Sandoz Inc.v.EKR Therapeutics, LLC

Patent Trial and Appeal BoardApr 24, 2015

12971084 (P.T.A.B. Apr. 24, 2015)

Trials@uspto.gov Paper No. 20 571-272-7822 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 IPR2015-00005 Patent 8,455,524 B2 ____________ Before JACQUELINE WRIGHT BONILLA, SHERIDAN K. SNEDDEN, and ZHENYU YANG, Administrative Patent Judges. YANG, Administrative Patent Judge. DECISION Denying Institution of Inter Partes Review 37 C.F.R. § 42.108 IPR2015-00005 Patent 8,455,524 B2 2 INTRODUCTION Sandoz Inc. (“Petitioner”) filed a Petition for an inter partes review of claims 1–28 of U.S. Patent No. 8,455,524 B2 (Ex. 1001, “the ’524 patent”). Paper 1 (“Pet.”). EKR Therapeutics, LLC (“Patent Owner”) filed a Preliminary Response. Paper 8 (“Prelim. Resp.”). We have jurisdiction under 35 U.S.C. § 314. For the reasons provided below, we determine 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. Related Proceedings According to the parties, Patent Owner previously asserted the ’524 patent against Petitioner in Chiesi USA, Inc., et al. v. Sandoz Inc. et al., 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 by Patent Owner, including IPR2015-00006 (US 7,612,102 B2), IPR2015-00007 (US 7,659,290 B2), and IPR2015- 00008 (US 7,659,291 B2). The ’524 Patent The ’524 patent relates to “ready-to-use premixed pharmaceutical compositions of nicardipine or a pharmaceutically acceptable salt and methods for use in treating cardiovascular and cerebrovascular conditions.” Ex. 1001, Abstract. According to the ’524 patent, before its invention, IPR2015-00005 Patent 8,455,524 B2 3 nicardipine hydrochloride was sold in capsule form and in an injectable intravenous form. Id. at 1:24–25. The injectable intravenous form, CARDENE® I.V., marketed in glass ampuls in a concentration of 2.5 mg/mL, must be diluted in a compatible intravenous fluid before administration. Id. at 1:28–32. 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 1:44–47. Other disadvantages include variable pH levels, potential for contamination, dosage errors, and safety hazards associated with the use of glass ampuls. Id. at 1:47–55. The ’524 patent describes its invention as overcoming these disadvantages. Id. at 1:56–62. Illustrative Claims Claims 1–3 and 8 are independent claims. Claims 1 and 3 are representative. They read as follows: 1. A method for treating acute elevations of blood pressure in a human subject in need thereof, said method comprising parenterally administering a pre-mixed aqueous solution comprising from about 0.1 to 0.4 mg/mL nicardipine or a pharmaceutically acceptable salt thereof; a tonicity agent; and a buffer; wherein the aqueous solution requires no dilution before administration and has a pH from about 3.6 to about 4.7, the aqueous solution stored in a container such that the aqueous solution is in contact with non-polar polymers, the aqueous solution when stored in the 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 IPR2015-00005 Patent 8,455,524 B2 4 thereof and (ii) a total impurity formation of less than about 3%. 3. A method for treating acute elevations of blood pressure in a human subject in need thereof, said method comprising parenterally administering to a subject in need thereof, a pre- mixed aqueous solution with a pH from about 3.6 to about 4.7 comprising: from about 0.1 to 0.4 mg/mL nicardipine hydrochloride; a tonicity agent selected from (i) about 4.5% to about 5% dextrose or (ii) about 0.8% to about 0.9% sodium chloride; and a buffer; the aqueous solution contained in a pharmaceutically acceptable container such that the aqueous solution is in contact with non-polar polymers, the aqueous solution when stored in the 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 a total impurity formation of less than about 3%. Claim 2 is similar to claim 1, and claim 8 is similar to claim 3. The only difference is that the methods of claims 2 and 8 are “for inducing hypotension,” whereas the methods of claims 1 and 3 are “for treating acute elevations of blood pressure.” Asserted Grounds of Unpatentability Petitioner asserts the following grounds, each of which challenges the patentability of claims 1–28: IPR2015-00005 Patent 8,455,524 B2 5 Basis References § 103 Cardene PDR1 and JP ’3642 § 103 Cardene PDR, JP ’364, Baaske,3 and the ’405 patent4 The earliest asserted priority date of the challenged claims is April 18, 2006. Ex. 1001, 1:8–15. Thus, each asserted reference qualifies as prior art under 35 U.S.C. § 102(b). In support of its patentability challenge, Petitioner relies on the Declaration of Dr. Alpaslan Yaman (Ex. 1002). ANALYSIS Claim Construction In an inter partes review, the Board interprets a claim term in an unexpired patent according to its broadest reasonable construction in light of the specification of the patent in which it appears. 37 C.F.R. § 42.100(b); In re Cuozzo Speed Techs., LLC, 778 F.3d 1271, 1279–81 (Fed. Cir. 2015). Under that standard, absent any special definitions, we assign claim terms their ordinary and customary meaning, as would be understood by one of ordinary skill in the art at the time of the invention, in the context of the 1 Cardene® I.V., Physicians’ Desk Reference, 2004 WL 2459623 (Ex. 1005, “Cardene PDR”). 2 Kenichi et al., Japanese Patent Publication JP 2002-177364, published on June 25, 2002 (Ex. 1004, “JP ’364”) 3 Baaske et al., Stability of nicardipine hydrochloride in intravenous solutions, Am. J. Health Syst. Pharm. 53: 1701–05 (1996) (Ex. 1006, “Baaske”). 4 McFarlane et al., U.S. Patent No. 5,164,405, issued November 17, 1992 (Ex. 1003, “’405 patent”). IPR2015-00005 Patent 8,455,524 B2 6 entire patent disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). The parties dispute the construction of the term “a pre-mixed aqueous solution,” as recited in each independent, challenged claim. See Pet. 6–8; Prelim. Resp. 20–23. We determine that, for purposes of this Decision, it is unnecessary to expressly construe the term. Petitioner also asks us to construe “a total impurity formation,” as recited in each independent, challenged claim. Petitioner proposes, and Patent Owner does not object, that we construe this term to mean “a total nicardipine-related impurity formation.” Pet. 8–9. For purposes of this Decision, we adopt Petitioner’s construction. Real Party in Interest Patent Owner urges that we deny the Petition because Petitioner fails to identify Sandoz AG and ACS Dobfar Info S.A. (“Dobfar”) as real parties in interest with respect to the Petition. Prelim. Resp. 6–16. With the panel’s authorization, Petitioner filed a Reply (Paper 13), and Patent Owner filed a Sur-reply (Paper 17), addressing this issue. Because we deny the Petition as Petitioner has not established a reasonable likelihood that it would prevail in showing the unpatentability of at least one challenged claim, we need not reach the real-party-in-interest issue. IPR2015-00005 Patent 8,455,524 B2 7 Patentability Analysis Prior Art Teachings Cardene PDR teaches that CARDENE® I.V., available for intravenous administration, is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desirable. Ex. 1005, 4. Each ampul contains 25 mg nicardipine hydrochloride in 10 mL solution (i.e., at a concentration of 2.5 mg/mL) and should be diluted with 240 mL of compatible intravenous fluid before infusion, resulting in a solution at a concentration of 0.1 mg/mL. Id. at 1, 9. JP ’364 teaches “a prefilled syringe having little adsorption of a drug.” Ex. 1004, 2. Such a syringe is filled with a drug liquid or an injection liquid before transporting. Id. at 3. According to JP ’364, A prefilled syringe has many advantages, such as being very simple to operate, allowing correct dosing without dose error because the drug liquid and dose have already been set, and avoiding bacterial infection because the drug does not need to be prepared, even in an emergency. Id. JP ’364 specifically teaches nicardipine hydrochloride as a pharmacologically effective substance in the liquid. Id. at 3, 4. The ’405 patent teaches “a stable pharmaceutical composition containing nicardipine hydrochloride, a non-chloride isotonicity agent, a buffering agent and a pharmaceutically acceptable aqueous vehicle for parenteral administration.” Ex. 1003, Abstract. According to the ’405 patent, controlling the pH level of the formulation is essential to maintain the aqueous solubility of the nicardipine salts. Id. at 4:26–30. Specifically, the ’405 patent teaches using citrate buffer to maintain “the pH of the IPR2015-00005 Patent 8,455,524 B2 8 composition in the range of about 3.5–4.5.” Id. at 4:42–46. In addition, the ’405 patent teaches that solutions containing either 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. Baaske teaches that solutions containing nicardipine hydrochloride at concentrations of 0.05 mg/mL and 0.5 mg/mL are stable in glass containers for up to seven days. Ex. 1006, 1, 3. In contrast, according to Baaske, “[c]oncentrations of nicardipine hydrochloride slowly decreased in PVC containers, sometimes to less than 85% of the initial drug concentration within 24 hours.” Id. at 3. Obviousness over Cardene PDR and JP ’364 Petitioner asserts that claims 1–28 would have been obvious over the combination of Cardene PDR and JP ’364. Pet. 12–34. We determine that Petitioner has not established a reasonable likelihood it would prevail on this basis. We conclude so for at least two independent reasons. First, all challenged claims recite, either directly or through their dependency, a nicardipine solution with “a pH from about 3.6 to about 4.7.” Petitioner, relying on Dr. Yaman’s Declaration, argues that A POSA [person of ordinary skill in the art] would have recognized that the dilution of concentrated Cardene® I.V. having a pH of 3.5 in accordance with the Cardene PDR instructions would provide solutions with a pH falling within the range of, or a pH at least significantly overlapping with, “about 3.6 to about 4.7.” A POSA would have been motivated to select such a pH range in a pre-mixed nicardipine 0.1 mg/mL IPR2015-00005 Patent 8,455,524 B2 9 solution. Further optimization of the pH to maintain the solubility and stability of parenteral formulations would have been a routine step for a POSA. Pet. 19 (internal citations omitted); Ex. 1002 ¶¶ 129–31. We are not persuaded. Cardene PDR teaches that the commercially available, concentrated nicardipine hydrochloride (2.5 mg/mL) has a pH of 3.5. Ex. 1005, 1. Neither party contends that Cardene PDR expressly discloses the pH of a diluted solution having 0.1 to 0.4 mg/mL nicardipine hydrochloride. Citing Dr. Yaman’s testimony, Petitioner argues that diluting the concentrated nicardipine hydrochloride of Cardene PDR “would provide solutions with a pH falling within the range of, or a pH at least significantly overlapping with, ‘about 3.6 to about 4.7.’” Pet. 19 (citing Ex. 1002 ¶¶ 129–30). As noted by Patent Owner, however, evidence of record indicates that diluting a concentrated nicardipine hydrochloride can yield pH levels outside the claimed range of “about 3.6 to about 4.7.” Prelim. Resp. 29. For example, Patent Owner refers to Baaske for teaching that the pH levels of diluted nicardipine hydrochloride can be as high as 5.9, notably higher than 4.7, the highest pH in the recited pH range. Id. (citing Ex. 1006, 3). Such evidence on the pH levels does not support Dr. Yaman’s opinion. The Petition and evidence cited therein do not establish sufficiently that Cardene PDR teaches, expressly or inherently (i.e., as necessarily present or a natural result of dilution), a composition comprising from about 0.1 to 0.4 mg/mL nicardipine and having a pH from about 3.6 to about 4.7, as required in the challenged claims. IPR2015-00005 Patent 8,455,524 B2 10 In addition, Petitioner does not rely on JP ’364 to support its argument regarding the pH levels. In fact, as Patent Owner points out, JP ’364 does not discuss the pH of any nicardipine solutions. Prelim. Resp. 29. We are not persuaded that a skilled artisan, knowing the teachings of Cardene PDR and JP ’364, would have been motivated to select the pH range for a pre- mixed nicardipine solution as claimed. Second, all challenged claims recite, either directly or through their dependency, an impurity-formation limitation, requiring the nicardipine solution “when stored in the container for at least three months at room temperature exhibiting . . . (ii) a total impurity formation of less than about 3%.” 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. 24. According to Petitioner, “[b]y merely choosing to follow the teachings of the Cardene PDR and JP ’364, a POSA would obtain a pre-mixed nicardipine hydrochloride solution” satisfying the recited impurity-formation limitation. Id. We are not persuaded. “[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 IPR2015-00005 Patent 8,455,524 B2 11 present, or the natural result of the combination of elements explicitly disclosed by the prior art.” PAR Pharm., 773 F.3d at 1196. For purposes of this Decision, we assume, without deciding, that one of ordinary skill in the art would have had a reason to combine the teachings of the prior art. Even so, it still “matters greatly whether anything the skilled artisan would be prompted by the prior art to do is in fact within the scope of the . . . claim.” In re Kao, 639 F.3d 1057, 1066 (Fed. Cir. 2011). Thus, 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. This, Petitioner has failed to do. As Patent Owner correctly points out, 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. See Prelim. Resp. 30, 31. Nor does Petitioner provide any independent testing data to support its inherency theory on the impurity- formation limitation. Thus, we are not persuaded 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 sum, because Petitioner fails to sufficiently account for at least the pH levels and the impurity-formation limitation in the challenged claims, we conclude that Petitioner has not established a reasonable likelihood it would prevail in showing that claims 1–28 would have been obvious over the combination of Cardene PDR and JP ’364. IPR2015-00005 Patent 8,455,524 B2 12 Obviousness over Cardene PDR, JP ’364, Baaske, and the ’405 Patent Petitioner asserts that claims 1–28 would have been obvious over the combination of Cardene PDR, JP ’364, Baaske, and the ’405 Patent. Pet. 34–57. We determine that Petitioner has not established a reasonable likelihood it would prevail on this basis. We conclude so because the teachings of Baaske and the ’405 patent do not remedy the deficiency of Cardene PDR and JP ’364 regarding the impurity-formation limitation, as discussed above. According to Petitioner, the ’405 patent teaches that “no more than 1.5% of the nicardipine hydrochloride could have formed impurities during 12 months at room temperature.” Pet. 45 (citing Ex. 1002 ¶ 204; Ex. 1003, 6:42–60, Example IIC, Table 7). Petitioner also refers to Baaske for teaching nicardipine solutions remain stable in glass containers. Id. (citing Ex. 1006, 3). In view of these teachings, Petitioner concludes, “a POSA would have reasonably expected that a nicardipine hydrochloride solution stored in a non-polar container would have had both the stability and purity levels claimed.” Id. (citing Ex. 1002 ¶ 205). We are not persuaded. As Petitioner acknowledges, the ’405 patent reports stability data for 1.0 mg/mL and 2.5 mg/mL nicardipine hydrochloride solutions, both of which are outside of the concentration range of “from 0.1 to 0.4 mg/mL,” as recited in the challenged claims. See Pet. 45; Ex. 1003, 6:46–60, 7:11–17. The ’405 patent also shows data of nicardipine hydrochloride solutions “using a 1:10 dilution.” Ex. 1003, 9:40–41. The dilution results in nicardipine hydrochloride solutions of 0.1 mg/mL and 0.25 mg/mL, within the claimed concentration range. The data of the diluted nicardipine IPR2015-00005 Patent 8,455,524 B2 13 hydrochloride solutions, however, relate to the compatibility with buffered formula, and not stability or purity. Id. at 9:38–45. Indeed, the diluted solutions were examined only for appearance “after mixing,” and not for any prolonged period of time, certainly not the “at least three months” as required in the challenged claims. Id. at 9:46–47, Tables 9 and 10. Similarly, 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. Ex. 1006, 1. Furthermore, Baaske only reports that the nicardipine hydrochloride solutions are stable for up to seven days, significantly shorter than the recited “at least three months.” Id. Petitioner, again, resorts to an inherency argument. Pet. 46. But, as explained above, neither the prior art nor any other evidence of record addresses adequately the impurity formation of “from about 0.1 to 0.4 mg/mL” nicardipine solutions over “at least three months,” as recited in the challenged claims. For example, Petitioner does not provide any independent testing data to support the inherency theory. Thus, we are not persuaded that the impurity-formation limitation is necessarily present, or is the natural result of the combination of the teachings of Cardene PDR, JP ’364, Baaske, and the ’405 Patent. In sum, because Petitioner does not sufficiently explain how the combined prior art teachings would have suggested the impurity-formation limitation, we conclude that Petitioner has not established a reasonable likelihood it would prevail in showing that claims 1–28 would have been IPR2015-00005 Patent 8,455,524 B2 14 obvious over the combination of Cardene PDR, JP ’364, Baaske, and the ’405 Patent. 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 1–28 of the ’524 patent. ORDER Accordingly, it is ORDERED that Petitioner’s request for an inter partes review of claims 1–28 of the ’524 patent is denied. IPR2015-00005 Patent 8,455,524 B2 15 For 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 For PATENT OWNER: Edgar H. Haug Nicholas F. Giove FROMMER LAWRENCE & HAUG LLP ehaug@flhlaw.com ngiove@flhlaw.com

Sandoz Inc. v. EKR Therapeutics, LLC