with from 1 to 35 mg being preferred, and 10 to 25 being most
`preferred.” Pet. 21; Ex. 1003, 6:52–66.
`Patent Owner asserts that when reading Grint “[o]ne of skill in the art
`would have understood that the lower end of the dosage and concentration
`ranges—not the full range—applied to subcutaneous administration.”
`Prelim. Resp. 25. To support this assertion, Patent Owner relies on Grint’s
`reference to Goodman1 as disclosing manners by which methotrexate
`administration is conventionally practiced. Id. at 24; Ex. 1003, 5:22–23.
`According to Patent Owner, because Goodman does not disclose
`subcutaneous administration of methotrexate, and teaches that
`“administration of [methotrexate] in high dosages may be extremely
`
`
`
` 1
`
` Ex. 2006, GOODMAN AND GILMAN’S, THE PHARMACOLOGICAL BASIS OF
`THERAPEUTICS 1299 (7th ed 1985).
`
`
`
`9
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`

`IPR2014-01091
`Patent 8,664,231 B2
`
`dangerous and should be performed only by experienced chemotherapists,”
`the skilled worker would not understand that all of the disclosed dosages and
`concentration ranges of methotrexate could be used for all routes of
`administration or to treat all diseases. Prelim. Resp. 24–25 (quoting Ex.
`2006, 1266–7).
`As previously discussed, Patent Owner’s argument concerning
`administered dosages is misplaced as the claims at issue do not recite
`administering any specific dosages. With respect to the concentration of
`methotrexate, based on the record before us, we are not persuaded by Patent
`Owner’s conclusory statement that a skilled artisan would have understood
`that only the lower end of Grint’s disclosed concentration range for a
`parenteral unit dosage form would have applied to a subcutaneous injection.
`Prelim. Resp. 25.
`Thus, based on the information presented at this stage of the
`proceeding, we are persuaded that Petitioner has shown a reasonable
`likelihood of establishing sufficiently that each limitation of claims 1, 2, 4–
`6, 11–13, 17, and 22 is disclosed by Grint. Pet. 15–22.
`Accordingly, we determine that Petitioner has established a
`reasonable likelihood that it would prevail in showing that Grint anticipates
`claims 1, 2, 4–6, 11–13, 17, and 22 of the ’231 patent.
`C. Obviousness over Grint (Ex. 1003) and Insulin Admin. (Ex. 1015)
`Petitioner asserts that dependent claims 7–10, 14–16, and 19–21 are
`obvious over Grint in view of Insulin Admin. Pet. 22. Patent Owner
`opposes Petitioner’s assertion. Prelim. Resp. 28–29.
`
`
`
`
`
`10
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`
`1. Insulin Admin.
`Insulin Admin. is a position statement by the American Diabetes
`Association addressing issues regarding the use of conventional insulin
`administration in the self-care of an individual with diabetes. Ex. 1015,
`S121. The article explains that several pen-like devices and insulin-
`containing cartridges are available that deliver insulin subcutaneously
`through a needle. Id. at S123. These devices have been shown to improve
`accuracy of insulin administration and/or adherence. Id. The article also
`explains that certain individuals, such as those dependent on others for
`drawing their insulin, may benefit from using prefilled syringes. Id.
`2. Analysis
`Claim 7 requires the medicament comprising methotrexate of
`independent claim 1 to be “present in a form suitable for patient self-
`administration.” Claims 8 and 9 specifically require the medicament to be
`contained in an injection device for a single application, while claim 10
`further requires the injection device to be a ready-made syringe, and claim
`20 requires the injection device to be a pen injector. Claims 14–16, 19, and
`21 recite additional limitations relating to the medication storage, the
`injection device and the dosages per application administered by the device.
`Petitioner asserts that Grint discloses methods for treating
`inflammatory autoimmune diseases by administering subcutaneous
`injections of concentrated methotrexate, as discussed with respect to the
`anticipation ground. Pet. 22. Petitioner acknowledges, however, that Grint
`does not expressly disclose that its methotrexate is packaged in a form
`suitable for self-administration, such as an injection device. Id. According
`to Petitioner, packaging medications in forms suitable for self-
`
`
`
`
`11
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`administration, such as being contained in an injection device for a single
`application, or prepared as a ready-made syringe, were known in the art
`prior to the claimed invention. Id. In support of this assertion, Petitioner
`relies on Insulin Admin. as disclosing the use of a “pen-like device,” i.e., an
`injection device or a pen injector, and the use of a “prefilled syringe,” i.e., a
`“ready-made syringe” for self-administration of insulin. Id. at 23; Ex. 1015,
`S121, S123.
`Petitioner further relies on Declarations of Drs. Gammon and
`Weinblatt as providing evidence of the motivation to prepare an injectable
`medication in a form suitable for patient self-administration, i.e., for
`convenience, compliance, and cost-savings. Pet. 22–23; Ex. 1012 ¶ 79; Ex.
`1013 ¶ 50. Petitioner asserts also that the ’231 patent itself recognizes that it
`was routine in the art at the time of the invention to formulate injectable
`drugs into ready-made syringes and injection devices to allow for self-
`administration, and to increase patient compliance and comfort. Pet. 23; Ex.
`1001, 2:26–36, 6:54–61. According to Petitioner, based on the teachings of
`the prior art and the knowledge of those skilled in the art at the time of the
`invention, providing Grint’s concentrated methotrexate solution in a form
`suitable for patient self-administration, such as contained in an injection
`device, ready-made syringe, or pen injector, would have required no more
`than routine effort by an ordinary artisan. Pet. 24.
`Patent Owner responds that Insulin Admin. does not remedy the
`alleged deficiencies of Grint with respect to independent claim 1. Prelim.
`Resp. 28. Petitioner, however, does not rely on Insulin Admin. to address
`limitations of claim 1. Nor has Patent Owner established, on this record,
`
`
`
`
`12
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`that a deficiency exists regarding the limitations of the independent claim
`with respect to Grint’s disclosure.
`Further, Patent Owner asserts that Insulin Admin. has no relevance to
`the pending claims because self-administration of insulin teaches nothing
`about the safe self-administration of methotrexate, a toxic substance. Id. at
`29. Moreover, Patent Owner asserts that the ’231 patent makes clear that
`preparing or even drawing methotrexate from a bottle is subject to strict
`restrictions. Id.
`Although we agree with Patent Owner that Insulin Admin. does not
`provide details of the “safe self-administration of methotrexate,” Petitioner
`does not rely on that reference for this teaching. Rather, Petitioner contends
`that the relevance of Insulin Admin. relates to its disclosure that the specific
`injection devices recited by the challenged claims were known at the time of
`the invention. Pet. 23. As Petitioner also notes, the ’231 patent
`acknowledges that ready-made syringes containing methotrexate were also
`known in the prior art. Id. at 23–24; Ex. 1001, 2:26–31. Indeed, the ‘231
`patent explains that this dosage form was provided prior to the invention to
`eliminate the step of drawing up a methotrexate formulation in a syringe and
`to avoid the strict restrictions applicable to such a step. Id. at 2:7–19.
`Thus, based on the information presented at this stage of the
`proceeding, Petitioner has shown sufficiently that there is a reasonable
`likelihood that Petitioner would prevail in showing that claims 7–10, 14–16,
`and 19–21 are unpatentable over Grint and Insulin Admin.
`
`
`
`
`
`
`
`13
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`

`

`IPR2014-01091
`Patent 8,664,231 B2
`
`
`D. Obviousness over Grint (Ex. 1003) and Alsufyani (Ex. 1006)
`Petitioner asserts that dependent claim 18 is obvious over Grint in
`view of Alsufyani. Pet. 27. Patent Owner opposes Petitioner’s assertion.
`Prelim. Resp. 29.
`
`1. Alsufyani
`Alsufyani is a journal article discussing subcutaneous administration
`of methotrexate and an antirheumatic drug treatment for children with
`juvenile idiopathic arthritis. Ex. 1006, 179. In particular, Alsufyani
`describes a study showing that the majority of children with juvenile
`idiopathic arthritis who have experienced an inadequate response to oral
`methotrexate, or who have developed toxicity to oral methotrexate, will gain
`a substantial benefit of an improved response without increased toxicity after
`switching to subcutaneous methotrexate. Id. at 180–181.
`2. Analysis
`Claim 18 recites “juvenile rheumatoid arthritis” as the autoimmune
`disese treated by the method of independent claim 1. Petitioner asserts that
`claim 18 would have been obvious over Grint for the reasons discussed
`above with respect to the anticipation ground. Pet. 27. According to
`Petitioner, a person of ordinary skill in the art at the time the invention was
`made would have understood that Grint’s disclosed method of treating
`rheumatoid arthritis included treatment of juvenile rheumatoid arthritis
`because methotrexate was used widely to treat juvenile rheumatoid arthritis
`prior to Grint’s invention. Id. In support of this contention, Petitioner refers
`to the Declaration of Dr. Weinblatt (Ex. 1012 ¶¶ 66–69), who states that “it
`was known since at least 1992 that [methotrexate] could be used to treat
`juvenile rheumatoid arthritis.” Id. at ¶ 66; Pet 27–28.
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`Further, Petitioner asserts that Alsufyani teaches that subcutaneously
`administered methotrexate is an effective therapy for juvenile rheumatoid
`arthritis. Pet. 27; Ex. 1006, 179, Abstract. According to Petitioner, one of
`ordinary skill in the art would have been motivated, with a reasonable
`expectation of success, to use highly concentrated solutions of methotrexate
`to treat juvenile rheumatoid arthritis, based on the combined teachings of
`Grint and Alsufyani. Pet. 27.
`Patent Owner argues that claim 18 is not rendered obvious by the
`combination of Grint and Alsufyani because “Alsufyani does not teach
`subcutaneous administration of concentrated methotrexate for treating
`[juvenile idiopathic arthritis].” Prelim. Resp. 29 (Emphasis omitted). This
`argument, however, is not persuasive as Petitioner’s challenge of claim 18
`relies upon the combined teachings of Grint and Alsufyani.
`Patent Owner asserts further that Alsufyani does not remedy the
`alleged deficiency of Grint discussed regarding the limitations of
`independent claim 1. Id. As previously discussed, Patent Owner has not
`established that a deficiency exists regarding Grint’s disclosure and the
`limitations of claim 1.
`Based on the information presented at this stage of the proceeding,
`Petitioner has shown sufficiently that there is a reasonable likelihood that
`Petitioner would prevail in showing that claim 18 is unpatentable over Grint
`and Alsufyani.
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`E. Obviousness over the PDR (Ex. 1007) or Hospira (Ex. 1009)
`and Brooks (Ex. 1008)
`Petitioner asserts that claims 1–5, 11–13, 17, and 22 are obvious over
`
`the PDR or Hospira in view of Brooks. Pet. 32. Patent Owner opposes
`Petitioner’s assertion. Prelim. Resp. 30.
`1. The PDR
`The PDR is a book compiling drug product information, i.e.,
`
`manufacturer package inserts, used primarily as a reference for physicians.
`The PDR includes product information for the proprietary drug Mexate®,
`which is methotrexate sodium for injection. Ex. 1007, 762. This product
`information includes a warning relating to the risk of toxicity and death
`associated with the use of methotrexate. Id. The PDR explains that the drug
`is: (a) available in 20, 50, 100, and 250 mg single dose vials of lyophilized
`sterile powder; (b) indicated in the symptomatic control of severe psoriasis;
`(c) administered by intramuscular, intravenous, intraarterial or intrathecal
`route; and (d) recommended at a starting dose, based on an average 70 kg
`adult, of 10 to 25 mg as a single intramuscular or intravenous injection per
`week of until an adequate response is achieved, wherein a dose of 50 mg per
`week ordinarily should not be exceeded. Id. at 763–64. The direction for
`use of the methotrexate vial for intramuscular or intravenous administration
`is to “reconstitute with 2 to 10 ml of Sterile Water for injection, USP, 0.9%
`Sodium Chloride Injection, USP, or Bacteriostatic Water for Injection, USP
`with Parabens or Benzyl Alcohol.” Id. at 764. Regarding stability, the PDR
`states that the product “is stable for four weeks at room temperature (25°C)
`at concentrations of 2 to 125 mg/ml.” Id.
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`2. Hospira
`Hospira is a package insert for a methotrexate product formulated as a
`
`solution for injection containing 100mg/ml, and packaged as 10 and 50 ml
`single-use vials. Ex. 1009, 1, 13. Hospira describes therapeutic indications
`for methotrexate include severe psoriasis, and that the injection may be
`administered by the intramuscular, intravenous, intraarterial, or intrathecal
`routes. Id. Hospira explains that cases of severe psoriasis have responded to
`weekly single oral, intramuscular or intravenous doses of 10–25 mg/week.
`Id. at 3. Regarding shelf-life, Hospira describes the product, “[a]s packaged
`for sale,” as stable for 30 months. Id. at 12. After dilution, infusion
`solutions, i.e., for intravenous administration, have been demonstrated to
`remain stable for 30 days under certain conditions. Id. Hospira cautions,
`however, that the diluted product should be used immediately. Id.
`3. Brooks
`Brooks is a journal article comparing the pharmacokinetics of
`
`methotrexate after intramuscular and subcutaneous injections in patients
`with rheumatoid arthritis. Ex. 1008, 91. Brooks explains that statistical
`analysis of its study results “suggests that the pharmacokinetic parameters
`are similar for these 2 routes of administration.” Id. at 93. Brooks states
`that its “findings suggest that [methotrexate] concentrations achieved by
`each method of delivery are statistically and clinically similar, and that
`[intramuscular] and [subcutaneous] injections are interchangeable routes of
`[methotrexate] administration.” Id. Brooks also reports that most patients
`found the subcutaneous injection less painful than the intramuscular
`injection. Id.
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`4. Analysis
`Petitioner asserts that each of the PDR and Hospira teach a method for
`
`treating psoriasis, an inflammatory autoimmune disease, comprising
`administering an intramuscular injection of methotrexate having a
`concentration as high as 125 mg/ml. Pet. 33. Petitioner asserts that Brooks
`teaches that intramuscular and subcutaneous routes of administering
`methotrexate are interchangeable. Id. According to Petitioner, an ordinary
`artisan would have understood from the combined teachings of either the
`PDR or Hospira and Brooks, that the disclosed methotrexate concentrations
`could be administered subcutaneously. Id. Specifically, Petitioner asserts
`that an ordinary artisan would have been motivated to administer the
`concentrated methotrexate solutions disclosed in the PDR and Hospira
`subcutaneously because Brooks taught that such a route is “interchangeable”
`with the intramuscular route and may be even a “more convenient and less
`painful” way of administering methotrexate. Id. at 33–34 (quoting Ex. 1008,
`93).
`Patent Owner asserts that, in addition to omitting any discussion of
`
`subcutaneous administration, neither the PDR nor Hospira “teach using
`methotrexate concentrations above 30 mg/ml to treat inflammatory
`diseases.” Prelim. Resp. 31. According to Patent Owner, one of skill would
`have used either the 20 or 50 mg vial of methotrexate described in the PDR
`for treatment of psoriasis based on the disclosed dosing schedule of 10 to 25
`mg/week, with the caution that 50 mg/week should ordinarily not be
`exceeded. Id. at 32. Patent Owner asserts that reconstituting these vials
`with 2 to 10 ml of Sterile Water for Injection, as instructed by the PDR,
`would result, at most, in preparing a concentration of 25mg/ml, e.g.,
`
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`reconstituting the 50 mg vial with 2 ml of an acceptable carrier. Patent
`Owner argues that although reconstituting the vials containing 100 or 250
`mg of methotrexate with 2 ml of Sterile Water for Injection would result in
`concentrations greater than 30 mg/ml, a skilled artisan would not do so
`because the majority of the contents of these reconstituted vials would have
`to be destroyed after administering the recommended dose for psoriasis, as
`each vial is intended for a single use. Id.
`
`Regarding Hospira, Patent Owner asserts that the reference provides
`general information with “no direct connection between a specific
`concentration, or dose, and a specific way of administration and/or
`indication.” Id. at 33. According to Patent Owner, Hospira does not provide
`actual guidance for treating psoriasis with the methotrexate supplied as
`100mg/ml because doing so would lead to an “absurd result” of
`administering 100 μL of the injection solution for the recommended 10 mg
`dose and then discarding the remainder of the single-use vial. Id. at 33–34.
`
`Further, Patent Owner refers to a product information sheet for
`methotrexate vials containing 10mg/ml and 100 mg/ml provided by a
`different manufacturer, asserting that its description “explicitly limits the
`intramuscular route of injection to the 10mg/ml solution for injection.” Id.
`at 34 n.2 (citing Ex. 2018, “Method of Administration).2 Thus, Patent
`Owner asserts that one of skill in the art would understand that Hospira does
`not disclose an intramuscular injection of the 100mg/ml solution of
`methotrexate. Id. at 34.
`
`
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` 2
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` Ex. 2018, Ebewe Pharma, Methotrexat “Ebewe” 10mg/ml and 100 mg/ml
`solution for injection and infusion.
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`Additionally, Patent Owner asserts that “Brooks does not teach that
`
`subcutaneous and intramuscular routes of injection are ‘interchangeable’ in
`terms of all characteristics – merely that they are allegedly therapeutically
`interchangeable in terms of biological activity.” Id. at 36. In particular,
`Patent Owner asserts that Brooks fails to disclose anything about
`methotrexate concentration and local toxicity (including skin necrosis),
`which one of ordinary skill in the art would consider when choosing a route
`of administration. Id. Further, Patent Owner asserts that Brooks’ conclusion
`about bioavailability is questioned in a later publication, which states that it
`is not certain that the bioavailability of intravenous, intramuscular and
`subcutaneous [methotrexate] is strictly comparable.” Prelim. Resp. 37
`(citing Ex. 1004).
`Based on the information presented at this stage of the proceeding,
`Petitioner has shown sufficiently that there is a reasonable likelihood that
`Petitioner would prevail in showing that claims 1–5, 11–13, 17, and 22 are
`unpatentable over the PDR or Hospira, and Brooks. In particular, Petitioner
`has shown sufficiently that the PD