DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of a compound of formula A1 in which R0 is an alkyl group having 1 to 30 carbon atoms substituted with one or more fluorine atoms in the reply filed on 06/12/2026 is acknowledged. In view of Applicant’s arguments, the species election set forth on 04/16/2026 is hereby withdrawn.
Furthermore, because the species of a claimed invention previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the species election requirement as set forth in the Office action mailed on 04/16/2026 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 1-8 are pending and under consideration.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Japan on 03/03/2021. The priority document was retrieved and entered into the application file on 11/06/2023.
The earliest effective filing date to which the instant application is entitled is 03/03/2022.
Information Disclosure Statement
Receipt of information disclosure statements on 09/01/2023 and 03/12/2025 is acknowledged. The signed and initialed PTO-1449‘s have been mailed with this action.
Drawings
The drawings filed 09/01/2023 are accepted.
Claim Objections
Claims 1 and 6 are objected to because of the following informalities:
Claim 1 recites “a nucleic acid comprising a structure represented by: the following general formula (A1) or (A2),…
[wherein…a filled circle indicates a bond],” which is improper. The brackets surrounding the “wherein” clause are improper. It would be remedial to remove the brackets surrounding the “wherein” clause.
Furthermore, the recitation of “[Chemical Formula 1]” is improper, as it conflicts with the claimed “general formula (A1) or (A2).” Given that the instant claim set is drawn to formulas A1 or A2, it would be remedial to amend the instant claim language to delete the recitation of “[Chemical Formula 1]” and modify the labeling of formulas A1 and A2 such that each structure is labeled by its full title of “formula (A1)” or “formula (A2).”
Finally, with regard to claim 1, the inclusion of a colon following “by” in line does not comport with standard grammatical and/or linguistic conventions. It would be remedial to amend the instant claim language to remove said colon, thereby comporting with standard grammatical and/or linguistic conventions.
Claim 6 recites “the nucleic acid according to Claim 1, which is cell membrane permeable.” While this recitation is not strictly improper, it is inconsistent with the rest of the instant claim language, which uses wherein clauses to further limit the instantly claimed nucleic acid. For purposes of internal consistency, it would be remedial to amend the instant claim language such that it is internally consistent with the rest of the instant claim language, for example by reciting “the nucleic acid according to Claim 1, wherein the nucleic acid is cell membrane permeable” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3 and 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Asanuma et al., 2010 (hereinafter Asanuma 2010) in view of Watanabe et al., 2019 (hereinafter Watanabe; as cited in Applicant IDS), Patani and LaVoie, 1996 (hereinafter Patani), Kashida et al., 2016 (hereinafter Kashida), Alagia et al., 2014 (hereinafter Alagia), and Janas et al., 2019 (hereinafter Janas), as evidenced by Riess, 2005 (hereinafter Riess).
Claim 1 recites “a nucleic acid comprising a structure represented by: the following general formula…(A2) [shown in Appendix I]…wherein” R0 is an alkyl group having 1 to 30 carbon atoms that is/are substituted with one or more fluorine atoms or an alkyl group having 10 to 30 carbon atoms that is/are not substituted with a fluorine atom, wherein “n11 and n12 each independently represent an integer of 1 or more; [and] B is a nucleobase.” In comparison, Asanuma discloses the development of acyclic threoninol nucleic acids, which were synthesized by tethering each of the genetic nucleobases to D-threoninol molecules, which were then incorporated as building blocks into a scaffold bearing phosphodiester linkages (abstract; Figure 1). The structures of these acyclic threoninol nucleic acids are depicted in Figure 1 (shown in Appendix II), which substantially overlap with the instantly claimed A2 structure. The only difference between the instantly claimed A2 structure and that of Asanuma is the instantly claimed R0 group. While Asanuma includes an R group at the instantly claimed position, the R of Asanuma is a methyl group, which does not read on any of the instantly claimed R0 groups. However, the disclosure of Asanuma establishes that acyclic threoninol nucleic acids (depicted in Figure 1) form unexpectedly stable duplexes (page 14703, column 2, paragraph 3) and comprise an R group of a methyl group attached at the same position as the instantly claimed R0 group.
Regarding the instantly claimed R0 group, Watanabe discloses that the addition of perfluorocarbon groups into nucleic acids enhances their cellular uptake (Abstract; Introduction: paragraph 2; Conclusion). As is known to those of ordinary skill in the art, perfluorocarbon groups are alkyl groups in which every hydrogen has been replaced with a fluorine (reviewed in Riess). Accordingly, it is considered that perfluorocarbon groups read on the instantly claimed R0 group, as even a single perfluorocarbon group reads on the instantly claimed alkyl group having 1 carbon atom that is substituted with three (i.e. at least one) fluorine atoms.
While Watanabe does not disclose specific modification of the methyl group disclosed in Asanuma, the disclosure of Watanabe establishes that perfluorocarbon groups enhance cellular uptake. Furthermore, Patani discloses that substitution of hydrogen for fluorine is a commonly employed monovalent isosteric replacement, as the steric parameters for hydrogen and fluorine are similar (see section 1. Fluorine vs Hydrogen Replacements). Therefore, it would have been obvious to someone of ordinary skill in the art to modify the methyl group of Asanuma to instead comprise fluorine in place of hydrogen (i.e. a perfluorocarbon group), thereby enhancing cellular uptake of the nucleic acid, as disclosed in Watanabe.
Thus, Asanuma and Watanabe collectively disclose and/or motivate the formula of instant claim 1, wherein said formula comprises an R0 group of an alkyl group having 1 to 30 carbon atoms that is/are substituted with one or more fluorine atoms and n12 is an integer of 1 or more.
With regard to claim 2, which recites “said R0 [of the nucleic acid according to claim 1] is an alkyl group having 1 to 30 carbon atoms that is substituted with at least two fluorine atoms, as set forth above, Watanabe discloses that the addition of perfluorocarbon groups into nucleic acids enhances their cellular uptake (Abstract; Introduction: paragraph 2; Conclusion). As is known to those of ordinary skill in the art, perfluorocarbon groups are alkyl groups in which every hydrogen has been replaced with a fluorine (reviewed in Riess). Accordingly, it is considered that perfluorocarbon groups read on the instantly claimed R0 group, as even a single perfluorocarbon group reads on the instantly claimed alkyl group having 1 carbon atom that is substituted with three (i.e. at least one) fluorine atoms. Thus, it is considered that Watanabe discloses and/or motivates each and every additional limitation of instant claim 2.
With regard to claim 3, which recites “said R0 [of the nucleic acid according to claim 2] is a perfluoroalkyl group having 1 to 10 carbon atoms, or a group having 1 to 5 etheric oxygen atoms between carbon atoms of a perfluoroalkyl group having 1 to 10 carbon atoms,” as set forth above, Watanabe discloses that the addition of perfluorocarbon groups into nucleic acids enhances their cellular uptake (Abstract; Introduction: paragraph 2; Conclusion). As is known to those of ordinary skill in the art, perfluorocarbon groups are alkyl groups in which every hydrogen has been replaced with a fluorine (reviewed in Riess). Additionally, as set forth above, regarding the instantly claimed range of length for said alkyl group, Asanuma discloses a methyl group at the instantly claimed R0 position, which reads on the instantly claimed range of 1 to 10. Additionally, while Watanabe does not disclose specific modification of the methyl group disclosed in Asanuma, the disclosure of Watanabe establishes that perfluorocarbon groups enhance cellular uptake, thereby motivating conversion of the methyl group of Asanuma to a perfluorocarbon group as taught by Watanabe. Thus, it is considered that Asanuma and Watanabe collectively disclose and/or motivate each and every additional limitation of instant claim 3.
With regard to claim 5, which recites “n12 [of the nucleic acid according to Claim 1]…is 5 or more,” as set forth above, Asanuma and Watanabe collectively disclose and/or motivate the formula of instant claim 1. However, the cited art does not explicitly teach that n12 is 5 or more, as is instantly claimed. This deficiency is cured by Kashida, Alagia, and Janas. Kashida discloses that threoninol nucleic acids (i.e. as disclosed in Asanuma, set forth above) form extremely stable duplexes (abstract). As is known to those of ordinary skill in the art, therapeutic nucleic acids such as siRNAs are double stranded, as disclosed in Alagia (page 17873, paragraph 1). Alagia further discloses that the inclusion of threoninol nucleic acids (i.e. as disclosed in Asanuma, set forth above) in therapeutic double stranded RNAs such as siRNAs evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, and stimulates the innate immune system to a lesser extent (abstract). Finally, while the disclosure of Janas is drawn to GalNAc-siRNA conjugates comprising 2’-deoxy-2’-fluoro nucleotides (abstract), this disclosure nonetheless establishes that duplex siRNA agents are known to tolerate the addition of fluorine modifications. As set forth above, Watanabe discloses that inclusion of perfluorocarbon groups (comprising fluorine) enhances the cellular uptake of nucleic acids (Abstract; Introduction: paragraph 2; Conclusion). Therefore, one of ordinary skill in the art would reasonably expect that modifying siRNAs with perfluorocarbon group(s) would predictably enhance their cellular uptake. In summary, threoninol nucleic acids form extremely stable duplexes, such as therapeutic siRNA duplexes, and modifying the nucleotides of said duplexes with perfluorocarbon group(s) enhances their cellular uptake. Finally, as is known to those of ordinary skill in the art, siRNAs are greater than 5 nucleotides in length, with an average length of approximately 21-23 nucleotides (Alagia: page 17873, paragraph 1). Thus, it is considered that Kashida, Alagia, and Janas collectively disclose and/or motivate each and every additional limitation of instant claim 5.
With regard to claim 6, which recites “the nucleic acid according to Claim 1, which is cell membrane permeable,” as set forth above, Asanuma and Watanabe collectively disclose and/or motivate the formula of instant claim 1. Furthermore, as set forth above, Watanabe discloses that inclusion of perfluorocarbon groups (comprising fluorine) enhances the cellular uptake of nucleic acids by making their permeability higher (Abstract; Introduction: paragraph 2; Conclusion). Thus, adding perfluorocarbon groups to the acyclic threoninol nucleic acids disclosed in Asanuma 2010 and Asanuma 2008 must predictably enhance the permeability of said nucleic acids. Furthermore, given that Asanuma and Watanabe collectively disclose and/or motivate the nucleic acid structure of claim 1, as set forth above, the nucleic acid structure of both instant claim 1 and of Asanuma and Watanabe must be structurally identical and therefore must necessarily have identical functions. See MPEP § 2114 and § 2173.05(g). Accordingly, it is considered that Asanuma and Watanabe (with particular regard to Watanabe) collectively disclose each and every additional limitation of instant claim 6.
With regard to claim 7, which recites “a cell membrane permeabilizing agent comprising the nucleic acid according to Claim 1 as an active ingredient,” as set forth above, Asanuma and Watanabe collectively disclose and/or motivate the instantly claimed nucleic acid structure. Furthermore, the recited preamble of “a cell membrane permeabilizing agent” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while Asanuma, Watanabe, and Schäfer do not explicitly disclose a cell membrane permeabilizing agent comprising the claimed nucleic acid, Asanuma and Watanabe do disclose and/or motivate the claimed nucleic acid, which is the only recited claim limitation with patentable weight at instant claim 7. Thus, Asanuma and Watanabe are considered to collectively disclose and/or motivate each and every limitation of instant claim 7. Furthermore, one of ordinary skill in the art would reasonably predict that the structure collectively disclosed by Asanuma and Watanabe must effectively permeabilize the cell membrane, as Watanabe teaches that the addition of perfluorocarbon groups enhances cell membrane permeabilization (Abstract).
With regard to claim 8, which recites “a nucleic acid drug comprising the nucleic acid according to Claim 1 as an active ingredient,” as set forth above Asanuma and Watanabe collectively disclose and/or motivate the instantly claimed nucleic acid structure. Additionally, as set forth above, Kashida discloses that threoninol nucleic acids (i.e. as disclosed in Asanuma, set forth above) form extremely stable duplexes (abstract). As is known to those of ordinary skill in the art, therapeutic nucleic acids such as siRNAs are double stranded, as disclosed in Alagia (page 17873, paragraph 1). Alagia further discloses that the inclusion of threoninol nucleic acids (i.e. as disclosed in Asanuma 2010 and Asanuma 2008, set forth above) in therapeutic double stranded RNAs such as siRNAs evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, and stimulates the innate immune system to a lesser extent (abstract). Finally, while the disclosure of Janas is drawn to GalNAc-siRNA conjugates comprising 2’-deoxy-2’-fluoro nucleotides (abstract), this disclosure nonetheless establishes that duplex siRNA agents are known to tolerate the addition of fluorine modifications. As set forth above, Watanabe discloses that inclusion of perfluorocarbon groups (comprising fluorine) enhances the cellular uptake of nucleic acids (Abstract; Introduction: paragraph 2; Conclusion). Therefore, one of ordinary skill in the art would reasonably expect that modifying siRNAs with perfluorocarbon group(s) would predictably enhance their cellular uptake. Thus, it is considered that Kashida, Alagia, Janas, and Watanabe collectively disclose and/or motivate each and every additional limitation of instant claim 8.
Given that:
Asanuma discloses the structure of acyclic threoninol nucleic acids, wherein said structure is identical to that of formula A2, with the exception of the instantly claimed R0 group (which is a methyl group in Asanuma);
Watanabe discloses that the addition of perfluorocarbon groups (wherein each hydrogen has been replaced with a fluorine per Riess) into nucleic acids enhances their cellular uptake;
Patani discloses that fluorine and hydrogen are bioisosteres that are easily substitutable for one another;
Kashida discloses that threoninol nucleic acids form extremely stable duplexes;
Alagia discloses that the inclusion of threoninol nucleic acids in siRNAs (approximately 21-23 nucleotides in length) evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, and stimulates the innate immune system to a lesser extent; and
Janas discloses that siRNAs tolerate fluorine modifications,
it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Asanuma to comprise an R group comprising at least one alkyl group (as disclosed in Asanuma) substituted with at least one fluorine to enhance cellular uptake (as disclosed in Watanabe and Patani) to predictably generate an acyclic threoninol nucleic acid displaying enhanced cellular uptake. One would have been motivated to make such a modification in order to receive the expected benefit of generating an acyclic threoninol nucleic acid better capable of crossing cellular membranes.
Furthermore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to incorporate said acyclic threoninol nucleic acid with enhanced cellular uptake into a therapeutic duplex such as an siRNA (as disclosed in Alagia) to predictably generate an extremely stable (as disclosed in Kashida) therapeutic siRNA that evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, stimulates the innate immune system to a lesser extent, and displays enhanced cellular uptake (as disclosed in Watanabe). One would have been motivated to make such a modification in order to receive the expected benefit of generating an extremely stable therapeutic siRNA that evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, stimulates the innate immune system to a lesser extent, and displays enhanced cellular uptake.
Claims 1 and 4-8 are rejected under 35 U.S.C. 103 as being unpatentable over Asanuma et al., 2010 (hereinafter Asanuma 2010) in view of Huo et al., 2019 (hereinafter Huo, Kashida et al., 2016 (hereinafter Kashida), Alagia et al., 2014 (hereinafter Alagia), and WO 2012/083185 A2 (hereinafter Rozema).
Claim 1 recites “a nucleic acid comprising a structure represented by: the following general formula…(A2) [shown in Appendix I]…wherein” R0 is an alkyl group having 1 to 30 carbon atoms that is/are substituted with one or more fluorine atoms or an alkyl group having 10 to 30 carbon atoms that is/are not substituted with a fluorine atom, wherein “n11 and n12 each independently represent an integer of 1 or more; [and] B is a nucleobase.” In comparison, Asanuma discloses the development of acyclic threoninol nucleic acids, which were synthesized by tethering each of the genetic nucleobases to D-threoninol molecules, which were then incorporated as building blocks into a scaffold bearing phosphodiester linkages (abstract; Figure 1). The structures of these acyclic threoninol nucleic acids are depicted in Figure 1 (shown in Appendix II), which substantially overlap with the instantly claimed A2 structure. The only difference between the instantly claimed A2 structure and that of Asanuma is the instantly claimed R0 group. While Asanuma includes an R group at the instantly claimed position, the R of Asanuma is a methyl group, which does not read on any of the instantly claimed R0 groups. However, the disclosure of Asanuma establishes that acyclic threoninol nucleic acids (depicted in Figure 1) form unexpectedly stable duplexes (page 14703, column 2, paragraph 3) and comprise an R group attached at the same position as the instantly claimed R0 group.
Regarding the instantly claimed R0 group, wherein said R0 group is an alkyl group having 10 to 30 carbon atoms that is/are not substituted with a fluorine atom, Huo discloses that nucleic acids are uniquely programmable over other molecules that interact with membranes (page 1, column 2, paragraph 2). An example of such programmability is that nucleic acids (which are hydrophilic) may be connected to a hydrophobic moiety to increase their hydrophobicity, thereby resulting in nucleic acid amphiphiles that can efficiently cross the lipid bilayer of the cell membrane (page 1, column 2, paragraphs 2-4). Huo further discloses that such hydrophobic groups include alkyl chains with either 12 (C12), 18 (C18), or 26 (C26) carbons, with C26 alkyl chains resulting in the best piercing into cell membranes, with C12 and C18 displaying intermediate insertion efficiency (page 8, column 2, paragraph 1). The alkyl chains disclosed in Huo read on the instantly claimed range of 10 to 30 carbons and further do not comprise any fluorine atoms, as instantly claimed.
While Huo does not disclose specific modification of the methyl group disclosed in Asanuma to be a larger alkyl group, the disclosure of Huo establishes that alkyl groups enhance nucleic acid membrane permeability. Therefore, it would have been obvious to someone of ordinary skill in the art to modify the methyl group of Asanuma to instead be a longer alkyl group (i.e. C12, C18, or C26), thereby enhancing cellular uptake of the nucleic acid. Said another way, the existing methyl group of Asanuma is an alkyl group; therefore, the disclosure of Huo motivates extending that alkyl group to a length of C12, C18, or C26 to enhance cellular uptake of the nucleic acid.
Thus, Asanuma and Huo collectively disclose and/or motivate the formula of instant claim 1, wherein said formula comprises an R0 group of an alkyl group having 10 to 30 carbon atoms that is/are not substituted with a fluorine atom and n12 is an integer of 1 or more.
With regard to claim 4, which recites “said R0 [of the nucleic acid according to claim 1] is an alkyl group having 10 to 30 carbon atoms that is not substituted with a fluorine atom,” as set forth above, Huo discloses that nucleic acids are uniquely programmable over other molecules that interact with membranes (page 1, column 2, paragraph 2). An example of such programmability is that nucleic acids (which are hydrophilic) may be connected to a hydrophobic moiety to increase their hydrophobicity, thereby resulting in nucleic acid amphiphiles that can efficiently cross the lipid bilayer of the cell membrane (page 1, column 2, paragraphs 2-4). Huo further discloses that such hydrophobic groups include alkyl chains with either 12 (C12), 18 (C18), or 26 (C26) carbons, with C26 alkyl chains resulting in the best piercing into cell membranes, with C12 and C18 displaying intermediate insertion efficiency (page 8, column 2, paragraph 1). The alkyl chains disclosed in Huo read on the instantly claimed range of 10 to 30 carbons and further do not comprise any fluorine atoms, as instantly claimed. Thus, it is considered that Huo discloses each and every additional limitation of instant claim 4.
With regard to claim 5, which recites “n12 [of the nucleic acid according to Claim 1]…is 5 or more,” as set forth above, Asanuma and Huo collectively disclose and/or motivate the formula of instant claim 1. However, the cited art does not explicitly teach that n12 is 5 or more, as is instantly claimed. This deficiency is cured by Kashida, Alagia, and Janas. Kashida discloses that threoninol nucleic acids (i.e. as disclosed in Asanuma, set forth above) form extremely stable duplexes (abstract). As is known to those of ordinary skill in the art, therapeutic nucleic acids such as siRNAs are double stranded, as disclosed in Alagia (page 17873, paragraph 1). Alagia further discloses that the inclusion of threoninol nucleic acids (i.e. as disclosed in Asanuma 2010 and Asanuma 2008, set forth above) in therapeutic double stranded RNAs such as siRNAs evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, and stimulates the innate immune system to a lesser extent (abstract). Finally, while the disclosure of Rozema is broadly drawn to a peptide-based in vivo siRNA delivery system (abstract), Rozema also discloses that siRNAs may be conjugated to hydrophobic moieties such as alkyl groups (page 11, lines 12-25; page 24, lines 12-20; page 43, lines 12-19) while retaining their therapeutic function. As set forth above, Huo discloses that inclusion of alkyl groups enhances the cellular uptake of nucleic acids by creating nucleic acid amphiphiles (page 1, column 2, paragraphs 2-4; page 8, column 2, paragraph 1). Therefore, one of ordinary skill in the art would reasonably expect that modifying siRNAs with alkyl groups would predictably enhance their cellular uptake. In summary, threoninol nucleic acids form extremely stable duplexes, such as therapeutic siRNA duplexes, and modifying the nucleotides of said duplexes with alkyl groups enhances their cellular uptake. Finally, as is known to those of ordinary skill in the art, siRNAs are greater than 5 nucleotides in length, with an average length of approximately 21-23 nucleotides (Alagia: page 17873, paragraph 1). Thus, it is considered that Kashida, Alagia, Huo, and Rozema collectively disclose and/or motivate each and every additional limitation of instant claim 5.
With regard to claim 6, which recites “the nucleic acid according to Claim 1, which is cell membrane permeable,” as set forth above, Asanuma and Huo collectively disclose and/or motivate the formula of instant claim 1. Furthermore, as set forth above, Huo discloses that inclusion of alkyl groups enhances the cellular uptake of nucleic acids by creating nucleic acid amphiphiles (page 1, column 2, paragraphs 2-4; page 8, column 2, paragraph 1). Thus, adding alkyl groups to the acyclic threoninol nucleic acids disclosed in Asanuma must predictably enhance the permeability of said nucleic acids. Furthermore, given that Asanuma and Huo collectively disclose and/or motivate the nucleic acid structure of claim 1, as set forth above, the nucleic acid structure of both instant claim 1 and of Asanuma 2010, Asanuma 2008, Watanabe, and Schäfer must be structurally identical and therefore must necessarily have identical functions. See MPEP § 2114 and § 2173.05(g). Accordingly, it is considered that Asanuma and Huo (with particular regard to Huo) collectively disclose each and every additional limitation of instant claim 6.
With regard to claim 7, which recites “a cell membrane permeabilizing agent comprising the nucleic acid according to Claim 1 as an active ingredient,” as set forth above, Asanuma and Huo collectively disclose and/or motivate the instantly claimed nucleic acid structure. Furthermore, the recited preamble of “a cell membrane permeabilizing agent” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Accordingly, while Asanuma and Huo do not explicitly disclose a cell membrane permeabilizing agent comprising the claimed nucleic acid, Asanuma and Huo do disclose and/or motivate the claimed nucleic acid, which is the only recited claim limitation with patentable weight at instant claim 7. Thus, Asanuma and Huo are considered to collectively disclose and/or motivate each and every limitation of instant claim 7. Furthermore, one of ordinary skill in the art would reasonably predict that the structure collectively disclosed by Asanuma and Huo must effectively permeabilize the cell membrane, as Huo teaches that the addition of hydrophobic alkyl groups enhances cell membrane permeabilization (page 1, column 2, paragraphs 2-4; page 8, column 2, paragraph 1).
With regard to claim 8, which recites “a nucleic acid drug comprising the nucleic acid according to Claim 1 as an active ingredient,” as set forth above Asanuma and Huo collectively disclose and/or motivate the instantly claimed nucleic acid structure. Additionally, as set forth above, Kashida discloses that threoninol nucleic acids (i.e. as disclosed in Asanuma, set forth above) form extremely stable duplexes (abstract). As is known to those of ordinary skill in the art, therapeutic nucleic acids such as siRNAs are double stranded, as disclosed in Alagia (page 17873, paragraph 1). Alagia further discloses that the inclusion of threoninol nucleic acids (i.e. as disclosed in Asanuma set forth above) in therapeutic double stranded RNAs such as siRNAs evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, and stimulates the innate immune system to a lesser extent (abstract). Finally, while the disclosure of Rozema is broadly drawn to a peptide-based in vivo siRNA delivery system (abstract), Rozema also discloses that siRNAs may be conjugated to hydrophobic moieties such as alkyl groups (page 11, lines 12-25; page 24, lines 12-20; page 43, lines 12-19) while retaining their therapeutic function. As set forth above, Huo discloses that inclusion of alkyl groups enhances the cellular uptake of nucleic acids by creating nucleic acid amphiphiles (page 1, column 2, paragraphs 2-4; page 8, column 2, paragraph 1). Therefore, one of ordinary skill in the art would reasonably expect that modifying siRNAs with alkyl groups would predictably enhance their cellular uptake. Thus, it is considered that Kashida, Alagia, and Rozema collectively disclose and/or motivate each and every additional limitation of instant claim 8.
Given that:
Asanuma discloses the structure of acyclic threoninol nucleic acids, wherein said structure is identical to that of formula A2, with the exception of the instantly claimed R0 group;
Huo discloses that the addition of hydrophobic alkyl groups (i.e. C12, C16, or C28) into nucleic acids enhances their ability to cross the cell membrane;
Kashida discloses that threoninol nucleic acids form extremely stable duplexes;
Alagia discloses that the inclusion of threoninol nucleic acids in siRNAs (approximately 21-23 nucleotides in length) evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, and stimulates the innate immune system to a lesser extent; and
Rozema discloses that siRNAs tolerate alkyl modifications,
it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the structure of Asanuma (which already comprises an alkyl R group) to comprise an R group comprising an alkyl group (which is hydrophobic per Huo) with at least 12, 16, of 28 carbons to enhance the ability of the nucleic acid to cross the cell membrane, as disclosed in Huo. One would have been motivated to make such a modification in order to receive the expected benefit of generating an acyclic threoninol nucleic acid better capable of crossing cellular membranes.
Furthermore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to incorporate said acyclic threoninol nucleic acid with enhanced cellular uptake into a therapeutic duplex such as an siRNA (as disclosed in Alagia) to predictably generate an extremely stable (as disclosed in Kashida) therapeutic siRNA that evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, stimulates the innate immune system to a lesser extent, and is better capable of crossing cellular membranes (as disclosed in Huo). One would have been motivated to make such a modification in order to receive the expected benefit of generating an extremely stable therapeutic siRNA that evinces significantly higher activity than that of unmodified RNAs, imparts extremely strong resistance to serum and exonucleases, stimulates the innate immune system to a lesser extent, and is better capable of crossing cellular membranes.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 19/045,852 (corresponds to US 2025/0313838 A1) in view of Alagia et al., 2014 (hereinafter Alagia), Watanabe et al., 2019 (hereinafter Watanabe; as cited in Applicant IDS), and Huo et al., 2019 (hereinafter Huo).
MPEP 804 II B 1 states:
The specification can be used as a dictionary to learn the meaning of a term in the patent claim. Toro Co. v. White Consol. Indus., Inc., 199 F.3d 1295, 1299, 53 USPQ2d 1065, 1067 (Fed. Cir. 1999)… Further, those portions of the specification which provide support for the patent claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the patent. In re Vogel, 422 F.2d 438, 441-42, 164 USPQ 619, 622 (CCPA 1970).
The following rejections are in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Copending application ‘852 recites “a nucleic acid for transfection in which a nucleic acid targeted for introduction into a cell and a cell membrane-permeable group are linked together, and the cell membrane-permeable group has a structure represented by one of the general formulas (A1) to (A4) [formula A2 shown in Appendix III] shown below:…
(wherein in formulas (A1) to (A3), R0 represents an alkyl group of 1 to 30 carbon atoms substituted with one or more fluorine atoms, a group composed of an alkyl group of 2 to 30 carbon atoms substituted with one or more fluorine atoms and having one to five ether-bonded oxygen atoms between carbon atoms, an alkyl group of 10 to 30 carbon atoms not substituted with any fluorine atoms, or a group composed of an alkyl group of 10 to 30 carbons not substituted with any fluorine atoms but having one to five ether-bonded oxygen atoms between carbon atoms; n12, n12 and n13 each independently represent an integer of 1 or greater, B represents a nucleic acid base; and black dots indicate bonding sites).”
As shown in Appendices I and III, structure A2 of both the instant (see instant claim 1) and copending applications are identical. Furthermore, the R0 group limitations recited at claim 1 of both the instant and copending applications are also identical. Thus, copending and instant claim 1 are not patentably distinct from each other.
Copending claim 2 recites “the nucleic acid for transfection according to Claim 1, the nucleic acid targeted for introduction into a cell is an siRNA,” which is not patentably distinct from instant claim 8, which recites “a nucleic acid drug comprising the nucleic acid according to Claim 1 as an active ingredient.” As is known to those of ordinary skill in the art (and reviewed in Alagia), siRNAs are nucleic acid drugs. Thus, copending claim 2 and instant claim 8 are not patentably distinct from each other.
Copending claims 3 and 4 respectively recite “R0 represents an alkyl group of 1 to 30 carbon atoms substituted with at least two fluorine atoms” and “R0 represents a perfluoroalkyl group of 1 to 10 carbon atoms…”. Instant claims 2 and 3 respectively recite identical limitations. Thus, copending claims 3 and 4 and instant claims 2 and 3 are not patentably distinct from each other.
Copending claim 5 recites “R0 represents an alkyl group of 10 to 30 carbon atoms not substituted with any fluorine atoms…”. In comparison, instant claim 4 recites “R0 is an alkyl group having 10 to 30 carbon atoms that is not substituted with a fluorine atom.” These recitations are identical and thus, copending claim 5 and instant claim 4 are not patentably distinct from each other.
Copending claim 6 recites “the nucleic acid for transfection according to Claim 1, wherein n12 is 2 or greater...”. In comparison, instant claim 5 recites “the nucleic acid according to Claim 1, wherein n12…is 5 or more.” While these ranges overlap, they are not identical. However, as set forth above, Alagia discloses siRNAs comprising acyclic threoninol nucleic acids (abstract), wherein siRNAs comprise approximately 21-23 nucleotides (page 17873, paragraph 1). Thus, Alagia motivates siRNAs (as in the copending application) of 21-23 nucleotides in length, which falls within the range of both copending claim 6 and instant claim 5. Therefore, copending claim 6 (in view of Alagia) is not patentably distinct from instant claim 5.
Copending claims 7-9 are all drawn to methods, wherein said methods are respectively a nucleic acid transfection method comprising bringing the nucleic acid for transfection according to Claim 1 into contact with a cell, a method for producing the nucleic acid for transfection according to Claim 1, and a method for treating or preventing cancer, comprising administering an effective amount of the nucleic acid for transfection according to claim 1 to a subject. All of these methods require the nucleic acid of copending claim 1, which is not patentably distinct from the nucleic acid of instant claim 1, as set forth above. Accordingly, copending claims 7-9 are not patentably distinct from instant claim 1.
With regard to instant claims 6 and 7, which respectively recite “the nucleic acid according to Claim 1…is cell membrane permeable” and “a cell membrane permeabilizing agent comprising the nucleic acid according to Claim 1 as an active ingredient,” as set forth above, Watanabe teaches that the addition of perfluorocarbon groups (comprising fluorine) enhances the cellular uptake of nucleic acids by making their permeability higher (Abstract; Introduction: paragraph 2; Conclusion). Thus, adding perfluorocarbon groups to the nucleic acids of both the instant and copending applications (as recited therein) must predictably enhance the permeability of said nucleic acids. Additionally, as set forth above, Huo discloses that inclusion of alkyl groups enhances the cellular uptake of nucleic acids by creating nucleic acid amphiphiles (page 1, column 2, paragraphs 2-4; page 8, column 2, paragraph 1). Furthermore, when structures are identical, they must have identical functions per MPEP § 2114 and § 2173.05(g). Finally, the recited preamble of “a cell membrane permeabilizing agent” does not generate or otherwise result in a structural difference of the product claimed therein, meaning the claim body recites a structurally complete invention, while the preamble only states a purpose or intended use for the invention and is thus not a claim limitation given patentable weight (see MPEP § 2111.02(II)). Therefore, given that the structures of the instant and copending applications are identical, it is thus considered that instant claims 6 and 7 are not patentably distinct from copending claim 1.
Given that the copending application recites identical nucleic acid structures to that of the instant application, that Alagia discloses siRNAs 21-23 nucleotides in length comprising acyclic threoninol nucleic acids, that Watanabe and Huo respectively disclose that the addition of perfluorocarbon groups or hydrophobic alkyl groups to nucleic acids enhances their ability to cross the cell membrane, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to increase the length of the nucleic acid residues recited in the copending application (i.e. to overlap with the instantly recited range) to predictably generate a therapeutic siRNA (as per Alagia) with enhanced ability to cross the cell membrane (as per Watanabe and Huo). One would have been motivated to make such a modification in order to receive the expected benefit of generating a therapeutic siRNA (as per Alagia) with enhanced cellular uptake (as per Watanabe and Huo).
This is a provisional nonstatutory double patenting rejection.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
With regard to the claimed range of an alkyl group having 1 to 30 carbon atoms that is substituted with one or more fluorine atoms, US 2014/0065223 A1 (hereinafter Schäfer; as cited in Applicant IDS) discloses perfluorinated compounds for the non-viral transfer of nucleic acids (abstract), wherein said compounds comprise perfluorocarbons comprising C1-C10, C1-C20, or C1-C30 (paragraph [0048]), thereby motivating routine experimentation to manipulate the length of the instantly claimed alkyl group (see MPEP § 2144.05(II)(A)) via routine experimentation to optimize its function, thereby arriving at the instantly claimed range.
Conclusion
No claims are allowed.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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