Trials@uspto.gov
`571.272.7822
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` Paper 54
` Entered: February 7, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`KOIOS PHARMACEUTICALS LLC,
`Petitioner,
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`v.
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`MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE
`MBH,
` Patent Owner.
`____________
`
`Case IPR2016-01370
`Patent 8,664,231 B2
`____________
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, TONI R. SCHEINER, and ERICA A. FRANKLIN,
`Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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`571.272.7822
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` Paper 54
` Entered: February 7, 2018
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
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`KOIOS PHARMACEUTICALS LLC,
`Petitioner,
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`v.
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`MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE
`MBH,
` Patent Owner.
`____________
`
`Case IPR2016-01370
`Patent 8,664,231 B2
`____________
`
`Before JACQUELINE WRIGHT BONILLA, Vice Chief Administrative
`Patent Judge, TONI R. SCHEINER, and ERICA A. FRANKLIN,
`Administrative Patent Judges.
`
`SCHEINER, Administrative Patent Judge.
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
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`INTRODUCTION
`I.
`Koios Pharmaceuticals LLC (“Petitioner”) filed a Petition on July 20,
`2016, requesting an inter partes review of claims 1–22 of U.S. Patent No.
`8,664,231 B2 (Ex. 1001, “the ’231 patent”). Paper 1 (“Pet.”). Petitioner
`provided the Declarations of Donald R. Miller, Pharm.D (Ex. 1033), and
`Michael H. Schiff, M.D. (Ex. 1034), in support of its positions. medac
`Gesellschaft für klinische Spezialpräparate mbH (“Patent Owner”) filed a
`Preliminary Response on November 10, 2016. Paper 11 (“Prelim. Resp.”).
`We instituted inter partes review on February 8, 2017 as to claims 1–
`22. Paper 13 (“Institution Decision” or “Inst. Dec.”). Specifically, we
`instituted inter partes review on the following grounds:
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`Reference(s)
`
`Grint1
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`Basis
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`Claim(s)
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`§ 102(b)2 1, 2, 4–6, 11–
`13, 17, and 22
`7–10, 14–16,
`and 19–21
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`§ 103(a)
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`Grint, Arthur,3 Moitra,4 and
`Insulin Admin.5
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`1 U.S. Patent No. 6,544,504 B1, issued April 8, 2003 (Ex. 1003, “Grint”).
`2 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
`(2011) (“AIA”), amended 35 U.S.C. §§ 102 and 103. Because the ’231
`patent has an effective filing date before March 16, 2013, we refer to the
`pre-AIA versions of 35 U.S.C. §§ 102 and 103.
`3 Valerie Arthur et al., A Study of Parenteral Use of Methotrexate in
`Rheumatic Conditions, 11 J. CLINICAL NURSING 256 (2002) (Ex. 1023,
`“Arthur”).
`4 R.K. Moitra et al., Caveats to the Use of Parenteral Methotrexate in the
`Treatment of Rheumatic Disease, 44 RHEUMATOLOGY 256 (2005) (Ex. 1025,
`“Moitra”).
`5 Am. Diabetes Ass’n, Insulin Administration, 26 DIABETES CARE S121
`(Supp. 1 2003) (Ex. 1015, “Insulin Admin.”).
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`Reference(s)
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`Grint and Alsufyani6
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`Wyeth7
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`Wyeth, Brooks,8 Arthur, and
`Moitra
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`Basis
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`Claim(s)
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`§ 103(a)
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`§ 102(b)
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`§ 103(a)
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`18
`1–6, 11–13,
`17, 18, and 22
`1–6, 11–13,
`17, 18, and 22
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`Inst. Dec. 37.
`Patent Owner filed a Patent Owner Response (Paper 24, “PO Resp.”),
`and provided the Declarations of Elena M. Massarotti, M.D. (Ex. 2018),
`Sean Nicholson, Ph.D. (Ex. 2032), Thomas M. Zizic, M.D. (Ex. 2092), and
`John S. Clark, Pharm.D. (Ex. 2093) in support of its positions. Petitioner
`filed a Reply (Paper 37, “Reply”), and Patent Owner filed a Surreply (Paper
`43, “Surreply”). We granted Patent Owner’s request to file the Surreply to
`allow Patent Owner to cite to additional portions of Dr. Zizic’s deposition
`testimony intended to provide the full context of portions of Dr. Zizic’s
`deposition testimony cited by Petitioner in the Reply. Paper 42, 2–3.
`Additionally, Patent Owner filed a Motion to Exclude Evidence
`(Paper 39, “Motion to Exclude” or “Mot. to Exclude”), Petitioner filed a
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`6 Khayriah Alsufyani et al., The Role of Subcutaneous Administration of
`Methotrexate in Children with Juvenile Idiopathic Arthritis Who Have
`Failed Oral Methotrexate, 31 J. RHEUMATOLOGY 179 (2004) (Ex. 1006,
`“Alsufyani”).
`7 Wyeth Pharmaceuticals, Methotrexate Sodium for Injection (2004) (Ex.
`1021, “Wyeth”).
`8 Paul J. Brooks et al., Pharmacokinetics of Methotrexate Administered by
`Intramuscular and Subcutaneous Injections in Patients with Rheumatoid
`Arthritis, 33 ARTHRITIS & RHEUMATISM 91 (1990) (Ex. 1008, “Brooks”).
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`Response to the Motion to Exclude (Paper 46), and Patent Owner filed a
`Reply in support of the Motion to Exclude (Paper 49).
`We heard oral argument on November 7, 2017. A transcript of the
`argument has been entered into the record. Paper 53 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. This Final Written
`Decision is issued pursuant to 35 U.S.C. § 318(a) and 37 C.F.R. § 42.73. To
`prevail, Petitioner must establish facts supporting its challenge by a
`preponderance of the evidence. See 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`For the reasons that follow, we determine that Petitioner has not proven by a
`preponderance of the evidence that claims 1–22 are unpatentable. Patent
`Owner’s Motion to Exclude Evidence is dismissed as moot.
`A. Related Proceedings
`Petitioner and Patent Owner identify a district court action involving
`the ’231 patent, titled medac Pharma, Inc. v. Antares Pharma, Inc., No.
`1:14-cv-1498-JBS-KMW (D.N.J.). Pet. 2; Paper 4, 2. The parties also
`identify two prior proceedings at the Board, IPR2014-01091 (“the -1091
`IPR”) and IPR2016-00649 (“the -649 IPR”), as well as Decisions on
`Institution in each of those cases, addressing challenges of the same patent
`and claims at issue here. Pet. 2–3; Paper 12, 3; Frontier Therapeutics, LLC
`v. medac Gesellschaft für klinische Spezialpräparate mbH, Case IPR2016-
`00649 (PTAB Sept. 1, 2016) (Paper 10); Antares Pharma, Inc. v. medac
`Gesellschaft für klinische Spezialpräparate mbH, Case IPR2014-01091
`(PTAB Jan. 6, 2015) (Paper 7). The district court litigation settled in April
`2015. Paper 4, 2. The -1091 IPR and -649 IPR proceedings were terminated
`in view of settlements in April 2015 and December 2016, respectively. Pet.
`3; Paper 12, 3.
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`Patent Owner also identifies U.S. Patent Application Serial No.
`14/635,542 (“the ’542 application”), filed March 2, 2015 (now abandoned).
`Paper 4, 2.
`B. The ’231 Patent
`The ’231 patent relates to a method for treating inflammatory
`autoimmune diseases, such as rheumatoid arthritis, juvenile arthritis, and
`psoriasis, by subcutaneously administering a concentrated methotrexate
`solution comprising more than 30 mg/ml of methotrexate. Ex. 1001,
`Abstract, 3:59–67, 8:43–47. Methotrexate is a cytostatic agent that has been
`known since the early 1950s in the field of oncology, particularly for treating
`leukemia in children and breast cancer. Id. at 1:14–17, 1:24–27.
`Methotrexate also was used to treat psoriasis, and first observed in the late
`1950s as a treatment for individual rheumatoid arthritis cases. Id. at 1:28–
`32.
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`According to the ’231 patent, “[o]ver 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 orally or parenterally, once a week, over a long period of time,
`sometimes throughout the patient’s lifetime. Id. at 2:37–41. Methotrexate is
`dosed significantly lower in the treatment of rheumatoid arthritis than in the
`treatment of tumors, sometimes up to 1,000 times lower. Id. at 1:56–59.
`Anti-rheumatic therapy is therefore referred to as “low-dosage methotrexate
`therapy.” Id. at 1:59–60. In this capacity, methotrexate is administered only
`once per week, in dosages ranging from 5–30 mg per week in Germany, and
`up to 40 mg per week in other European countries. Id. at 1:60–65.
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`The ’231 patent discloses a ready-made syringe and carpule
`containing a methotrexate solution, as well as a pen-injector comprising the
`ready-made syringe and/or carpule. Id. at 1:5–13. The ’231 patent states
`that ready-made syringes containing methotrexate for the treatment of
`rheumatoid arthritis are known from the prior art, where the active substance
`is present at a concentration of up to 25 mg/ml in a pharmaceutically
`acceptable solvent. Id. at 2:26–31. The ’231 patent, however, further states
`that “subcutaneous administration in particular has its difficulties . . . due to
`the problem of having to inject the required relatively large amount of active
`substance solution (e.g. up to 3 ml . . . ) under the skin every week, which
`was especially difficult to convey to children.” Id. at 2:44–51. In other
`words, the ’231 patent recognizes that although the prior art ready-made
`syringes have had a positive impact on patient compliance (i.e., the degree of
`treatment acceptance on the part of the patient), injecting large amounts of
`liquid under the skin leads to reduced patient compliance. Id. at 4:14–16,
`4:65–5:13.
`According to the ’231 patent, a need therefore exists for a
`methotrexate solution that can be administered to patients, including
`children, as easily and painlessly as possible, to provide a high degree of
`patient compliance. Id. at 2:53–58. The ’231 patent seeks to address this
`need by providing methotrexate formulations in higher concentrations than
`those known in the prior art, which in turn allows for a smaller liquid
`volume for injection. Id. at 3:16–27, 5:5–23. The ’231 patent states that the
`smaller volumes of liquid are easier to convey to patients, particularly
`children, and can be expected to have a further positive impact on patient
`compliance. Id. at 5:5–23.
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`C. Illustrative Claim
`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.
`Id. at 8:43–47. Dependent claims 2–22 recite additional limitations
`regarding methotrexate concentrations and dosages; the types of solvent
`used; the types of inflammatory autoimmune diseases treated; suitability for
`self-administration; the medicament being contained in an injection device
`(such as a ready-made syringe or a pen injector) and in a storage container
`(such as a carpule); and administering single and multiple applications. Id.
`at 8:48–10:20.
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`ANALYSIS
`II.
`A. Level of Ordinary Skill in the Art
`Petitioner asserts that “[t]he cited art demonstrates the level of skill in
`the art,” and
`[f]urther, a person of ordinary skill in the art would have either
`a Pharm.D. or Ph.D. in pharmaceutical sciences, pharmacology,
`or a related discipline; an M.D. or D.O. with experience in
`using oral and injectable [methotrexate] to treat inflammatory
`autoimmune diseases; or a person with a lesser degree with
`several years of experience in formulating and/or administering
`methotrexate for injection, such as a nurse or pharmacy
`technician.
`Pet. 11. Patent Owner provides a similar description of a person having
`ordinary skill in the art. PO Resp. 15. In comparison with Petitioner’s
`description, Patent Owner’s description limits the Pharm.D. and Ph.D.
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`degrees to the fields of pharmacology, pharmaceutics, and chemistry; does
`not refer to a D.O.; and allows for a person with a lesser degree to have
`several years of experience only in the context of “methotrexate
`preparation.” See id. Accordingly, because Petitioner’s description
`encompasses a wider range of individuals having ordinary skill in the art,
`and such a description is supported by the record as a whole, we adopt
`Petitioner’s description of the level of ordinary skill in the art, but we note
`that our disposition of this case would not differ under either Petitioner’s or
`Patent Owner’s description.
`B. Claim Construction
`In an inter partes review, claim terms in an unexpired patent are
`interpreted according to their broadest reasonable construction in light of the
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`Cuozzo Speed Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016). Under
`that standard, claim terms generally are given their ordinary and customary
`meaning, as would be understood by one of ordinary skill in the art in the
`context of the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,
`1257 (Fed. Cir. 2007). Only terms which are in controversy need to be
`construed and only to the extent necessary to resolve the controversy. See
`Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011);
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
`1999).
`We determine that only the claim term “subcutaneously,” which
`appears in independent claim 1 (“subcutaneously administering . . . a
`medicament”), requires discussion for resolution of the controversy in this
`case. In the Petition, Petitioner asserted that “subcutaneously” means
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`“[u]nder the skin.” Pet.10. In the Preliminary Response, Patent Owner
`argued that subcutaneous administration is distinct from, and does not
`include, intramuscular or intravenous administration, despite the fact that all
`three involve administration at some location under the skin. Prelim. Resp.
`20–21.
`In the Institution Decision, we agreed with Patent Owner that the
`broadest reasonable construction of “subcutaneously” in light of the
`specification denotes a route of administration that is distinct from
`intramuscular (in a muscle) or intravenous (in a vein). Inst. Dec. 12–13. We
`noted that the specification of the ’231 patent expressly uses those three
`terms separately, indicating that they have different meanings. Ex. 1001,
`4:4–6 (“The medicaments of the present invention are administered . . . by
`intravenous, intramuscular or subcutaneous injection.”); id. at 5:32–35.
`Neither Petitioner nor Patent Owner disputes our preliminary
`determination. PO Resp. 14–15. Having reviewed our interpretation in light
`of the full record developed at trial, we maintain our determination that
`“subcutaneously” means administration under the skin, but does not include
`intramuscular or intravenous administration.
`C. Anticipation by Grint
`Petitioner asserts that Grint anticipates claims 1, 2, 4–6, 11–13, 17,
`and 22 of the ’231 patent under 35 U.S.C. § 102(b). Pet. 12–22. Patent
`Owner argues that Petitioner has failed to prove by a preponderance of the
`evidence that Grint discloses both “subcutaneous administration” and a
`medicament comprising methotrexate at a “concentration of more than 30
`mg/ml” (PO Resp. 18), “much less those elements as ‘arranged as in the
`claim[s]’” (id.).
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`1. Grint
`Grint describes treating autoimmune diseases, such as rheumatoid
`arthritis and psoriasis, by administering a combination of interleukin 10 and
`methotrexate. Ex. 1003, 2:23–35. Grint states that it was unexpectedly
`discovered that a combined/concurrent administration of interleukin 10 and
`methotrexate causes synergistic and unexpectedly strong benefits. Id. at
`2:44–51. The interleukin 10 and methotrexate may be administered either
`together in a single pharmaceutical composition or separately. Id. at 3:20–
`21.
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`Grint states that methotrexate “may be administered in a manner as is
`conventionally practiced,” citing to Goodman.9 Id. at 5:20–23 (citing Ex.
`2019, 126610). Grint specifically identifies parenteral, intraperitoneal, and
`intravenous administration of methotrexate. Id. at 5:64–65, 7:5. Grint
`further teaches that the methotrexate is compounded “for convenient and
`effective administration in effective amounts” ranging from about 0.1 to 400
`mg (preferably from 1 to 35 mg and most preferably from 10 to 25 mg), in
`proportions ranging from about 0.1 to about 40 mg/ml in a pharmaceutically
`acceptable carrier. Id. at 6:60–7:1.
`Example 1 of Grint presents a study evaluating the safety and
`tolerability of administering a combination of interleukin-10 and
`methotrexate to patients with active rheumatoid arthritis. Id. at 7:40–48,
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`9 Paul Calabresi & Robert E. Parks, Jr., Antiproliferative Agents and Drugs
`Used for Immunosuppression, in GOODMAN AND GILMAN’S THE
`PHARMACOLOGICAL BASIS OF THERAPEUTICS 1247, 1266 (7th ed. 1985) (Ex.
`2019, “Goodman”).
`10 Grint appears to contain a typographical error in citing to page 1299 of
`Goodman, as opposed to page 1266. Compare Ex. 2019, 1266 (discussing
`methotrexate) with id. at 1299 (discussing cyclosporine).
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`7:66–8:2. In that study, Grint indicates that doses of methotrexate in the
`amount of 12.5–25 mg/week were given to the patients by oral,
`subcutaneous, or intramuscular administration. Id. at 7:56–57, 8:1–2.
`2. Analysis
`Claim 1 recites “subcutaneously administering . . . a medicament
`comprising methotrexate . . . at a concentration of more than 30 mg/ml” to a
`patient in need of treatment for an inflammatory autoimmune disease. Ex.
`1001, 8:44–47. In contending that Grint anticipates this claim, Petitioner
`relies on Grint’s statement that “methotrexate is generally present in from
`about 0.1 to about 40 mg/ml of carrier,” together with Grint’s Example 1,
`which describes a study in which a 12.5–25 mg/week dose of methotrexate
`was given to rheumatoid arthritis patients by oral, subcutaneous, or
`intramuscular administration. Pet. 13–14 (citing Ex. 1003, 6:66–7:1, 7:56–
`57, 8:1–2).
`Additionally citing Grint’s disclosure that methotrexate should be
`“compounded for convenient and effective administration in effective
`amounts,” Petitioner, supported by Dr. Schiff, contends that one of ordinary
`skill in the art “would have understood Grint to disclose subcutaneous
`administration of [methotrexate] in concentrations greater than 30 mg/ml for
`the treatment of inflammatory autoimmune diseases.” Pet. 16–17 (citing Ex.
`1003, 6:60–61; Ex. 1034 ¶¶ 49–53). On one hand, Dr. Schiff testifies that
`one of ordinary skill in the art “would have recognized that a 35 mg/ml
`concentration of [methotrexate] (within the range disclosed by Grint) could
`be used to administer a 35 mg dose (within the ‘preferred’ dosage range
`disclosed by Grint) using a 1 ml solution . . . consistent with Grint’s teaching
`that methotrexate should be ‘compounded for convenient and effective
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`administration in effective amounts.’” Ex. 1034 ¶ 52 (quoting Ex. 1003,
`6:60–61). Similarly, Petitioner contends that one of ordinary skill in the art
`would have known that “the higher concentrations of [methotrexate]
`disclosed in Grint, such as 35 mg/ml, should be paired with the higher
`dosages . . . disclosed in Grint, such as 35 mg, in order to administer
`[methotrexate] in ‘effective amounts,’ such as 1 ml.” Id. at 18 (citing Ex.
`1033 ¶ 46; Ex. 1034 ¶¶ 53–55). On the other hand, Petitioner argues that
`Grint’s “reference to ‘conventional practice’ comes in the context of
`administration forms [i.e., modes], not concentration levels, and would not
`have dissuaded the skilled artisan from subcutaneously administering the
`more than 30 mg/ml concentrations disclosed in Grint.” Id. (citing Ex. 1034
`¶ 56).
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`Patent Owner argues that Grint does not disclose the elements of the
`challenged claims, much less their arrangement as in the claims (PO Resp.
`17–22), and that Grint’s disclosure of using methotrexate in a “convenient
`and effective” way is so broad and generic as to provide no information to
`one of ordinary skill in the art about how to compound or administer it (id. at
`19). In particular, Patent Owner contends that “Grint never correlates any
`[methotrexate] concentration with any mode of administration—including
`parenteral, intraperitoneal, or intravenous.” Id. at 18. Patent Owner
`explains that Grint refers to subcutaneous administration only in Example 1,
`but Example 1 is silent about methotrexate concentration. Id. at 19. Patent
`Owner notes that Dr. Schiff cites Grint’s “reference to ‘convenient and
`effective administration’” together with Grint’s Example 1 (disclosing a
`methotrexate dose of 12.5–25 mg/week (Ex. 1003, 7:56–57)) as the basis for
`his conclusion that “Grint’s teachings ‘could be used to administer a 35 mg
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`dose,’” but contends that Dr. Schiff “never says he used such a dose or
`points to where in Grin[t] that teaching is to be found.” Id. at 21 (citing Ex.
`1034 ¶¶ 51–52.
`Moreover, Patent owner’s witness, Dr. Massarotti, testifies that
`parenteral administration encompasses at least eighteen different modes of
`administration that avoid or circumvent the gastrointestinal tract, including
`intravenous, intramuscular, subcutaneous, intrathecal, intraperitoneal, etc.
`Ex. 2018 ¶ 22. Patent Owner argues that Petitioner “never even tries to
`suggest that Grint correlated a specific concentration . . . with any of those
`eighteen parenteral modes of administration” or even any of the modes of
`parenteral administration specifically disclosed in Grint. PO Resp. 20.
`According to Patent Owner and Dr. Massarotti, one of ordinary skill in the
`art would have recognized that different modes of administration have
`different concentration limits for methotrexate. Id.; Ex. 2018 ¶ 23. For
`instance, Dr. Massarotti provides examples of administration of intrathecal
`injections of methotrexate at 1 mg/ml and subcutaneous injections of
`methotrexate at 50 mg/2 ml (i.e., 25 mg/ml). Ex. 2018 ¶ 23 (citing Ex. 1021,
`24; Ex. 2001,11 5).
`With respect to Grint’s teaching that methotrexate “may be
`administered in a manner as is conventionally practiced” (Ex. 1003, 5:22–
`23), Patent Owner asserts that one of ordinary skill in the art would not have
`understood from Grint that it was conventional practice to administer
`methotrexate subcutaneously at a concentration above 30 mg/ml. PO Resp.
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`11 D. Kurnik et al., Bioavailability of Oral vs. Subcutaneous Low-Dose
`Methotrexate in Patients with Crohn’s Disease, 18 ALIMENTARY
`PHARMACOLOGY & THERAPEUTICS 57 (2003) (Ex. 2001).
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`16, 23–24. Rather, Dr. Massarotti and Dr. Zizic testify that the standard, i.e.,
`conventional, practice was to administer methotrexate subcutaneously at
`concentrations of 25 mg/ml or less. Ex. 2018 ¶¶ 17, 25–26, 33; Ex. 2092
`¶¶ 17, 28, 31. Patent Owner contends that Petitioner provides no evidence
`of any instance before the priority date of the ’231 patent in which
`methotrexate was actually administered subcutaneously at a concentration
`above 30 mg/ml to treat an inflammatory autoimmune disease. PO Resp.
`15–16, 23. Notably, Dr. Miller “testifies that a person of ordinary skill in
`the art would have wanted to use the higher concentration of [methotrexate]
`solution,” but never testifies that he had prepared a methotrexate solution for
`subcutaneous administration at a concentration above 30 mg/ml prior to
`2006. Ex. 1033 ¶ 60. Similarly, Dr. Schiff admitted that he never
`subcutaneously administered such a methotrexate solution. Ex. 1034 ¶ 123.
`Patent Owner further disagrees with Petitioner that Grint’s reference to
`“conventionally practiced” is limited to administration modes and does not
`apply to concentration levels. Id. at 24–25.
`Furthermore, Patent Owner argues that when a patent claims a
`numerical range, and the prior art discloses its own numerical range that
`overlaps the claimed range, the “prior art is only anticipatory if it describes
`the claimed range with sufficient specificity such that a reasonable fact
`finder could conclude that there is no reasonable difference in how the
`invention operates over the ranges.” PO Resp. 25–26 (quoting Ineos USA
`LLC v. Berry Plastics Corp., 783 F.3d 865, 869 (Fed. Cir. 2015)). Patent
`Owner argues that it is Petitioner’s burden to show that there is no
`reasonable difference in how the method of the challenged claims would
`operate over Grint’s 0.1–40 mg/ml range, and Petitioner has failed to make
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`that showing. Id. at 26. Also, Patent Owner alleges that combining Grint’s
`dose range (0.1–400 mg) and concentration range (0.1–40 mg/ml) results in
`volumes between 0.025 ml and 4,000 ml, and at the high and low ends of
`Grint’s resulting volume range, there are marked differences in how the
`claimed method operates. Id. at 26–27. Furthermore, Patent Owner argues,
`that given concerns relating to toxicity at the injection site, one of ordinary
`skill in the art would have been cautious about increasing concentration for
`subcutaneous injection. Id. at 29 (citing Ex. 2092 ¶ 26).
`In its Reply, Petitioner argues that the testimony of both Dr. Schiff,
`and Patent Owner’s own expert, Dr. Zizic, establishes that Grint anticipates
`claim 1. Reply 3–6. Petitioner specifically points to Dr. Zizic’s testimony
`that one of ordinary skill in the art would have known, before the priority
`date of the ’231 patent, that it would have been both convenient and
`effective to subcutaneously administer a 35 mg/ml concentration
`methotrexate solution to deliver a 35 mg dose of methotrexate using a 1 ml
`solution. Id. at 4–5 (citing Ex. 1039, 111:8–24).
`Petitioner criticizes Patent Owner’s argument that before the priority
`date of the ’231 patent, no one used methotrexate at concentrations above 25
`mg/ml to subcutaneously treat rheumatoid arthritis for two reasons—first,
`because the absence of a commercial embodiment of the claim predating its
`priority date does not negate anticipatory teachings of prior art publications,
`and second, because Dr. Zizic admitted at his deposition that, before the
`priority date of the ’231 patent, he had thought of administering
`methotrexate in concentrations above 25 mg/ml to his patients, and wanted
`to do so, but could not only because he did not have access to such solutions.
`Id. at 2, 7–10 (citing Ex. 1039, 114:15–115:2).
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`As to toxicity concerns, Petitioner argues that Dr. Zizic’s testimony
`demonstrates that one of ordinary skill in the art would not have been so
`concerned about potential tissue irritation concerns so as to forego the use of
`methotrexate solutions in concentrations above 30 mg/ml. Id. at 11–13
`(citing Ex. 1039, 119:10–122:6, 135:8–136:3). And, in regard to the issue of
`an overlapping range in the anticipating context, Petitioner argues that Patent
`Owner carries the burden of establishing the criticality of a claimed range in
`order to avoid a finding that an overlapping range recited by the prior art
`anticipates. Id. at 15 (citing Ineos, 783 F.3d at 871). In any event, Petitioner
`argues that the recited ranges in dependent claims 2 and 22 are not critical,
`and there is no evidence in the disclosure of the ’231 patent that the recited
`ranges are critical. Id. at 16 (citing Pet. 21).
`“A claim is anticipated only if each and every element as set forth in
`the claim is found, either expressly or inherently described, in a single prior
`art reference.” Verdegaal Bros., Inc. v. Union Oil Co., 814 F.2d 628, 631
`(Fed. Cir. 1987). Petitioner does not argue that Grint inherently anticipates
`claim 1, but instead relies on Grint’s express disclosures for its anticipation
`contention. See Pet. 12–17; Reply 3–13. In this regard, Grint generally
`discloses administering methotrexate in a concentration range of about 0.1
`mg/ml to about 40 mg/ml (Ex. 1003, 6:66–7:1) and elsewhere discloses
`subcutaneous administration of methotrexate (id. at 7:56–57, 8:1–2).
`For Grint to anticipate the requisite methotrexate concentration and
`the subcutaneous mode of administration must be “arranged as in the claim.”
`See Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359, 1369 (Fed. Cir.
`2008) (“[A] prior art reference—in order to anticipate under 35 U.S.C.
`§ 102—must not only disclose all elements of the claim within the four
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`corners of the document, but must also disclose those elements ‘arranged as
`in the claim.’” (quoting Connell v. Sears, Roebuck & Co., 722 F.2d 1542,
`1548 (Fed. Cir. 1983))). Word-for-word identity is not required and the
`analysis allows for some flexibility. Microsoft Corp. v. Biscotti, Inc., 878
`F.3d 1052, 1070˗71 (Fed. Cir. 2017). That is, the reference need not
`“‘expressly spell out’ all the limitations arranged or combined as in the
`claim, if a person of skill in the art, reading the reference, would ‘at once
`envisage’ the claimed arrangement or combination.” Kennametal, Inc. v.
`Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015) (quoting In
`re Petering, 301 F.2d 676, 681 (CCPA 1962)). Here, because claim 1
`requires subcutaneously administering methotrexate in a concentration of
`more than 30 mg/ml (Ex. 1001, 8:44–47), for Grint to anticipate, one of
`ordinary skill in the art must at once envisage the upper values of Grint’s
`disclosed concentration range—i.e., above 30 mg/ml—to be correlated with
`subcutaneous administration.
`Having considered the arguments and evidence presented by both
`parties, we conclude that Petitioner has not proven by a preponderance of the
`evidence that Grint anticipates independent claim 1. Our reasoning is as
`follows.
`As discussed above, Grint discloses parenteral administration of
`methotrexate generally, and intraperitoneal, intravenous, intramuscular, and
`subcutaneous administration specifically. Ex. 1003, 5:64–65, 7:5, 7:56–57,
`8:1–2. Grint further discloses that methotrexate “may be administered as
`conventionally practiced,” citing Goodman as an example, and Goodman
`additionally discloses intrathecal administration. Ex. 2019, 1266. Dr.
`Massarotti testifies that parenteral administration includes at least eighteen
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`different modes of administration—including each of the modes of
`administration identified in Grint and Goodman—and that it was known as
`of the priority date of the ’231 patent that different modes of parenteral
`administration were used clinically with different concentrations of
`methotrexate. Ex. 2018 ¶¶ 22–23 (citing Ex. 1021, 24; Ex. 2001, 5). Dr.
`Massarotti’s testimony on this point is unrebutted, and furthermore,
`Petitioner identifies no evidence of record that would support a finding that
`one of ordinary skill in the art would have had a basis to assume that, in
`Grint, the same methotrexate concentration ranges apply to each mode of
`parenteral administration.
`Accordingly, we agree with Patent Owner that one of ordinary skill in
`the art would not have understood all of the points within Grint’s disclosed
`concentration range to be applicable to each mode of methotrexate
`administration disclosed in Grint. See PO Resp. 20. Petitioner must
`therefore show that the higher concentrations of Grint’s range of about 0.1
`mg/ml to about 40 mg/ml—namely, the concentrations greater than 30
`mg/ml—would have been understood by one of ordinary skill in the art as
`applicable to subcutaneous administration in particular.
`Dr. Massarotti and Dr. Zizic testify that the conventional practice in
`the art was to administer methotrexate subcutaneously in concentrations of
`25 mg/ml or less. Ex. 2018 ¶¶ 17–18, 24, 26; Ex. 2092 ¶¶ 17, 28.
`Specifically, Dr. Massarotti testifies that to her knowledge, “no document
`published prior to July 21, 2006 reports the actual subcutaneous
`administration of methotrexate at a concentration greater than 25 mg/ml,”
`nor is she “aware of any others who have administered methotrexate
`subcutaneously for an inflammatory autoimmune disease or any other
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`condition at a concentration greater than 25 mg/ml prior to July 21, 2006.”
`Ex. 2018 ¶ 25. Similarly, Dr. Zizi
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