DURECT CORPORATION

Patent Trials and Appeals Board

Jan 28, 2022

2021005475 (P.T.A.B. Jan. 28, 2022)

UNITED STATES PATENT AND TRADEMARK OFFICE UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www.uspto.gov APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/870,745 01/12/2018 Adrian Neil Verity DURE-055 CON7 9001 111104 7590 01/28/2022 DURECT CORPORATION BOZICEVIC, FIELD & FRANCIS & LLP 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER ALAWADI, SARAH ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 01/28/2022 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): docket@bozpat.com patents@durect.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE _________________ BEFORE THE PATENT TRIAL AND APPEAL BOARD _________________ Ex parte ADRIAN NEIL VERITY _________________ Appeal 2021-005475 Application 15/870,745 Technology Center 1600 _________________ Before DEBORAH KATZ, ULRIKE W. JENKS, and TAWEN CHANG, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appeal 2021-005475 Application 15/870,745 2 Appellant1 seeks our review2, under 35 U.S.C. § 134(a), of the Examiner’s decision to reject claims3 212, 214, 215, 219-224, 231, and 232. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. Appellant’s specification is directed to delivery of agents for localized anesthetic effects. (Spec. ¶ 1.) Appellant’s claim 219 recites: A method for providing an anesthetic effect at a site in a subject, said method comprising administering by injection a composition at the site, and the administering comprises administering an effective amount of the composition to provide a sustained local anesthetic effect at the site of at least 24 hours after the administration, the composition consisting of: bupivacaine in an amount ranging from 1 wt% to 10 wt%, based on weight of the composition; cholesterol; a phosphatidylcholine; a phospholipid other than the phosphatidylcholine; an ester of caprylic acid with glycerol; water; and sodium chloride in an amount ranging from 0.01 wt% to 1 wt%, based on weight of the composition, 1 We use the word “Appellant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party-in-interest as Durect Corporation. (Appeal Br. 3.) 2 We consider the Final Office Action issued June 12, 2020 (“Final Act.”), the Appeal Brief filed March 10, 2021 (“Appeal Br.”), the Examiner’s Answer issued on July 23, 2021 (“Ans.”), and the Reply Brief filed September 22, 2021 (“Reply Br.”). 3 Appellant amended claim 219 to recite the limitations of claim 211 and, thus, to have all of the remaining claims depend from claim 219 instead of claim 211. (See Advisory Action issued September 25, 2020.) Appeal 2021-005475 Application 15/870,745 3 wherein a combined amount of the cholesterol, phospholipid, and phosphatidylcholine in the composition ranges from 1 wt% to 95 wt%, based on weight of the composition. (Appeal Br. 30.) The Examiner rejects Appellant’s claims under 35 U.S.C. § 103(a) as being obvious over Mantripragada (U.S. Patent Application Publication 2003/0211140, published November 13, 2003) and Sackler (U.S. Patent Application Publication 2002/0114835, published August 22, 2002). (See Final Act. 2-8.) Mantripragada is directed to methods of making pharmaceutical compositions and drug delivery systems (called “oil-core particles”) that provide sustained release of drugs. (See Mantripragada ¶ 1.) We agree with the Examiner’s findings, and Appellant does not dispute, that Mantripragada teaches the components of the recited composition administered in the methods of claims 219 and that Mantripragada teaches ranges of weight ratios of these components that encompass or overlap with the ranges claimed. (See Final Act. 4-5, citing Mantripragada ¶¶ 10, 11, 16, 53, 75, 77, 78.) Further to these findings, the Examiner determines that it would have been obvious to provide bupivacaine in a sustained release composition as claimed to a surgical wound in order to provide a plasma concentration of the drug from 200 ng/ml for 24 hours up to 4 days, because Sackler teaches treating patients by placing a local anesthetic in proximity to a nerve at a surgical site to provide controlled release of bupivacaine for plasma levels not exceeding 200 to 650 ng/ml for one, two, three days or longer. (See Final Act. 6-7, citing Sackler ¶¶ 17, 74.) Appeal 2021-005475 Application 15/870,745 4 Appellant argues that one of ordinary skill would not have had a reasonable expectation of success from Mantripragada and Sackler that administering a composition as recited in claims 219 provides a sustained local anesthetic effect of at least 24 hours. (See Appeal Br. 9-10, 13-18; see Reply Br. 3-11.) Appellant focuses on the “consisting of” language that characterizes the composition recited in the pending claims, arguing that Mantripragada teaches a composition without lysine would have been expected to result in less controlled release of bupivacaine from the oil-core, and therefore shorter effectiveness. (See id.) Appellant argues that because Mantripragada shows that particles containing bupivacaine and lysine exhibited release for less than 24 hours, one of ordinary skill would not have reasonably expected a composition without lysine to release bupivacaine for longer, at least 24 hours, as required in claim 219. (See id.) In support of this argument, Appellant cites to paragraph 42 of Mantripragada for the teaching that ionized forms of drugs, that is, in their salt form, will partition out of the core regions of oil-core particles and result in less encapsulated drug at certain pHs relative to the pKa of the drug. (See Appeal Br. 15.) We note that paragraph 42 does not mention lysine. In further support, Appellant cites to examples in Mantripragada that include lysine and to two exhibits showing that the side chain of lysine at a pH less than its pK is basic and that lysine is capable of obtaining protons to produce a basic solution. (See Appeal Br. 16, n.2.) In light of this evidence, we are persuaded that lysine could be a pH adjusting agent as discussed in paragraph 42 of Mantripragada, but we are not persuaded that it is the only pH adjusting agent that would be capable of filling the role described in paragraph 42. Appeal 2021-005475 Application 15/870,745 5 Appellant supports the argument that one of ordinary skill would not have had a reasonable expectation of the success of the claimed methods, which exclude lysine, by arguing that “Mantripragada provides at paragraph [0082] specific guidance for bupivacaine, noting that ‘to minimize the solubility of bupivacaine in the aqueous phase and keep the drug partitioned into the lipids’ the composition should be formulated to have a pH of 10 by adding 5 mM of lysine.” (Appeal Br. 22.) Appellant argues further that Mantripragada teaches that lysine is included in its bupivacaine formulations for a specific functional reason: to minimize the ionized form of drug and maximize the non-ionized form of drug, thereby reducing loss of bupivacaine from its oil-core particles in order to achieve controlled release. Mantripragada at e.g., paragraph [0042]. (Reply Br. 6- 7.) Both of these arguments rely on over-interpretations of the reference. Mantripragada explains that a preferable pH range for suspensions of the invention is from about 2 to about 10, that ionized forms of drugs will partition out of the core regions of an oil-core particle into the surrounding oil-immiscible phase, and that it is desirable that the drug be present in their free acid or free base forms. (See Mantripragada ¶ 42.) But Appellant points to no teaching in Mantripragada, and we find none, that expressly states adding lysine to achieve any of these goals. Despite Appellant’s characterization of the addition of lysine to the compositions in the examples of Mantripragada (see, e.g., Mantripragada ¶¶ 42, 82), a specific reason for adding lysine is not articulated. Instead, Mantripragada teaches that lysine is a preferred pharmaceutical excipient, as are Appeal 2021-005475 Application 15/870,745 6 phosphate, citrate, acetate, glucuronate, polysorbate, carboxymethylcellulose, gelatin, glucose, mannose, trehalose, mannitol, . . . sorbitol, as well as amino acids, or salts, including alkali or alkali metal salts of the above excipients that can form a salt, as well as such salts of halides, citrate, pyrophosphate, or sorbate and lactate. (See Mantripragada ¶ 75.) Thus, Mantripragada teaches other excipients without any special emphasis on lysine or its actions. In addition, rather than teaching that lysine is necessary for maintaining the partition of drugs and the pH of suspensions, Mantripragada provides for embodiments of its drug delivery system without lysine. (See Mantripragada ¶ 114; see Ans. 6-7.) Specifically, Example 12 provides a composition that includes a different drug, paclitaxel, but not lysine. (See Mantripragada ¶ 114.) Example 12 explains that paclitaxel in this formulation was present for at least 16 days. (See id. ¶ 118.) Appellant argues that Example 12 reports sustained drug release for up to 16 days in Figure 4, but that paclitaxel is a different drug with different properties than bupivacaine, including “an even higher pKa than bupivacaine . . . ” and that the Examiner has not established that the drugs would have equivalent controlled release profiles. (Reply Br. 9.) Appellant’s characterization of paclitaxel tends to undermine Appellant’s main argument that one of ordinary skill in the art would not have omitted lysine from the compositions of Mantripragada because it would result in less controlled drug release. (See id.) That is, Appellant argues that based on Mantripragada paragraph 42, one of ordinary skill in the art would have understood that “far more” bupivacaine would partition from oil-core particles with lower pH (e.g. pH 7) than if the pH of the particles were raised Appeal 2021-005475 Application 15/870,745 7 to above its pKa (8.1), for example, by adding lysine to obtain a pH of 10. (See Appeal Br. 19-21.) Because paclitaxel has a pKa even higher than that of bupivacaine, and thus has a pH even higher than physiologic level, Appellant’s reasoning would indicate that compositions with paclitaxel would also need lysine, perhaps even more lysine, to raise the pH above the pKa and achieve controlled release. Yet the composition of Example 12 contains no lysine and achieves controlled release for 16 days. Therefore, we are not persuaded by Appellant’s arguments that one of ordinary skill in the art would have understood from Mantripragada that lysine is solely responsible for controlled drug release in such compositions. The Examiner also finds that paragraph 42 of Mantripragada does not necessarily indicate compositions with bupivacaine must include lysine because Mantripragada also teaches that bupivacaine can be present in its free-base form, which is more soluble in the oily phase of the oil-core particles. (See Ans. 6, et al., citing Mantripragada ¶ 42 (“At physiological pH values, some drugs exist in a salt form. Such ionized forms are not particularly stable in a hydrophobic environment, and will partition out of the core regions of an oil-core particle, and into the surrounding oil- immiscible phase. . . . It is therefore considered desirable that the drugs to be used in the hydrophobic core of the inventive particles be present in their free acid or free base forms.”), ¶ ¶103, 111 (describing particles made with bupivacaine free-base).) Appellant argues that even if bupivacaine is provided as a free base, at least some of it will convert to a protonated ionized form. (See Appeal Br. 20-21.) This argument does not explain the express teaching in Mantripragada paragraph 42 that because of the separations that can result Appeal 2021-005475 Application 15/870,745 8 from conversions of salt forms, it is “desirable that the drugs to be used in the hydrophobic core of the inventive particles be present in their free acid or free base forms” to avoid these effects. Furthermore, as the Examiner notes, drugs can be incorporated into different parts of the Mantripragada drug delivery system other than in the oil-core, for example the surfactant coating. (See Ans. 6, citing Mantripragada ¶ 40 (“In some embodiments of the invention, the drug can be incorporated into the surfactant coating, as well as, or instead of, the core, or subsequently adhered to the surfactant coating, by selection of surfactant and drug having appropriate chemical properties.”).) Appellant acknowledges that bupivacaine may be incorporated in the surfactant coating, but argues only that omitting lysine would make it more likely that bupivacaine would partition out of the core region. (See Reply Br. 8-9.) This argument is not responsive to the Examiner’s finding. In light of the teachings in Mantripragada of using bupivacaine forms other than its salts and of incorporating bupivacaine into regions of the oil- core particles other than in the core, we are not persuaded by Appellant’s arguments that Mantripragada teaches away from the claimed methods because these methods use compositions that exclude lysine. (See Appeal Br. 10, 18-23.) The portions of Mantripragada related to pH requirements that Appellant cites do not necessarily relate to these other bupivacaine delivery systems and, thus, these cites do not persuade us that Mantripragada would have discouraged one of ordinary skill in the art from omitting lysine in every composition suggested. See In re Gurley, 27 F3d 551, 553 (Fed. Cir. 1994) (“A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be discouraged from Appeal 2021-005475 Application 15/870,745 9 following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant.”) Furthermore, we are not persuaded that, as Appellant argues, because all of the “inventive bupivacaine compositions described in Mantripragada contain lysine,” one of ordinary skill in the art would have understood that lysine is a required component of those compositions or the compositions recited in Appellant’s claims. (See Reply Br. 5.) See In re Mills, 470 F.2d 649, 651 (CCPA 1972) (“All the disclosures in a reference must be evaluated, including nonpreferred embodiments . . . and a reference is not limited to the disclosure of specific working examples.”). In addition, we are not persuaded by Appellant’s arguments that one of ordinary skill in the art would not have had a reasonable expectation of success in the claimed methods from the teachings of Mantripragada and Sackler. “Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness.” In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985). Appellant does not persuade us that one of ordinary skill in the art would not have had a reasonable expectation of success using a drug delivery system as suggested in Mantripragada, with the components recited in claim 219, that would release drug for up to 16 days, along with the teachings in Sackler of controlled release of bupivacaine in proximity to a surgical site with a plasma concentration of 200-650 ng/ml for a prolonged period of time. We are further not persuaded by Appellant’s argument that the Examiner erred because one of ordinary skill in the art would not have substituted sodium chloride for lysine in the compositions of Mantripragada. (See Reply Br. 6-8, 11-12.) We are persuaded, instead, that one of ordinary Appeal 2021-005475 Application 15/870,745 10 skill in the art would have considered a composition that includes sodium chloride but excludes lysine to have been obvious because Mantripragada lists several different possible excipients, including amino acids and sodium chloride as suitable excipients. (See Mantripragada ¶ 53.) Appellant argues that the compositions of Mantripragada and Sackler are different and that Sackler would not have provided those of ordinary skill in the art with an expectation of success in the claimed methods. (See Appeal Br. 17; see Reply Br. 9-11.) Appellant argues that Mantripragada involves oil-core compositions, whereas Sackler involves bupivacaine delivered in solid, polymeric microspheres and that the Examiner fails to show that oil core solids would have properties similar to solid, polymeric microspheres. (See id.) The Examiner cites Sackler for its teachings of treating a patient in need of a surgical procedure by placing an anesthetic in proximity to the surgical site with controlled release for a prolonged period with a plasma concentration of 200-650 ng/ml. (See Final Act. 6.) The Examiner’s rejection is based on providing a bupivacaine formulation based on the teachings of Mantripragada to a surgical wound wherein the plasma concentration of bupivacaine is from 200ng/ml for 24 hours and provides anesthesia for up to 4 days. (See Final Act. 6-7.) The rejection is not based on a combination of the formulations disclosed in Mantripragada and Sackler. Thus, Appellant’s argument is not persuasive. We are not persuaded by any of Appellant’s arguments that the Examiner erred in rejecting either claim 219 as being obvious over Mantripragada and Sackler. Accordingly, we affirm the rejection of claims 219. Appeal 2021-005475 Application 15/870,745 11 Claim 212 Claim 212 recites: “The method of claim 219, wherein the bupivacaine is present in free base form.” (Appeal Br. 30.) Appellant argues that the Examiner fails to show that the free base form of bupivacaine would provide a reasonable expectation of success in achieving all features of the claimed invention because paragraph 42 of Mantripragada teaches away from using a drug in the free base form without a pH adjuster. (See Appeal Br. 24.) For the reasons discussed above, we are not persuaded by these arguments. Claims 214, 215 Claims 214 and 215 depend from claim 219 and recite that the bupivacaine is present in the composition in an amount ranging “from 1 wt% to 5 wt%” and “from 1 wt% to 2 wt%,” based on the weight of the composition, respectively. (Appeal Br. 30.) Appellant argues in light of paragraph 46 of Mantripragada, which discloses a broad drug loading of from about 0.1 mg/mL to about 750 mg/mL, a skilled artisan would have to “pick and choose” to arrive at the recited amount of bupivacaine. (Appeal Br. 25.) This argument does not persuade us that the Examiner erred because “picking and choosing may be entirely proper in the making of a 103, obviousness rejection, where the applicant must be afforded an opportunity to rebut with objective evidence any inference of obviousness which may arise from the similarity of the subject matter which he claims to the prior art . . . .” In re Arkley, 455 F.2d 586, 587-88 (CCPA 1972). Appellant does not direct us to objective evidence demonstrating the non-obviousness of the method claims 214 or 215. Appeal 2021-005475 Application 15/870,745 12 Appellant argues further that the Examiner fails to provide a reasonable expectation of success for use of bupivacaine at this concentration in the claimed methods and that Example 8 of Mantripragada uses bupivacaine at 1.5% but failed to provide a sustained local anesthetic effect of at least 24 hours after administration. See FIGS. 1 and 2, discussed above. (See Appeal Br. 25, citing Mantripragada Figs. 1 and 2.) We are not persuaded by these arguments because the Examiner’s rejection for obviousness, not anticipation, and Appellant has not shown that the claimed range of drug concentration is not encompassed by the teachings of Mantripragada. We are not persuaded that Mantripragada fails to provide a reasonable expectation of success for the facts it teaches. Claims 220-222 Appellant’s claims 220-222 depend on claim 219 and require that the sustained local anesthetic effect is for at least 36, 48, and 72 hours after the administration, respectively. (Appeal Br. 31.) Appellant argues that one of ordinary skill in the art would not have had a reasonable likelihood of success in achieving these effects for the reasons given in regard to claim 219. As explained above, we are not persuaded by Appellant’s arguments regarding claim 219 and are not persuaded by these same arguments regarding dependent claims 220-222. Claims 223 and 224 Claim 223 recites the method of claim 219, “wherein the sustained local anesthetic effect is for up to 4 days after the administration.” (Appeal Br. 31.) Claim 224 recites the method of claim 219, “wherein the site is a surgical wound.” (Appeal Br. 27.) Appellant argues that Mantripragada Appeal 2021-005475 Application 15/870,745 13 fails to disclose an anesthetic effect of up to four days or administration to a site that is a surgical wound. (See Appeal Br. 27.) The Examiner cites Sackler to show that both of these elements would have been obvious to one of ordinary skill in the art. (See Final Act. 6.) As explained above, we are not persuaded by Appellant’s argument that Sackler fails to cure any deficiency of Mantripragada because it involves a different composition. (See Appeal Br. 27.) Appellant does not even address Sackler in regard to claim 224. Accordingly, we are not persuaded by Appellant’s arguments regarding claims 223 and 224. Claim 231 Independent claim 231 includes a limitation to a sustained mean steady state plasma concentration (Css) of the bupivacaine of at least 200 ng/mL for a period of 24 hours. (See Appeal Br. 31.) Appellant argues that Mantripragada fails to address these limitations and that Sackler does not cure the deficiency for reasons discussed above. (See Appeal Br. 28.) As also discussed above, we are not persuaded by these arguments. Conclusion Upon consideration of the record and for the reasons given, we affirm the Examiner’s rejection. In summary: Claims Rejected 35 U.S.C. § Basis Affirmed Reversed 212, 214, 215, 219- 224, 231, 232 103(a) Mantripragada, Sackler 212, 214, 215, 219- 224, 231, 232 Appeal 2021-005475 Application 15/870,745 14 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136. AFFIRMED