Ex Parte SULLENGER

Patent Trial and Appeal BoardJul 20, 2015

12610330 (P.T.A.B. Jul. 20, 2015)

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. 12/610,330 11/01/2009 Bruce A. SULLENGER 5667-00157 1218 26753 7590 07/20/2015 Andrus Intellectual Property Law, LLP 100 EAST WISCONSIN AVENUE, SUITE 1100 MILWAUKEE, WI 53202 EXAMINER SHIN, DANA H ART UNIT PAPER NUMBER 1674 MAIL DATE DELIVERY MODE 07/20/2015 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 BRUCE A. SULLENGER __________ Appeal 2012-010469 Application 12/610,330 Technology Center 1600 __________ Before JEFFREY N. FREDMAN, ROBERT A. POLLOCK, and JACQUELINE T. HARLOW, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a method for making a Dicer substrate. The Examiner rejected the claims as anticipated and as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellant identifies the Real Party in Interest as Duke University (see App. Br. 3). Appeal 2012-010469 Application 12/610,330 2 Statement of the Case Background In “RNA interference (RNAi), endogenously formed (e.g., naturally produced intracellularly) or exogenously introduced (e.g., transfected, or introduced by a microorganism, into a cell) double-stranded RNA (‘dsRNA’) is processed by Dicer (an RNAse III family enzyme) into discrete, small RNA duplexes of between 21–25 basepairs” (Spec. 1). “[D]uplexes will be referred to as small interfering RNA (siRNA) if the strands of the duplexes are perfectly complementary, or as microRNAs (miRNAs) if the strands of the duplexes are imperfectly base paired” (id.). The Claims Claims 6–10 are on appeal. Claim 6 is representative and read as follows: 6. A method for making a Dicer substrate, comprising: (a) synthesizing a nucleic acid molecule comprising (i) a targeting moiety comprising an aptamer, and (ii) a first single stranded RNA, wherein the targeting moiety and the first single stranded RNA are a contiguous nucleic acid molecule; and (b) hybridizing a second single stranded RNA with the first single stranded RNA in forming an RNA silencing moiety that is dsRNA which can act as a Dicer substrate, and wherein the two strands of dsRNA have full complementarity or partial complementarity; wherein the targeting moiety is capable of binding to a receptor on the surface of a cell and, upon binding, the nucleic acid molecule is subsequently internalized into the cell and transported inside the cell to the cytoplasm for accessing Dicer. Appeal 2012-010469 Application 12/610,330 3 The Issues A. The Examiner rejected claims 6–9 under 35 U.S.C. §§ 102(a)/102(e) as anticipated by Davis2 (Ans. 4–5). B. The Examiner rejected claim 10 under 35 U.S.C. § 103(a) as obvious over Davis and Lee3 (Ans. 5–7). A. 35 U.S.C. §§ 102(a)/102(e) over Davis The Examiner finds that: Davis teaches that one can make an aptamer-RNAi construct, wherein aptamer binds to a cell surface protein and a dsRNA/shRNA (comprising a sense strand and an antisense strand) is targeted to a desired target sequence for RNAi- mediated target sequence inhibition. Davis teaches that the aptamer conjugated to the dsRNA/shRNA enhances cellular uptake of the dsRNA/shRNA, which is a substrate of Dicer that generates siRNAs from dsRNA/shRNA. Davis teaches that the aptamer-RNAi construct is delivered to the cytoplasm of the targeted cells, wherein aptamer is attached to the 3’ or 5’ end of either the sense or antisense strand. (Ans. 5). The issue with respect to this rejection is: Does the evidence of record support the Examiner’s conclusion that Davis anticipates claim 6? Findings of Fact 1. Davis teaches “an RNAi construct may comprise one or more aptamers . . . . An aptamer is a nucleic acid that interacts with a target of interest to form an aptamer:target complex” (Davis ¶ 9). 2 Davis, M., US 2005/0256071 A1, published Nov. 17, 2005. 3 Yoontae Lee et al., MicroRNA Maturation: Stepwise Processing and Subcellular Localization, 21 EMBO J. 4663–4670 (2002). Appeal 2012-010469 Application 12/610,330 4 2. Davis teaches that “[i]ncorporation or attachment of the aptamer to the sense or antisense strand allows each component to retain its activity; that is, the aptamer component retains the ability to interact with a specific target, and the sense and/or antisense strands retain their ability to inhibit target gene expression by an RNAi mechanism” (id.). 3. Davis teaches that “[a]ptamers of the present invention may be selected and/or optimized for interaction (e.g. binding) with the internalizing peptides discussed above. Such an interaction may facilitate cellular uptake of the aptamer and/or RNAi construct” (id. ¶ 100). 4. Davis teaches that the “sense strand should retain the ability to hybridize with the antisense strand, and, in the case of longer nucleic acids, should not interfere with the activity of RNAses, such as Dicer, that participate in cleaving longer double-stranded constructs to yield smaller, active siRNAs” (id. ¶ 68). Davis teaches that “the siRNA constructs can be generated by processing of longer double-stranded RNAs, for example, in the presence of the enzyme dicer” (id. ¶ 87). Davis teaches that “any duplex portion should be susceptible to processing by nucleases such as Dicer” (id. ¶ 91). 5. Davis teaches that “it is possible to design an RNA molecule targeted by an aptamer sequence at the 5’ end and containing an siRNA duplex at the 3’ end . . . . Luciferase downregulation will only be seen if the siGL3 duplex can reach the cytoplasm of the cells and still function despite the presence of the aptamer on the 5’ end of the sense strand” (id. ¶ 189). Appeal 2012-010469 Application 12/610,330 5 6. Davis teaches that “[p]roduction of RNAi constructs can be carried out by chemical synthetic methods or by recombinant nucleic acid techniques” (id. ¶ 67). 7. Davis teaches that the “aptamer may occur on either the sense or antisense strand and may occur at either the 3’ or 5’ end of either strand . . . typically an aptamer will be incorporated into a linear nucleic acid backbone of the RNAi construct” (id. ¶ 69). 8. Davis teaches that “double-stranded structure may be formed by a single self-complementary nucleic acid strand or two complementary nucleic acid strands. Duplex formation may be initiated either inside or outside the cell” (id. ¶ 84). 9. Davis teaches that the “aptamer and/or polynucleotide may be internalized by a cell, and binding of the aptamer to a target molecule, such as a peptide, polypeptide, or protein, may facilitate internalization of the polynucleotide into the cell” (id. ¶ 69). 10. Davis teaches an xPSM-A10-3 aptamer sequence that “targets the prostate-specific membrane antigen (PSMA) that is overexpressed on prostate acinar epithelial cells” (id. ¶¶ 179, 181). 11. Davis teaches an siGL3 siRNA sequence that “will likely still be able to function when attached to the 3’ end of the aptamer sequence” (id. ¶¶ 183, 188). 12. Davis teaches that the “combination of the xPSM-A10-3 and siGL3 sequences yielded the following for the sense strand of this aptamer- siRNA conjugate . . . . The aptamer sequence is at the 5’ end and the siGL3 sense strand is located at the 3’ end” (id. ¶¶ 184–185). Appeal 2012-010469 Application 12/610,330 6 13. Davis teaches that the “single-stranded molecule will need to be annealed to the antisense strand of the siGL3 duplex . . . . This will lead to a duplex region from nucleotides 60-77 on the xPSM-A10-3-siGL3 sequence given previously” (id. ¶ 186). Principles of Law A prior art reference can only anticipate a claim if it discloses all the claimed limitations “arranged or combined in the same way as in the claim.” Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1361 (Fed. Cir. 2012). The “question for the purposes of anticipation is ‘whether the number of categories and components’ disclosed in [the prior art] is so large that the combination . . . ‘would not be immediately apparent to one of ordinary skill in the art.’ Wrigley, 683 F.3d at 1361.” Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1382 (Fed. Cir. 2015). Analysis Davis teaches a Dicer substrate, specifically “an RNAi construct [that] may comprise one or more aptamers . . . . An aptamer is a nucleic acid that interacts with a target of interest to form an aptamer:target complex” (FF 1). Davis teaches that the aptamer functions as a targeting moiety (FF 2–3). Davis teaches “to design an RNA molecule targeted by an aptamer sequence at the 5’ end and containing an siRNA duplex at the 3’ end” (FF 5) where the aptamer and first single stranded RNA form a contiguous nucleic acid molecule (FF 7). Davis teaches a first step of chemical synthesis of the RNAi construct (FF 6) followed by a step of duplex formation by hybridization (FF 8). Davis teaches that “binding of the aptamer to a target Appeal 2012-010469 Application 12/610,330 7 molecule . . . may facilitate internalization of the polynucleotide into the cell” (FF 9). Davis teaches a specific example, Example 4, where a contiguous nucleic acid molecule is composed of an xPSM-A10-3 aptamer and siGL3 siRNA sequence and the “aptamer sequence is at the 5’ end and the siGL3 sense strand is located at the 3’ end” (FF 12). Davis teaches hybridizing the antisense strand of the siGL3 siRNA to the nucleic acid molecule to form a duplex siRNA (FF 13). Davis teaches that the xPSM-A10-3 aptamer is capable of binding a receptor on a cell (FF 10). Appellant contends that nowhere in Davis is a specific embodiment taught that includes all of the limitations of the present claims. That is, nowhere in Davis is it taught to synthesize a nucleic acid molecule that comprises an aptamer and a first single stranded RNA and to hybridize a second single stranded RNA with the first to form a dsRNA silencing moiety that acts as a Dicer substrate. (App. Br. 11). We find this argument unpersuasive. Davis directly teaches aptamer- siRNA constructs (FF 1) in which a single stranded RNA comprising both an aptamer and siRNA sequence (FF 5) are hybridized to a second single stranded siRNA sequence (FF 8) to form a dsRNA silencing moiety (FF 2) cleavable by the Dicer enzyme (FF 4). Further, as already discussed above, Example 4 of Davis teaches formation of a specific aptamer-siRNA molecule capable of binding a cell receptor (FF 10–13) and “which is a long dsRNA that serves as a Dicer substrate. Note that it is art-accepted scientific knowledge that long dsRNAs Appeal 2012-010469 Application 12/610,330 8 serve as a substrate of Dicer enzyme, which cleaves long dsRNAs into short siRNAs of about 21 base pairs” (Ans. 12). Appellant contends that “[w]hile the Examiner picks and chooses from the various teachings of Davis to arrive at the conclusion that the reference teaches the invention claimed in claims 6-9, the Examiner does not explain why one skilled in the art would have made those selections” (App. Br. 13). Appellant contends that it “is only by picking and choosing from Davis, using the claimed invention as a blueprint, that one could even contend otherwise” (id. at 14). We are not persuaded. In Example 4 of Davis, no picking and choosing is required to anticipate claim 6 (FF 10–13). The scope of Davis’ disclosure is substantially limited and focused on either stabilized siRNA constructs or aptamer-siRNA constructs (FF 1). Moreover, it would be immediately apparent from Davis to form aptamer-siRNA constructs (FF 1) in which a single stranded RNA comprising both an aptamer and siRNA sequence (FF 5) are hybridized to a second single stranded siRNA sequence (FF 8) to form a dsRNA silencing moiety (FF 2) cleavable by the Dicer enzyme (FF 4). Appellant contends that “Example 4 of Davis clearly does not teach that the chimeric RNA described necessarily serves as a Dicer substrate” (Reply Br. 6). We are not persuaded. The Examiner finds that long RNAs serve as Dicer substrates (Ans. 12) and Davis teaches that “the siRNA constructs can be generated by processing of longer double-stranded RNAs, for example, in the presence of the enzyme dicer” (Davis ¶ 87; FF 4). Davis teaches that Appeal 2012-010469 Application 12/610,330 9 “any duplex portion should be susceptible to processing by nucleases such as Dicer” (Davis ¶ 91; FF 4). Thus, Davis teaches that the chimeric DNA described in example should function as a Dicer substrate (FF 4). See In re Antor Media Corp., 689 F.3d 1282, 1289 (Fed. Cir. 2012) (“[W]e therefore hold that, during patent prosecution, an examiner is entitled to reject claims as anticipated by a prior art publication or patent without conducting an inquiry into whether or not that prior art reference is enabling. As long as an examiner makes a proper prima facie case of anticipation by giving adequate notice under § 132, the burden shifts to the applicant to submit rebuttal evidence of nonenablement.”) Appellants fail to provide any evidence rebutting the presumption that Davis is enabled. Conclusion of Law The evidence of record supports the Examiner’s conclusion that Davis anticipates claim 6. B. 35 U.S.C. § 103(a) over Davis and Lee Appellant does not argue separately the claims in the obviousness rejection. Having affirmed the anticipation rejection of claim 6 over Davis for the reasons given above, we also find that the combination with Lee renders claim 10 obvious for the reasons given by the Examiner (see Ans. 5– 7). Appeal 2012-010469 Application 12/610,330 10 SUMMARY In summary, we affirm the rejection of claim 6 under 35 U.S.C. §§ 102(a)/102(e) as anticipated by Davis. Pursuant to 37 C.F.R. § 41.37(c)(1), we also affirm the rejection of claims 7–9, as these claims were not argued separately. We affirm the rejection of claim 10 under 35 U.S.C. § 103(a) as obvious over Davis and Lee. 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 bar