Paper No. 13
` Entered: February 8, 2017
`
`Trials@uspto.gov
`571.272.7822
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`KOIOS PHARMACEUTICALS LLC,
`Petitioner,
`
`v.
`
`MEDAC GESELLSCHAFT FÜR KLINISCHE SPEZIALPRÄPARATE
`MBH,
` Patent Owner.
`____________
`
`Case IPR2016-01370
`Patent 8,664,231 B2
`____________
`
`Before JACQUELINE WRIGHT BONILLA, TONI R. SCHEINER, and
`ERICA A. FRANKLIN, Administrative Patent Judges.
`
`BONILLA, Administrative Patent Judge.
`
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`

`

`IPR2016-01370
`Patent 8,664,231 B2
`
`I.
`
`INTRODUCTION
`
`On July 20, 2016, Koios Pharmaceuticals LLC (“Petitioner”) filed a
`
`Petition requesting an inter partes review of claims 1–22 of U.S. Patent No.
`
`8,664,231 B2 (“the ’231 patent”) (Ex. 1001). Paper 1 (“Pet.”). medac
`
`Gesellschaft für klinische Spezialpräparate mbH (“Patent Owner”) filed a
`
`Preliminary Response to the Petition. Paper 11 (“Prelim. Resp.”).
`
`Under 35 U.S.C. § 314(a), an inter partes review may not be instituted
`
`unless it is determined that there is “a reasonable likelihood that the
`
`petitioner would prevail with respect to at least 1 of the claims challenged in
`
`the petition.” Based on the information presented in the Petition and
`
`Preliminary Response, we are persuaded that there is a reasonable likelihood
`
`Petitioner would prevail with respect to the claims challenged in the Petition.
`
`Accordingly, we institute an inter partes review of claims 1–22 of the ’231
`
`patent.
`
`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-01498-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
`
`
`
`2
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`

`

`IPR2016-01370
`Patent 8,664,231 B2
`
`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.
`
`Patent Owner also identifies U.S. Patent Application Serial No.
`
`14/635,542, filed March 2, 2015, which is currently pending at the Office.
`
`Paper 4, 2.
`
`B. The ’231 Patent
`
`The ’231 patent relates to a method for treating inflammatory
`
`autoimmune diseases, such as rheumatoid arthritis, juvenile rheumatoid
`
`arthritis, or 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 breast cancer and leukemia in children. Id. at 1:14–17, 1:24–27.
`
`Methotrexate also was used early on to treat psoriasis, and first observed in
`
`the late 1950s as a treatment for individual rheumatoid arthritis cases. Id. at
`
`1:28–32.
`
`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. Thus,
`
`antirheumatic therapy is referred to as “low-dosage methotrexate therapy.”
`
`Id. at 1:56–60. In this capacity, methotrexate is administered only once per
`
`
`
`3
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`IPR2016-01370
`Patent 8,664,231 B2
`
`week, in dosages ranging from 5.0 to 30.0 mg per week in Germany, and up
`
`to 40.0 mg per week in other European countries. Id. at 1:60–65.
`
`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 in the
`case of a certain dosage) 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 a 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 pain-free as possible, and in turn 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
`
`
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`4
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`IPR2016-01370
`Patent 8,664,231 B2
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`states that the smaller volumes of liquid are easier to convey to patients, in
`
`particular children, and can be expected to have a further positive impact on
`
`patient compliance. Id. at 5:5–23.
`
`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, solvent, inflammatory
`
`autoimmune diseases, self-administration, and the medicament being
`
`contained in an injection device for one or more applications, such as a pen
`
`injector, and in a storage container, such as a carpule.
`
`D. Proposed Grounds of Unpatentability
`
`Petitioner challenges the patentability of claims 1–22 of the ’231
`
`patent on the following grounds:
`
`Reference(s)
`
`Grint (Ex. 1003)1
`
`Statutory
`Basis
`
`§ 102(b)
`
`Claims Challenged
`
`1, 2, 4–6, 11–13, 17, and 22
`
`
`1 Grint et al., U.S. Patent No. 6,544,504 B1 (issued Apr. 8, 2003) (“Grint”)
`(Ex. 1003).
`
`
`
`5
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`

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`IPR2016-01370
`Patent 8,664,231 B2
`
`
`Reference(s)
`
`Grint and Arthur (Ex. 1023)2
`alone, or further in view of
`either Moitra (Ex. 1025)3 or
`Insulin Admin. (Ex. 1015)4
`
`Statutory
`Basis
`
`§ 103(a)
`
`Claims Challenged
`
`7–10, 14–16, and 19–21
`
`Grint and Alsufyani (Ex. 1006)5 § 103(a)
`
`18
`
`Wyeth (Ex. 1021)6
`
`§ 102(b)
`
`1–6, 11–13, 17, 18, and 22
`
`Wyeth, Brooks (Ex. 1008),7 and
`Arthur, further in view of
`Moitra or Insulin Admin.
`
`§ 103(a)
`
`1–22
`
`
`2 Valerie Arthur et al., A Study of Parenteral Use of Methotrexate in
`Rheumatic Conditions, 11 J. CLINICAL NURSING 256 (2002) (“Arthur”) (Ex.
`1023). Petitioner also cites to Valerie Arthur et al., Letter to the Editor, 28 J.
`RHEUMATOLOGY 1, 212 (2001) (“Arthur 2001”) (Ex. 1024).
`
`3 R.K. Moitra et al., Caveats to the Use of Parenteral Methotrexate in the
`Treatment of Rheumatic Disease, 44 RHEUMATOLOGY 256 (2005) (“Moitra”)
`(Ex. 1025).
`
`4 Am. Diabetes Ass’n, Insulin Administration, 26 DIABETES CARE S121
`(Supp. 1 2003) (“Insulin Admin.”) (Ex. 1015).
`
`5 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) (“Alsufyani”)
`(Ex. 1006).
`
`6 WYETH PHARMACEUTICALS, METHOTREXATE SODIUM FOR INJECTION
`(2004) (“Wyeth”) (Ex. 1021). Petitioner also cites to Wyeth
`Pharmaceuticals, Methotrexate Sodium Tablets, Methotrexate Sodium for
`Injection, Methotrexate LPF® Sodium (Methotrexate Sodium Injection) and
`Methotrexate Sodium Injection, in PHYSICIANS’ DESK REFERENCE 3415 (57th
`ed. 2003) (“PDR for Wyeth”) (Ex. 1022).
`
`7 Paul J. Brooks et al., Pharmacokinetics of Methotrexate Administered by
`Intramuscular and Subcutaneous Injections in Patients with Rheumatoid
`Arthritis, 33 ARTHRITIS & RHEUMATISM 91 (1990) (“Brooks”) (Ex. 1008).
`
`
`
`6
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`IPR2016-01370
`Patent 8,664,231 B2
`
`
`Reference(s)
`
`Hoekstra (Ex. 1004)8 and
`Jørgensen (Ex. 1005)9
`
`Hoekstra, Jørgensen, and
`Arthur, in further view of
`Insulin Admin.
`
`Hoekstra, Jørgensen, and
`Alsufyani
`
`Statutory
`Basis
`
`§ 103(a)
`
`Claims Challenged
`
`1–6, 11–13, 17, and 22
`
`§ 103(a)
`
`7–10, 14–16, and 19–21
`
`§ 103(a)
`
`18
`
`
`Pet. 9–10. Petitioner also relies on the declarations of Donald Miller,
`
`Pharm.D. (Ex. 1033) and Michael H. Schiff, M.D. (Ex. 1034).
`
`II. ANALYSIS
`
`A. 35 U.S.C. § 325(d)
`
`In the -1091 IPR and -649 IPR proceedings, we instituted inter partes
`
`reviews as to the same patent and claims challenged by Petitioner in this
`
`case. Frontier Therapeutics, LLC v. medac Gesellschaft für klinische
`
`Spezialpräparate mbH, Case IPR2016-00649, slip op. at 30–31 (PTAB Sept.
`
`1, 2016) (Paper 10); Antares Pharma, Inc. v. medac Gesellschaft für
`
`klinische Spezialpräparate mbH, Case IPR2014-01091, slip op. at 24 (PTAB
`
`Jan. 6, 2015) (Paper 7). Several grounds that Petitioner asserts in this case
`
`are the same as those previously presented by the -1091 IPR and the -649
`
`IPR petitioners. These include the challenges relying on (i) Grint under
`
`
`8 Monique Hoekstra et al., Bioavailability of Higher Dose Methotrexate
`Comparing Oral and Subcutaneous Administration in Patients with
`Rheumatoid Arthritis, 31 J. RHEUMATOLOGY 645 (2004) (“Hoekstra”) (Ex.
`1004).
`
`9 Jan T. Jørgensen et al., Pain Assessment of Subcutaneous Injections, 30
`ANNALS PHARMACOTHERAPY 729 (1996) (“Jørgensen”) (Ex. 1005).
`
`
`
`7
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`IPR2016-01370
`Patent 8,664,231 B2
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`§ 102(b) (compare Pet. 9, with Frontier, slip op. at 5, and Antares, slip op. at
`
`5); (ii) Grint and Alsufyani under § 103(a) (compare Pet. 9, with Frontier,
`
`slip op. at 5, and Antares, slip op. at 5); (iii) Hoekstra and Jørgensen under
`
`§ 103(a) (compare Pet. 10, with Antares, slip op. at 5); and (iv) Hoekstra,
`
`Jørgensen, and Alsufyani under § 103(a) (compare Pet. 10, with Antares,
`
`slip op. at 5). The -1091 IPR and -649 IPR petitioners did not assert any
`
`challenges involving the Arthur, Moitra, or Wyeth references. See Frontier,
`
`slip op. at 5–6; Antares, slip op. at 4–5.
`
`After institution in each of the -1091 IPR and -649 IPR cases, the
`
`parties reached settlement agreements and jointly moved to terminate. -649
`
`IPR, Paper 15; -1091 IPR, Paper 17. We granted the joint requests in both
`
`of these cases and terminated the proceedings without rendering final written
`
`decisions. -649 IPR, Paper 20; -1091 IPR, Paper 21. Petitioner states that it
`
`has no relationship with the petitioners in the -1091 IPR and -649 IPR cases.
`
`Pet. 3; Ex. 1035 ¶ 2.
`
`
`
`Patent Owner argues that we should exercise our discretion and not
`
`institute trial in this case because this is the third IPR on the same claims of
`
`the ’231 patent, and in filing when it did, Petitioner had the advantage of an
`
`institution decision and two preliminary responses by Patent Owner on the
`
`same claims challenged here. Prelim. Resp. 8–9, 12–14. Patent Owner
`
`further argues that the new prior art asserted in this case––Arthur, Moitra,
`
`and Wyeth––is redundant and cumulative of the art used in the -1091 IPR
`
`and -649 IPR. Id. at 9–12.
`
`
`
`Petitioner, on the other hand, argues that we should reject Patent
`
`Owner’s arguments because Petitioner is not in privity with, and has no
`
`relation to, either of the petitioners in the -1091 IPR and -649 IPR cases.
`
`
`
`8
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`

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`IPR2016-01370
`Patent 8,664,231 B2
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`Pet. 61 (citing Ex. 1035 ¶ 2). Petitioner further asserts that in this case the
`
`Petition introduces new legal and factual arguments, prior art references, and
`
`expert declarations. Id. Also, Petitioner states that the Board has not
`
`previously adjudicated the merits of the arguments and references presented
`
`in the Petition. Id. at 62. At the time the Petition was filed, the -1091 IPR
`
`had been terminated by a private settlement before a final decision was
`
`entered (id.), and the -649 IPR was later terminated in this manner as well.
`
`Under 35 U.S.C. § 325(d), in determining whether to institute inter
`
`partes review, we “may take into account whether, and reject the petition or
`
`request because, the same or substantially the same prior art or arguments
`
`previously were presented to the Office.” 35 U.S.C. § 325(d). We decline
`
`to exercise our discretion in this case to deny institution. In doing so, we
`
`accept Petitioner’s representation that it is not in privity with, and has no
`
`relationship with, either of the petitioners in the -1091 IPR and -649 IPR
`
`cases. Pet. 3, 61; Ex. 1035 ¶ 2. Furthermore, the -1091 IPR and -649 IPR
`
`were terminated, upon the submission of joint requests to which Patent
`
`Owner was a party, before the merits of those proceedings could be resolved
`
`in final written decisions. We have previously declined to exercise our
`
`discretion under § 325(d) to deny institution in similar circumstances. See,
`
`e.g., Square, Inc. v. Protegrity Corp., Case CBM2014-00182, slip op. at 7–8
`
`(PTAB Mar. 5, 2015) (Paper 16) (declining to exercise discretion to deny
`
`petition (filed on August 29, 2014), where previously-filed petition based on
`
`the same prior art and substantially similar arguments was filed by a
`
`different petitioner and the first proceeding (instituted on April 15, 2014)
`
`settled before issuance of a final written decision).
`
`
`
`9
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`IPR2016-01370
`Patent 8,664,231 B2
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`
`
`Additionally, although Patent Owner argues that Arthur, Moitra, and
`
`Wyeth are cumulative of the art used in the -1091 IPR and -649 IPR cases,
`
`Patent Owner also acknowledges that unlike analogous prior art references
`
`applied in the -1091 IPR and -649 IPR, Wyeth contains a disclosure
`
`regarding subcutaneous administration. Prelim. Resp. 10–11.
`
`“[S]ubcutaneously administering” the medicament is a material limitation in
`
`the ’231 patent’s claims. Accordingly, we do not view Wyeth as being
`
`“substantially the same prior art” as asserted in the -1091 IPR and -649 IPR
`
`proceedings.
`
`B. Petitioner’s Declarations
`
`1. Dr. Miller
`
`Patent Owner argues that the expert opinions expressed by Dr.
`
`Miller should be given no weight. Prelim. Resp. 14–16. Patent Owner
`
`contends that Dr. Miller lacks adequate clinical experience as a pharmacist
`
`in preparing methotrexate and treating inflammatory autoimmune diseases
`
`with methotrexate. Id. at 14–15. Patent Owner also finds part of Dr.
`
`Miller’s testimony to be flawed and illogical, and elsewhere inconsistent
`
`with Dr. Schiff’s testimony. Id. at 15–16 (citing Ex. 1033 ¶¶ 9, 71; Ex. 1034
`
`¶ 123).
`
`We have considered Patent Owner’s arguments, but for the purpose of
`
`institution, on the limited record before us, we are not persuaded that Dr.
`
`Miller lacks credibility to the extent that his declaration should be given no
`
`weight whatsoever. For instance, Dr. Miller testifies that he has co-authored
`
`articles on the subject of treating rheumatoid arthritis with methotrexate and
`
`lectured on the topic of drugs for managing rheumatoid arthritis. Ex. 1033
`
`¶ 10. Dr. Miller’s credentials provide sufficient reason to consider his
`
`
`
`10
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`IPR2016-01370
`Patent 8,664,231 B2
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`declaration at this stage of the proceeding. And regardless, we have not
`
`found it necessary to rely on the specific portions of Dr. Miller’s testimony
`
`that Patent Owner objects to (i.e., Ex. 1033 ¶¶ 9, 71) in determining whether
`
`to institute inter partes review.
`
`2. Dr. Schiff
`
`Patent Owner likewise argues that Dr. Schiff’s opinions should not be
`
`given weight. Prelim. Resp. 17–19. Patent Owner identifies a prior
`
`consulting agreement that Dr. Schiff had with medac Pharma, Inc., under
`
`which Dr. Schiff received confidential information relating to the ’231
`
`patent, and Patent Owner states that Dr. Schiff’s acting as an expert here is
`
`inconsistent with that consulting agreement. Id. at 17 (citing Ex. 2007 ¶ 4.1;
`
`Ex. 2008; Ex. 2011 ¶¶ 5–6). Patent Owner also argues that Dr. Schiff’s
`
`testimony that the concentrated methotrexate solutions claimed in the ’231
`
`patent were known and employed by physicians before the priority date of
`
`the ’231 patent is unsupported by evidence and inconsistent with Dr.
`
`Schiff’s own clinical practice before 2006––namely, that he treated patients
`
`with autoimmune diseases with multiple subcutaneous injections of
`
`methotrexate having concentrations of 25 mg/ml as opposed to prescribing a
`
`more concentrated dose. Id. at 17–19.
`
`Whether Dr. Schiff breached his consulting agreement is not at issue
`
`here. Rather, Dr. Schiff’s testimony is relevant to the extent it addresses the
`
`understanding of one of ordinary skill in the art at the time of the invention.
`
`Patent Owner points to no authority stating that a consultant who received
`
`confidential information concerning an invention may not later present
`
`expert testimony addressing the understanding of one of ordinary skill in the
`
`art at the time of the invention. See id. at 17. In any event, on this
`
`
`
`11
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`Patent 8,664,231 B2
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`preliminary record, there is no indication that Dr. Schiff is relying on any of
`
`Patent Owner’s confidential information and we have not considered or
`
`relied on the redacted portions of Dr. Schiff’s testimony in this decision.
`
`
`
`We acknowledge Patent Owner’s other arguments regarding Dr.
`
`Schiff’s declaration, including asserted inconsistencies between Dr. Schiff’s
`
`testimony and his clinical practice, and have taken into account Patent
`
`Owner’s arguments in determining the weight to give Dr. Schiff’s testimony.
`
`We further note that in instituting inter partes review, we have relied on Dr.
`
`Schiff’s testimony regarding his understanding of the express disclosures of
`
`the prior art, as opposed to Dr. Schiff’s testimony regarding the practice of
`
`physicians at the relevant time to the extent this latter testimony is not
`
`supported by additional evidence.
`
`C. Claim Construction
`
`In an inter partes review, the Board interprets claim terms in an
`
`unexpired patent according to the broadest reasonable construction in light
`
`of the specification of the patent in which they appear. Cuozzo Speed
`
`Techs., LLC v. Lee, 136 S. Ct. 2131, 2144–46 (2016); 37 C.F.R. § 42.100(b).
`
`Under that standard, we give claim terms their ordinary and customary
`
`meaning, as would be understood by one of ordinary skill in the art, when
`
`read in view of the specification. In re Translogic Tech., Inc., 504 F.3d
`
`1249, 1256–57 (Fed. Cir. 2007). “[O]nly those terms need be construed that
`
`are in controversy, and only to the extent necessary to resolve the
`
`controversy.” Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
`
`803 (Fed. Cir. 1999).
`
`Petitioner discusses the meaning of five claim terms, explaining that
`
`those terms are “presumed to take on their ordinary and customary meaning
`
`
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`12
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`that they would have to one of ordinary skill in the art.” Pet. 10–11. For
`
`example, Petitioner asserts that “subcutaneously” means “[u]nder the skin.”
`
`Id. at 10. Patent Owner does not propose different constructions for the
`
`claim terms, but clarifies that “subcutaneously” is distinct from, and does not
`
`include, “intramuscular” or “intravenous,” despite the fact that all three
`
`involve administration “literally” under the skin. Prelim. Resp. 20–21.
`
`We agree with Patent Owner that subcutaneously is a route of
`
`administration that is distinct from intramuscular (in a muscle) or
`
`intravenous (in a vein). 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 parenterally. In particular, the medicaments are administered
`
`by intravenous, intramuscular or subcutaneous injection.”); id. at 5:32–35.
`
`In view of our analysis, we determine that construction of the
`
`remaining claim terms is not necessary for purposes of this Decision.
`
`D. 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 opposes Petitioner’s assertion. Prelim. Resp. 21–23.
`
`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. The interleukin-10 and methotrexate may
`
`be administered either together in a single pharmaceutical composition or
`
`separately. Id. at 3:20–21. The methotrexate may be administered
`
`parenterally, including subcutaneously. Id. at 5:64, 7:56–59, 8:1–2. Grint
`
`
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`Patent 8,664,231 B2
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`states 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.
`
`2. Analysis
`
`Independent claim 1 recites “subcutaneously administering . . . a
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`medicament comprising methotrexate . . . at a concentration of more than 30
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`mg/ml.” In its arguments and claim charts, Petitioner points to where Grint
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`discloses every limitation of claim 1, as well as the limitations of the other
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`challenged claims. Pet. 12–22.
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`Claim 1’s limitation of “more than 30 mg/ml” overlaps the range of
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`methotrexate concentration (“about 0.1 to about 40 mg/ml”) disclosed in
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`Grint. See id. at 13–14. Nonetheless, Petitioner contends that one of
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`ordinary skill in the art would have understood Grint to disclose
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`subcutaneous administration of methotrexate in the claimed concentration
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`for the treatment of inflammatory autoimmune diseases. Id. at 16–17 (citing
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`Ex. 1034 ¶¶ 49–53). Petitioner cites to Dr. Schiff’s testimony, which in turn
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`relies on Grint’s disclosure that “[m]ethotrexate is compounded for
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`convenient and effective administration in effective amounts” preferably
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`ranging from 1 to 35 mg (Ex. 1003, 6:60–65), to conclude:
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`Given those disclosures, a skilled artisan would thus have
`understood Grint to disclose the subcutaneous administration of
`[methotrexate] in concentrations above 30 mg/ml for the
`treatment of inflammatory autoimmune diseases. For instance,
`the skilled artisan 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
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`“preferred” dosage range disclosed by Grint) using a 1 ml
`solution. Such a formulation would be consistent with Grint’s
`teaching
`that methotrexate should be “compounded for
`convenient and effective administration in effective amounts.”
`
`
`Ex. 1034 ¶ 52 (quoting Ex. 1003, 6:60–63).
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`In response, Patent Owner argues that Petitioner has not shown that
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`there is “no reasonable difference in how the invention operates” over
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`Grint’s 0.1–40 mg/ml range, and in fact, there is a difference in how the
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`invention operates over Grint’s range. Prelim. Resp. 22 (quoting Ineos USA
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`LLC v. Berry Plastics Corp., 783 F.3d 865, 869 (Fed. Cir. 2015)). Patent
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`Owner states that “even if it is (incorrectly) assumed that the disclosures of
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`Grint regarding dosages and concentrations apply equally to all methods of
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`administration,” then Grint would indicate injection volumes of from 0.0025
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`ml to 4,000 ml. Id. According to Patent Owner, however, “Petitioner itself
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`admits that volumes greater than 1 ml are not appropriate for subcutaneous
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`administration due to the pain caused.” Id.
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`When a patent claims a numerical range, and the prior art discloses its
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`own numerical range that overlaps the claimed range, “the prior art is only
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`anticipatory if it describes the claimed range with sufficient specificity such
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`that a reasonable fact finder could conclude that there is no reasonable
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`difference in how the invention operates over the ranges.” Ineos, 783 F.3d
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`at 869. In other words, to avoid anticipation, it is important to establish the
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`criticality of a claimed range to the operability of the claimed invention; if a
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`person of ordinary skill in the art would expect that the claimed invention
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`would operate differently, or not at all, outside of the claimed range, then the
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`claimed range is critical. Id. at 869–71. The inquiry must consider “[h]ow
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`one of ordinary skill in the art would understand the scope of the disclosure
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`or, stated differently, how one of ordinary skill in the art would understand
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`the relative size of a genus or species in a particular technology.” OSRAM
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`Sylvania, Inc. v. Am. Induction Techs., Inc., 701 F.3d 698, 706 (Fed. Cir.
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`2012).
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`
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`Here, Petitioner’s assertion that “a skilled artisan would have
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`understood Grint to disclose subcutaneous administration of [methotrexate]
`
`in concentrations greater than 30 mg/ml for the treatment of inflammatory
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`autoimmune diseases” is supported by Dr. Schiff’s testimony and reasoning.
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`Pet. 16–17; Ex. 1034 ¶¶ 49–52. On this record, therefore, we cannot
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`conclude that “one of ordinary skill would not have recognized [more than
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`30 mg/ml] as an acceptable value for the range provided in the prior art.”
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`OSRAM, 701 F.3d at 705–06.
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`Furthermore, at this stage, there is insufficient evidence that the
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`claimed concentration range is critical to the operability of the claimed
`
`invention. At most, the ’231 patent identifies higher concentration ranges
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`that “can be expected” to provide a “positive impact” on patient compliance.
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`Ex. 1001, 5:22–23. The ’231 patent provides no further evidence
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`confirming this expectation, including whether the positive impact is
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`significant enough such that the claimed method would be considered to
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`operate differently outside of the claimed concentration range. On the
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`contrary, the ’231 patent recognizes that the known methotrexate solutions
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`in ready-made syringes of the prior art already have had a positive impact on
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`patient compliance. Id. at 4:65–5:1.
`
`
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`Moreover, the additional advantages to patient compliance disclosed
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`in the ’231 patent are a result of smaller injection volumes. See id. at 2:45–
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`52 (disclosing as problematic having to inject a relatively large amount of
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`solution, e.g., up to 3 ml); id.at 5:5–23 (comparing the injection of a 3 ml
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`volume, which is described as difficult to convey to a patient, with a 0.6 ml
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`injection that can be expected to have a positive impact on patient
`
`compliance). Accordingly, under the ’231 patent’s theory, there would be
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`no difference in the difficulty of conveying an injection to a patient over
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`Grint’s concentration range of about 0.1 to about 40 mg/ml where the
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`injections are all provided at the same volume, for example in 1 ml volumes.
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`For this reason, Patent Owner’s argument that Grint could potentially
`
`indicate injection volumes of from 0.0025 ml to 4,000 ml is not persuasive.
`
`First, Patent Owner admits that its volume calculations are based on an
`
`incorrect assumption. Prelim. Resp. 22 (“[E]ven if it is (incorrectly)
`
`assumed that the disclosures of Grint regarding dosages and concentrations
`
`apply equally to all methods of administration, the smallest volume . . .
`
`would be 0.0025 ml, and the largest volume . . . would be 4,000 ml.”); see
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`also Ex. 1033 ¶ 46 (“[A] skilled artisan would have further understood that it
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`would be inconvenient and ineffective to use a 40 mg/ml concentration to
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`administer 1 mg of [methotrexate], as this would require a 0.025 ml solution,
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`which cannot be accurately drawn and administered.”). Second, another set
`
`of calculations may hold the volume constant (e.g., at 1 ml) across Grint’s
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`concentration range so that the concentration (and number of injections, if
`
`necessary) are varied depending on the size of the total dosage being
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`administered.
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`We recognize that there is less overlap between Grint’s concentration
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`range and the ranges set forth in the dependent claims, specifically claim 2
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`(reciting that the methotrexate concentration is “more than 30 mg/ml to 100
`
`mg/ml”) and claim 22 (reciting that the methotrexate concentration is “from
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`40 mg/ml to 80 mg/ml”). However, given the lack of evidence of criticality
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`of the claimed range on the current record, we find that at this stage there is
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`a reasonable likelihood that Petitioner would succeed in its challenge to the
`
`dependent claims identified in the Petition as being anticipated by Grint as
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`well. See Ineos, 783 F.3d at 869 (finding that the district court erred in
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`concluding that a prior art reference disclosed particular points within a
`
`range because “the disclosure of a range . . . does not constitute a specific
`
`disclosure of the endpoints of that range” but nevertheless affirming the
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`district court’s anticipation holding because the claimed range was not
`
`critical to the operability of the invention (quoting Atofina v. Great Lakes
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`Chem. Corp., 441 F.3d 991, 1000 (Fed. Cir. 2006)).
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`Based on the information presented at this stage of the proceeding, we
`
`are persuaded that Petitioner has shown a reasonable likelihood of
`
`establishing that each limitation of claims 1, 2, 4–6, 11–13, 17, and 22 is
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`disclosed by Grint. Pet. 12–22.
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`E. Obviousness over Grint and Arthur Alone, or Further in View of
`Either Moitra or Insulin Admin.
`
`
`Petitioner asserts that dependent claims 7–10, 14–16, and 19–21 of the
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`’231 patent are obvious over Grint and Arthur alone, or further in view of
`
`either Moitra or Insulin Admin. Pet. 22–28.10 Patent Owner opposes
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`Petitioner’s assertion. Prelim. Resp. 23–26.
`
`
`10 Petitioner cites to Arthur 2001 (Ex. 1024) as additional evidence. Pet. 9–
`10, 26–27. Petitioner merely states that Arthur’s findings are reported in
`summary format in Arthur 2001. Id. at 26–27. The relevance of Arthur
`2001 is unclear as the Petition does not cite Arthur 2001 as disclosing any
`claim limitations or as supportive of a reason to combine. Accordingly, we
`do not give Arthur 2001 any weight. See 37 C.F.R. § 42.104(b)(5) (“The
`Board may exclude or give no weight to the evidence where a party has
`
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`1. Arthur
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`Arthur discloses the results of a study comparing the safety and
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`efficacy of methotrexate administered by intramuscular and subcutaneous
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`injection to treat rheumatic conditions. Ex. 1023, at 256. In the study,
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`patients were taught to self-administer methotrexate subcutaneously and
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`were then discharged to perform this task at home. Id. The patients were
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`provided thr