Sandoz Inc.v.EKR Therapeutics, LLC

Patent Trial and Appeal BoardApr 24, 2015

12407557 (P.T.A.B. Apr. 24, 2015)

Trials@uspto.gov Paper 20 Tel: 571-272-7822 Entered: April 24, 2015 UNITED STATES PATENT AND TRADEMARK OFFICE _______________ BEFORE THE PATENT TRIAL AND APPEAL BOARD _______________ SANDOZ INC., Petitioner, v. EKR THERAPEUTICS, LLC, Patent Owner. _______________ Case IPR2015-00008 Patent 7,659,291 _______________ Before JACQUELINE WRIGHT BONILLA, SHERIDAN K. SNEDDEN, and ZHENYU YANG, Administrative Patent Judges. SNEDDEN, Administrative Patent Judge. DECISION Denying Institution of Inter Partes Review 37 C.F.R. § 42.108 IPR2015-00008 Patent 7,659,291 2 I. INTRODUCTION Sandoz Inc. (“Petitioner”) filed a Petition (Paper 1; “Pet.”) to institute an inter partes review of claims 1–12 of US 7,659,291 B2 (Ex. 1001; “the ’291 patent”). Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center (“Patent Owner”) filed a corrected Patent Owner Preliminary Response. Paper 12 (“Prelim. Resp.”). We have jurisdiction under 35 U.S.C. § 314. The standard for instituting an inter partes review is set forth in 35 U.S.C. § 314(a), which states that an inter partes review may not be instituted unless “the information presented in the [Petition and Preliminary Response] shows that there is a reasonable likelihood that the petitioner would prevail with respect to at least 1 of the claims challenged in the petition.” Upon consideration of the above-mentioned Petition and Preliminary Response we conclude that Petitioner has not established a reasonable likelihood that it would prevail in showing the unpatentability of at least one challenged claim. Therefore, we deny the Petition for an inter partes review. A. Related Proceedings The parties represent that the ’291 patent is the subject of litigation filed by Patent Owner against Petitioner in Chiesi USA, Inc. v. Sandoz Inc., Case No. 1:13- cv-5723 (D.N.J.). Pet. 3; Paper 4, 1. Petitioner concurrently filed Petitions for inter partes review of claims in several other patents owned Patent Owner, including IPR2015-00005 (U.S. 8,455,524 B2), IPR2015-00006 (U.S. 7,612,102 B2), and IPR2015-00007 (U.S. 7,659,290 B2). B. The ’291 patent (Ex. 1001) The ’291 patent relates to ready-to-use premixed pharmaceutical IPR2015-00008 Patent 7,659,291 3 compositions of nicardipine, a calcium ion influx inhibitor useful for the treatment of cardiovascular and cerebrovascular disorders. Ex. 1001, Abstract, 1:1621. The formulations of the ’291 patent are described as “stable, allow medical personal to use prepared containers containing an injectable formulation off the shelf without additional preparation, avoid potential contamination problems, and eliminate dosage errors.” Id. at 1: 5459. The formulations are mixed from the point of manufacture and do not require dilution before administration to patients and have a pH within the range from about 3.6 to about 4.7. Id. at 3:1324; 11:2529. According to the ’291 patent, before its invention, nicardipine hydrochloride was sold in capsule form and in an injectable intravenous form. Id. at 1:20–32. The injectable intravenous form, CARDENE® I.V., is marketed in glass ampuls in a concentration of 2.5 mg/mL, and must be diluted in a compatible intravenous fluid before administration. Id. The requirement for diluting CARDENE® I.V. before use is associated with a number of disadvantages, the most significant of which is that the diluted solution is only stable for 24 hours at room temperature. Id. at 1:40–59. Other disadvantages include variable pH levels, potential for contamination, dosage errors, and safety hazards associated with the use of glass ampuls. Id. The ’291 patent describes its invention as overcoming these disadvantages. Id. C. Representative Claim Claim 1 is representative of the challenged claims, and is reproduced below: 1. A method for treating acute elevations of blood pressure in a human subject in need thereof, said method comprising parenterally administering a composition comprising from about 0.1 to 0.4 mg/mL nicardipine or a pharmaceutically IPR2015-00008 Patent 7,659,291 4 acceptable salt thereof; a tonicity agent; and a buffer; wherein the composition requires no dilution before administration and has a pH from about 3.6 to about 4.7, the composition when stored in container for at least three months at room temperature exhibiting (i) less than a 10% decrease in the concentration of nicardipine or pharmaceutically acceptable salt thereof and (ii) a total impurity formation of less than about 3%. D. Prior Art and Supporting Evidence Petitioner relies on the following prior art: U.S. Patent No. 5,164,405 to McFarlane, et al. (“McFarlane”). Ex. 1003. Japanese Patent Publication JP 2002-177364 published on June 25, 2002 by Kenichi, et al., entitled, “Drug Container” (“JP ’364”). Ex. 1004. Cardene® I.V., Physicians’ Desk Reference, 2004 WL 2459623 (“Cardene PDR”). Ex. 1005. Baaske, D. M., “Stability of nicardipine hydrochloride in intravenous solutions,” Am. J. Health Syst. Pharm., 1996, 53, 1701-05 (“Baaske”). Ex. 1006. Petitoiner further relies on the Declaration of Alpaslan Yaman, Ph.D. (“Yaman Decl.”) (Ex. 1002). E. Asserted Grounds Petitioner challenges claims 1–12 of the ’291 patent on the following grounds. Pet. 12–55. Reference[s] Basis Claims challenged Cardene PDR and JP ’364 § 103(a) 1–12 Cardene PDR, JP ’364, McFarlane, and Baaske, § 103(a) 1–12 IPR2015-00008 Patent 7,659,291 5 II. ANALYSIS A. Claim Interpretation 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); In re Cuozzo Speed Techs., LLC, 778 F.3d 1271, 1279–81 (Fed. Cir. 2015). Claim terms 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). Any special definition for a claim term must be set forth in the specification with reasonable clarity, deliberateness, and precision. In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). We determine that, for purposes of this Decision, it is unnecessary to expressly construe any claim term. B. Asserted Grounds of Unpatentability 1. Obviousness of Claims 1–12 over the Combination of Cardene PDR and JP ’364 Petitioner contends that claims 112 of the ’291 patent are rendered obvious by the combination of Cardene PDR and JP ’364. Pet. 1233. Each challenged claim recites a method of using a nicardipine hydrochloride formulation having a concentration of between 0.1 to 0.4 mg/mL and recites certain threshold stability and impurity requirements. Specifically, the claims require the nicardipine hydrochloride formulation to exhibit less than a 10% decrease in the concentration of nicardipine hydrochloride and a total impurity formation of less than about 3%, when the aqueous solution is stored in the container for at least three months (claims 12) to one year (claims 312) at room temperature. IPR2015-00008 Patent 7,659,291 6 The Petitioner provides an analysis and detailed claim chart mapping each element of the claims to a teaching in the combined prior art. Id. Petitioner relies on Cardene PDR for the teaching of a nicardipine hydrochloride formulation having a drug concentration of 0.1 mg/mL. Id. at 13. With regard to the stability and impurity requirements of the claims, Petitioner contends that JP ’364 discloses these elements. Id. at 14. JP ’364 discloses pre-mixed nicardipine hydrochloride solutions in containers suitable for long-term storage due to having “little adsorption of a drug.” Ex. 1004, Abstract, ¶¶ 2, 5, 35. Petitioner argues that “[t]otal impurity formation over time is an inherent property of the nicardipine hydrochloride solution and the container within which it is stored.” Pet. 20 (citing Yaman Decl. ¶ 145). Petitioner contends that the combination of Cardene PDR and JP ’364 achieves a pre-mixed nicardipine hydrochloride solution satisfying the recited impurity-formation limitations. Id. at 2021. We are not persuaded. Cardene PDR is an excerpt from the 2004 Physicians’ Desk Reference providing a summary of the drug Cardene I.V. (for intravenous administration contains 2.5 mg/mL of nicardipine hydrochloride). Ex. 1005. Cardene PDR discloses that Cardene I.V. is administered by slow continuous infusion at a concentration of 0.1 mg/mL, which requires each ampul (25 mg) to be diluted with 240 mL of compatible intravenous fluid (see below), resulting in 250 mL of solution at a concentration of 0.1 mg/mL. Id. at 9. As Patent Owner notes, however, Cardene PDR states that the diluted nicardipine hydrochloride solution is stable only for 24 hours at room temperature, and JP ’364 does not include any teaching of impurity formation. Prelim. Resp. 3031 (citing Ex. 1005, 10). Petitioner does not sufficiently explain how the prior art teachings can be combined to overcome these deficiencies to suggest a product meeting both the stability and impurity-formation limitations of the claims. IPR2015-00008 Patent 7,659,291 7 Petitioner’s inherency argument also fails. “[I]nherency may supply a missing claim limitation in an obviousness analysis.” PAR Pharm., Inc. v. TWI Pharm., Inc., 773 F.3d 1186, 1194–95 (Fed. Cir. 2014) (citations omitted). The Federal Circuit has cautioned, however, that the use of inherency doctrine “must be carefully circumscribed in the context of obviousness.” Id. at 1195. Inherency “may not be established by probabilities or possibilities.” Bettcher Indus., Inc. v. Bunzl USA, Inc., 661 F.3d 629, 639 (Fed. Cir. 2011) (citing In re Oelrich, 666 F.2d 578, 581 (CCPA 1981)). Instead, “the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art.” PAR Pharm., 773 F.3d at 1196. There is no evidence on record to show that simply placing the diluted formulation on Cardene PDR into the container disclosed by JP ’364 necessarily results in a product meeting both the stability and impurity-formation limitations of the claims. For example, Petitioner does not provide any independent testing data to support its inherency theory on the impurity-formation limitation. Thus, we are not persuaded that evidence of record sufficiently establishes that the impurity- formation limitation is necessarily present in, or is the natural result of, the combined teachings of Cardene PDR and JP ’364. In view of the above, we conclude that Petitioner has not established a reasonable likelihood it would prevail in showing that claims 1–12 would have been obvious over the combination of Cardene PDR and JP ’364. 2. Obviousness of Claims 1–12 over the Combination of Cardene PDR, JP ’364, McFarlane, and Baaske Petitioner asserts that claims 1–12 would have been obvious over the combination of Cardene PDR, JP ’364, McFarlane, and Baaske. Pet. 34–55. In this ground, Petitioner further relies on the teachings of McFarlane and Baaske to IPR2015-00008 Patent 7,659,291 8 meet the stability and impurity requirements of the challenged claims. We determine, however, that the teachings of McFarlane and Baaske fail to cure the deficiencies associated with the combination of Cardene PDR and JP ’364 discussed above. Petitioner argues that recited stability and purity limitations are inherent properties of the combined teachings of the cited prior art. Id. at 4245. As noted above, inherency requires the missing elements to be necessarily present, or the natural result of the combination of elements explicitly disclosed by the cited prior art. PAR Pharm., 773 F.3d at 1196. Thus, to establish inherency, Petitioner must present sufficient evidence, either from the prior art or through its own testing data, to show that nicardipine hydrochloride solutions prepared as suggested in the prior art, in fact, would satisfy the recited impurity-formation limitation, when stored in a container taught by JP ’364. Petitioner fails to make such a showing. Baaske discloses several admixtures containing either 0.5 mg/mL or 0.05 mg/mL nicardipine hydrochloride in 1) 5% dextrose and 0.45% sodium chloride injection, 2) 5% dextrose and 0.9% sodium chloride injection, 3) 0.45% sodium chloride injection, 4) 0.9% sodium chloride injection, 5) 5% dextrose and lactated Ringer's injection, 6) 5% dextrose injection, 7) lactated Ringer's injection, 8) 5% sodium bicarbonate injection, and 9) 5% dextrose injection with potassium chloride 40 meq/L. Ex. 1005, Abstract. The stability of these formulations was compared after storage for 7 days in either glass or polyvinyl chloride (PVC) containers. The results in Baaske show that most of the nicardipine hydrochloride admixtures were stable in glass containers for up to seven days, but not stable when stored in PVC containers. Id. Storage periods greater than 7 days were not tested. The subject matter disclosed in Baaske is different from the subject matter IPR2015-00008 Patent 7,659,291 9 of the claims, however, in that the concentrations of the nicardipine hydrochloride solutions studied in Baaske are 0.5 mg/mL and 0.05 mg/mL—both of which are outside of the claimed concentration range. Id. at 1. In addition, Baaske only reports that the nicardipine hydrochloride solutions are stable for up to seven days, significantly shorter than three month and one year time periods recited in the claims. Id. Petitioner, however, does not sufficiently explain how the differences in the teachings of Basske can be overcome in order to achieve both the stability and impurity-formation limitations of the claims. Petitioner further relies on the nicardipine hydrochloride solutions disclosed in Examples II and Examples IV of McFarlane in an attempt to establish that all the claimed elements were known in the prior art. Pet. 4245. Example II of McFarlane details the production of a 1 mg/mL and 2.5 mg/mL nicardipine hydrochloride formulations that contain sorbitol, sodium hydroxide, citric acid monohydrate and water. Ex. 1003, 6:5662, Table 2. McFarlane discloses that the 1 mg/mL or 2.5 mg/mL nicardipine hydrochloride showed “substantially identical” and “excellent stability for up to 3 years at 25°C., with no significant loss in potency.” Id. at 7:11–17, 7:28–31, Table 7. Example IV of McFarlane provides the results of an experiment that compares a buffered formula (0.0025M citrate equivalent) and unbuffered formula using Dextrose 5% Injection solution, of various pH from pH 37.5, using a 1:10 dilution. Id. at 9:35–10:32. The results show that higher pH values after dilution with the Dextrose 5% Injection solution was associated with precipitation of nicardipine. Id. The compositions of Examples II and Examples IV of McFarlane are different, however. Example II discloses 1 mg/mL and 2.5 mg/mL nicardipine hydrochloride solutions. Id. at 6:4254, 7:1017, 8:5668 (Table 7). While the IPR2015-00008 Patent 7,659,291 10 data in McFarlane Table 7 show that the concentration of those solutions decreased by less than 10% after 12 months at room temperature, they do not satisfy the element of the challenged claims requiring a final active ingredient concentration from about 0.1 to 0.4 mg/mL. Id. McFarlane Example IV discloses the 1:10 dilution of nicardipine hydrochloride solutions using a Dextrose 5% Injection solution. Id. at 9:3510:33. There is no data on this record, however, confirming that the recited stability and impurity-formation limitation of the claims are satisfied by the solutions disclosed in Example IV. On the contrary, evidence of record suggests that dilution of a concentrated nicardipine hydrochloride solution with a dextrose containing fluid renders the diluted formulation unstable. See Ex. 1005 (disclosing that a nicardipine hydrochloride solution diluted with dextrose containing injection fluids is stable for 24 hours at controlled room temperature when stored in glass or polyvinyl chloride containers.). In view of the above, we conclude that Petitioner has not established a reasonable likelihood it would prevail in showing that claims 1–12 would have been obvious over the combination of Cardene PDR, JP ’364, McFarlane, and Baaske. III. CONCLUSION For the foregoing reasons, the information presented in the Petition and accompanying evidence do not establish a reasonable likelihood that Petitioner would prevail in showing the unpatentability of any one of claims 1–12 of the ’291 patent. IPR2015-00008 Patent 7,659,291 11 IV. ORDER For the reasons given, it is ORDERED that Petitioner’s request for an inter partes review of claims 1– 12 of the ’291 patent is denied. PETITIONER: Matthew Kreeger Matthew D’Amore Elizabeth Cary Miller David J. Austin MORRISON & FOERSTER LLP mkreeger@mofo.com mdamore@mofo.com emiller@mofo.com daustin@mofo.com PATENT OWNER: Edgar H. Haug Nicholas F. Giove FROMMER LAWRENCE & HAUG LLP ehaug@flhlaw.com ngiove@flhlaw.com

Sandoz Inc. v. EKR Therapeutics, LLC