Ex Parte Mathad et al

Patent Trials and Appeals BoardJun 18, 2014

11572949 - (D) (P.T.A.B. Jun. 18, 2014)

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. 11/572,949 01/30/2007 Vijayavitthal Thippannachar Mathad BULK 3.3-084 4369 45776 7590 06/19/2014 DR. REDDY''S LABORATORIES, INC. 200 SOMERSET CORPORATE BLVD SEVENTH FLOOR BRIDGEWATER, NJ 08807-2862 EXAMINER CHANG, CELIA C ART UNIT PAPER NUMBER 1625 MAIL DATE DELIVERY MODE 06/19/2014 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte VIJAYAVITTHAL THIPPANNACHAR MATHAD, SHARAT PANDURANG NARASAPUR, PRAVINCHANDRA JAYANTILA VANKAWALA, MANOJ RAMESH KHAKAR, RAVI RAMA CHANDRA ELATI, SUBRAHMANYESWAR RAO CHALAMALA, and ARUN T.1 __________ Appeal 2012-004277 Application 11/572,949 Technology Center 1600 __________ Before TONI R. SCHEINER, DONALD E. ADAMS, and ERIC B. GRIMES, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of making crystalline form I of donepazil hydrochloride, which have been rejected as obvious and nonenabled. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. 1 According to Appellants, the Real Parties in Interest are Dr. Reddy’s Laboratories, Ltd. and Dr. Reddy’s Laboratories, Inc. (App. Br. 3). Appeal 2012-004277 Application 11/572,949 2 STATEMENT OF THE CASE “Donepezil hydrochloride is a reversible inhibitor of acetyl- cholinesterase and is the first agent with this mode of action for the treatment of mild to moderate dementia of Alzheimer’s Disease” (Spec. 1:12-14). The free base form of donepezil can be made by “condensation of 5,6-dimethoxy-2-piperidin-4-yl-methyl-indan-1-one . . . with benzyl bromide in presence of a base in a suitable solvent” (id. at 3:10-12). The donepezil free base can be “subsequently converted in to [sic] its hydrobromide salt,” followed by “conversion of donepezil hydrobromide . . . to the free base, and then to the hydrochloride salt” (id. at 3:12-15). Claims 1-3, 13, and 15-20 are on appeal. Claim 1 is the only independent claim and reads as follows: 1. A process for preparing stable crystalline form I of donepezil hydrochloride comprising: a) condensing 5,6-dimethoxy-2-piperidin-4-yl-methyl-indan-1-one with benzyl bromide and reacting a condensation product with hydrobromic acid to form donepezil hydrobromide, wherein the solvent for conducting the condensing comprises a C1-C4 straight chain or branched alcohol, a ketone, an ether, an ester, acetonitrile, or mixtures of any two or more thereof; and b) hydrolyzing donepezil hydrobromide, followed by reacting with aqueous hydrochloric acid. The claims stand rejected as follows: • Claims 1-3, 13, 15, and 16 under 35 U.S.C. § 103(a) based on Imai,2 Sugimoto,3 and Naidu4 (Ans. 6); and 2 Imai et al., US 5,985,864, Nov. 16, 1999. 3 Sugimoto et al., US 4,895,841, Jan. 23, 1990. 4 Naidu et al., US 2005/0288330 A1, Dec. 29, 2005. Appeal 2012-004277 Application 11/572,949 3 • Claims 1-3, 13, and 15-20 under 35 U.S.C. § 112, first paragraph, for lack of enablement (Ans. 5). I. The Examiner has rejected claims 1-3, 13, 15, and 16 as obvious based on Imai, Sugimoto, and Naidu. The Examiner finds that Imai disclosed a method of making donepezil hydrochloride form I by acidifying donepezil free base with hydrochloric acid and adding methyl t-butyl ether as antisolvent (Ans. 6). The Examiner finds that the claimed method differs from that of Imai in that Imai does not teach the claimed steps of preparing donepezil free base (i.e., forming donepezil free base from 5,6-dimethoxy-2- piperidin-4-yl-methyl-indan-1-one and benzyl bromide), reacting the free base with hydrobromic acid to form the hydrobromide, and hydrolyzing the hydrobromide to the free base (id. at 7). The Examiner finds that Sugimoto “disclosed available variations of pharmaceutically [acceptable] acid addition salts including the hydrobromide” (id.) and “[h]ydrolysis of an acid addition salt is evidenced by [Naidu] that such process will produce the free base” (id.). The Examiner concludes that the claimed process would have been obvious because the hydrobromide salt was a known pharmaceutically acceptable salt, it was known that some salt forms may have better processing quality than others, and all acid addition salts will produce the free base form upon hydrolysis (id.). Appellants argue that none of the cited references teaches either “condensing 5,6-dimethoxy-2-piperidin-4-yl-methyl-indan-l-one with benzyl bromide and reacting a condensation product with hydrobromic acid to form donepezil hydrobromide” or “hydrolyzing donepezil hydrobromide,” as Appeal 2012-004277 Application 11/572,949 4 required by claim 1 (App. Br. 10). Appellants argue that the references do not teach or suggest all of the elements of the claim (id.). We agree with Appellants that the Examiner has not provided sufficient evidence to show that the method of claim 1 would have been obvious based on the cited references. The condensation of 5,6-dimethoxy- 2-piperidin-4-yl-methyl-indan-1-one with benzyl bromide, as recited in step a) of claim 1, was a known method of making donepezil free base, as evidenced by Kumar.5 Claim 1, however, also requires reacting the free base with hydrobromic acid to convert it to the hydrobromide salt, then hydrolyzing the hydrobromide salt (to the free base) before reacting with hydrochloric acid to form the hydrochloride salt. As evidence that these steps represent “a conventional starting material preparation” (Ans. 7), the Examiner relies on Sugimoto and Naidu. The cited passages in Sugimoto state that the hydrobromide salt is a pharmacologically acceptable salt (Sugimoto, col. 12, ll. 29-31) and describe a process of making donepezil and converting it to the hydrochloride salt (id. at col. 34, ll. 14-49). The cited passage in Naidu describes a process of making amorphous donepezil hydrochloride by converting donepezil free base to donepezil oxalate, then reacting the donepezil oxalate with a base to produce donepezil free base and reacting it with hydrochloric acid and lyophilizing (Naidu 2, ¶¶ 40-46). Naidu also states that amorphous 5 Kumar et al., WO 2004/099142 A1 (2004), at 5:10-24. The Examiner cited Kumar in the explanation of the rejection (Ans. 7), although it was not included in the statement of the rejection. Appeal 2012-004277 Application 11/572,949 5 donepezil hydrochloride can be converted to polymorph (VI) by exposing it to humidity (id. at 2, ¶ 46). The Examiner also cites Kumar as evidence that “the hydrobromide salt indeed has different properties” (Ans. 7). The cited passage states that “[d]onepezil hydrobromide, in forms I and/or II crystals, is non sticky and has excellent filtering properties, enabling easy scraping and handling of filter cake” (Kumar 4:3-4). The cited passage in Kumar might provide a reason for a skilled worker to make crystalline form I donepezil hydrobromide, but the claims are directed to a method of making form I donepezil hydrochloride that comprises converting the free base form of donepezil to its hydrobromide salt, then hydrolyzing the hydrobromide salt back to the free base, before reacting the free base with hydrochloric acid to form the hydrochloride salt. Although Naidu shows that the free base can be converted into an acid addition salt, and then converted back to the free base before reacting with hydrochloric acid, the Examiner has not identified any advantage to be gained by, or any other specific reason for, carrying out the steps recited in claim 1. The Examiner therefore has not carried the initial burden of showing that the method of claim 1 would have been obvious based on the cited references to a person of ordinary skill in the art. II. The Examiner has rejected claims 1-3, 13, and 15-20 for lack of enablement “because the specification, while being enabling for employing solvents, base and antisolvents as disclosed in the specification, does not Appeal 2012-004277 Application 11/572,949 6 reasonably provide enablement for the process employing conditions as claimed i.e. without limitation on solvents, base and antisolvents” (Ans. 5). Appellants argue that crystalline form I of donepezil hydrochloride is known (App. Br. 14); that the Specification identifies several issued patents that disclose preparation of polymorphs of donepezil hydrochloride (id.); that Imai “teaches crystallization of form I of the hydrochloride salt using methanol with isopropyl ether, ethanol with isopropyl ether, and methanol alone” (id.); and that the Specification provides two working examples of preparing form I donepezil hydrochloride (id.). Appellants argue that the amount of experimentation required to practice the claimed invention is not undue (id.) We agree with Appellants that the Examiner has not shown that producing form I donepezil hydrochloride using the method of claim 1 would require undue experimentation for a person of ordinary skill in the art. The Examiner does not assert that claim 1 is nonenabled based on any of the steps actually recited in the claim. Rather, the Examiner finds that “processes for forming specific crystalline form in a product that forms polymorphic crystalline forms must be very specific in operating conditions” (Ans. 5). The Examiner also finds that the working examples in the Specification both use toluene to extract donepezil free base, then acidify in methanol and hydrochloric acid with methyl t-butyl ether as antisolvent to obtain form I donepezil hydrochloride (id. at 6). Finally, the Examiner cites Appeal 2012-004277 Application 11/572,949 7 two working examples in Imai as evidence that “[s]mall changes in operating condition will not produce the required form” (id.6). Thus, the Examiner’s concern appears to be with the amount of experimentation needed to crystallize donepezil hydrochloride under conditions that result in form I rather than some other polymorph. As Appellants have pointed out, however, form I donepezil hydrochloride is a known polymorph. Imai describes several methods of preparing it (Imai, col. 7, ll. 41-55) and provides several working examples (id. at col. 13, l. 11 to col. 14, l. 24; col. 17, l. 45 to col. 20, l. 32). The Specification identifies Imai as disclosing “[p]rocesses for preparing donepezil hydrochloride and some polymorphic forms” (Spec. 2:1-2). “[A] a patent need not teach, and preferably omits, what is well known in the art.” Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384 (Fed. Cir. 1986). “[T]he [enablement] requirement is satisfied if, given what they already know, the specification teaches those in the art enough that they can make and use the invention without ‘undue experimentation.’” Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1334 (Fed. Cir. 2003). Here, the evidence shows that those skilled in the art were already aware, before the filing of the present application, how to crystallize donepezil hydrochloride under conditions that result in crystalline form I rather than some other polymorph. The Examiner has not adequately shown that practicing the claimed method, based on the Specification’s disclosure 6 The Examiner cites Examples 4 and 7, but based on the Examiner’s description of them, the examples referred to appear to be 7 and 9. Appeal 2012-004277 Application 11/572,949 8 and the existing knowledge in the art, would have required undue experimentation. We therefore reverse the rejection for lack of enablement. SUMMARY We reverse the rejection of claims 1-3, 13, 15, and 16 under 35 U.S.C. § 103(a). We reverse the rejection of claims 1-3, 13, and 15-20 under 35 U.S.C. § 112, first paragraph. REVERSED lp