Ex Parte Ren et alDownload PDFPatent Trials and Appeals BoardApr 18, 201914820210 - (D) (P.T.A.B. Apr. 18, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 14/820,210 08/06/2015 Zhongxu Ren 21968 7590 04/18/2019 NEKT AR THERAPEUTICS 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 ATTORNEY DOCKET NO. CONFIRMATION NO. SHE0158.ll 1032 EXAMINER 455 Mission Bay Blvd., South, Suite 100 o DELL, DAVID K San Francisco, CA 94158 ART UNIT PAPER NUMBER 1625 MAIL DATE DELIVERY MODE 04/18/2019 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 ZHONGXU REN, BO-LIANG DENG, JENNIFER RIGGS-SAUTHIER, and MICAH HARVEY Appeal 2018-001132 Application 14/820,210 Technology Center 1600 Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and RACHEL H. TOWNSEND, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1,2 under 35 U.S.C. § 134 involving claims to a specific compound that is a calcium channel blocker. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the Real Party in Interest as Nektar Therapeutics (see App. Br. 3). 2 We have considered refer to the Specification of Aug. 6, 2015 ("Spec."); Final Office Action of Feb. 9, 2017 ("Final Action"); Appeal Brief of July 5, 2017 ("App. Br."); and Examiner's Answer of Sept. 11, 2017 ("Ans."). Appeal 2018-001132 Application 14/820,210 Statement of the Case Background "Drugs currently known as calcium channel blockers (CCB) (also called calcium antagonists), among other actions, inhibit calcium-evoked contractions in depolarized smooth muscles" (Spec. ,r 3). "This pharmacological property has, at a minimum, been one of the bases for the use of CCBs in the management of hypertension and coronary heart disease" (id.). "Although CCBs serve an important role in treating patients, their use is sometimes associated with ( among other things) extensive metabolism, often resulting in inactive metabolites and thus lower bioavailability. CCBs also exhibit several side effects" (id. ,r 9). The Claims Claims 4, 21, 33, and 35 are on appeal. Claim 4 is the sole independent claim, is representative and reads as follows: 4. A compound of Formula: 0 II H:,c"'-....( ~o,. ~ .. /c \-L2 "-/ 1r'":0 m . NOi and optical isomers, diastereomers, and enantiomers thereof, wherein: each n is independently an integer from 2 to 10; and each m is independently an integer from O to 19. 2 Appeal 2018-001132 Application 14/820,210 The Re} ection The Examiner rejected claims 4, 21, 33, and 35 under 35 U.S.C. § I03(a) as obvious over Cupka3 and Bentley4 (Final Act. 5-10). The Examiner finds that Cupka teaches "a small genus of compounds that includes the elected species of the instant claims as Formula I on column 1" (Final Act. 5). The Examiner acknowledges that Cupka "does not exemplify the species of claim 33. The elected species has all the structural features of the compound j [ of Cupka] except it is the ester of 2- (2-Methoxyethoxy) ethanol while the prior art is 2-ethoxyethanol ester" (Final Act. 7). The Examiner finds that Bentley evidences that polyethylene glycol (PEG) "is a well-known conjugate ester moiety used to increase solubility and bioavailability" (Final Act. 8). The Examiner finds "Example i of [ Cupka] is an mPEG compound where n is 1, therefore further mPEG compounds are within the teaching of [Cupka]. Using the mPEG analog of the prior art PEG compound is an obvious variation" (Final Act. 10). The issues with respect to this rejection are: (i) Does a preponderance of the evidence of record support the Examiner's conclusion that Cupka and Bentley suggest the compound of claim 4? (ii) If so, have Appellants presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness? 3 Cupka et al., AA 243591 Bl, published Sept. 17, 1985. We rely upon the translation of Cupka with a 9/11/2017 receipt date in the file record. 4 Bentley et al., US 2003/0143185 Al, published July 31, 2003. 3 Appeal 2018-001132 Application 14/820,210 Findings of Fact 1. Cupka teaches compounds that "are used as anti-anginous and antihypertensive substances" (Cupka 2). 2 Cupka teaches a generic compound of formula I, shown below, '' J where "R1 and R2 represent either aliphatic or branched alkyl residue with the number of carbon atoms being 1 to 5, while the alkyl residue may be interrupted in the chain by an oxygen atom and R1 and R2 may either be identical or different" (Cupka 2). 3. Cupka teaches "j) bis-ethoxy-ethyl-ester of 2,6-dimethyl-4-(2'- nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid" (Cupka 8). The Examiner provides the structure as shown below: 4 Appeal 2018-001132 Application 14/820,210 4. Cupka teaches "i) bis-methoxy-ethyl-ester of 2,6-dimethyl-4- ( 4'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid" (Cupka 7). The Examiner provides the structure as shown below: Meo~0 ; 0 ~oMe Example i 5. Bentley teaches "there is a need in the art for alternative compounds, or for approaches for modifying or improving upon existing compounds, that can maintain at least a certain degree or enhance the therapeutic activity ... while increasing solubility and bioavailability" (Bentley ,r 5). 6. Bentley teaches "[ s ]uitable polymers for covalent attachment to a PKC inhibitor include poly(alkylene glycols) .... In one embodiment of the invention, the polymer is a poly( ethylene glycol)" (Bentley ,r 7). 7. Bentley teaches "PEG has the formula ---CH2CH20-( CH2CH20)n---CH2CHz--- Formula II wherein n is from about 2 to about 2,000" (Bentley ,r,r 61---62). 8. Bentley teaches "methoxy-PEG-OH, or mPEG in brief, is a form of PEG wherein one terminus of the polymer is a methoxy group, while the other terminus is a hydroxyl group that is subject to ready chemical modification. The structure of mPEG is given below. ---CH30-(CH2CH20)n---CH2CHz--OH Formula III wherein n is as described above" (Bentley ,r,r 63---64). 5 Appeal 2018-001132 Application 14/820,210 Principles of Law Under the lead compound analysis rubric, we must first "determine[] whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or starting points, for further development efforts." Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir. 2012). "The second inquiry in the analysis is whether the prior art would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success." Id. at 1292. Prima facie obviousness can be rebutted by presenting evidence of secondary considerations and when such evidence is submitted, all of the evidence must be considered anew. In re Piasecki, 745 F.2d 1468, 1472- 1473 (Fed. Cir. 1984). Analysis We adopt the Examiner's findings regarding the scope and content of the prior art (Final Act. 5-10) and agree that claim 4 would have been obvious in view of Cupka and Bentley (FF 1-8). We address Appellants arguments below. Prima facie obviousness Appellants contend "[b ]ecause the Office has attempted to use a lead compound rationale to support an alleged finding of obviousness of the claims on appeal, following lead compound analysis is proper" (App. Br. 7). Following the lead compound analysis, Appellants contend that "[n]o proper reasoning has been identified in the Office Action as to why one of skill in the art would have modified Cupka Example i." (Id.). Appellants also contend 6 Appeal 2018-001132 Application 14/820,210 The only assertion made as to why one would have modified the compounds of Cupka in the manner of Bentley is the alleged teaching of increased solubility and bioavailability upon incorporation of a PEG moiety. . . . Bentley does not disclose this property of PEG. In addition, no rationale or factual findings are provided as to why the compound of Example i of Cupka would benefit from increased solubility and bioavailability. That is, it is not even alleged in the Office Action that the compound of Example i of Cupka suffers from low solubility or low bioavailability, such that one of skill in the art would have modified this compound to increase solubility and/or bioavailability. (App. Br. 8). We are not persuaded. Cupka teaches a base compound for use in anti-hypertensive treatment (FF 1-2) as well as fifteen specific variations of that base compound including compounds (i) and U) (FF 3--4). Cupka's base compound is, essentially nifedipine (cf Spec. 4, structure of nifedipine). Under the lead compound analysis, the ordinary artisan would have had reason to select anti-hypertensive compounds based on the generic structure disclosed by Cupka, including the two disclosed species (i) and U), in order to treat high blood pressure and angina in patients (FF 1 ). As to the issue of modifying either the generic compound or compounds (i) and U) from having one ethylene glycol group at the R1 or R2 positions as disclosed in Cupka (FF 2--4) to having two such groups (i.e. a "polyethylene glycol"), Bentley specifically teaches that inclusion of polyethylene glycol "can maintain at least a certain degree or enhance the therapeutic activity ... while increasing solubility and bioavailability" (FF 5). We agree with the Examiner that the ordinary artisan interested in improving Cupka's compounds for treatment of high blood pressure and 7 Appeal 2018-001132 Application 14/820,210 angina would have had reason and motivation to ensure the bioavailability of these compounds to enhance therapeutic activity as taught by Bentley (FF 5; cf Ans. 12). Thus, even under the lead compound analysis rubric, the prior art of Bentley provides reasons to modify Cupka' s compounds to improve their use in patient treatment (FF 5). To the extent that Appellants are contending that Bentley does not teach polyethylene glycol improves bioavailability and solubility, Bentley teaches otherwise. Bentley's direct contrasting of the need for improving these traits with the inventive use of polyethylene glycol to create "water- soluble, polymer-modified PKC inhibitors" (Bentley ,r 6) supports the Examiner's position that Bentley understands the addition of polyethylene glycol to a compound to function to increase solubility and bioavailability. Appellants provide no evidence, only attorney argument, rebutting this understanding of Bentley. However, "attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness." In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). Secondary Considerations Appellants contend "[o]bjective evidence of non-obviousness is provided in Example 3. Specifically, the results of a calcium channel binding assay are provided for compounds of the instant claims. In this assay, the compounds of the instant claims retain nanomolar inhibition (IC so), which is comparable to the inhibition ofnifedipine" (App. Br. 5). We are not persuaded for two reasons. First, the comparison with nifedipine is not with the closest prior art, which would be the compounds disclosed by Cupka. See In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("[W]hen unexpected results are used as evidence of 8 Appeal 2018-001132 Application 14/820,210 nonobviousness, the results must be shown to be unexpected compared with the closest prior art."). Second, Appellants provide no evidence that the result of Example 3 would have been unexpected, whether by way of a Declaration or citation to a statement in the Specification that this result is unexpected or otherwise surprising. "It is well settled that unexpected results must be established by factual evidence. Mere argument or conclusory statements ... [do] not suffice." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). Conclusion of Law (i) A preponderance of the evidence of record supports the Examiner's conclusion that Cupka and Bentley suggest the compound of claim 4. (ii) Appellants have not presented evidence of secondary considerations, that when weighed with the evidence of obviousness, is sufficient to support a conclusion of non-obviousness. SUMMARY We affirm the rejection of claims 4, 21, 33, and 35 under 35 U.S.C. § 103(a) as obvious over Cupka and Bentley. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 9 Copy with citationCopy as parenthetical citation