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 .
Application Status
Applicant’s remarks and amendments to the claims filed July 2, 2026 are acknowledged. Claims 48-49, and 65-66 were amended. Claims 48-49, 52, 54, 56-66, and 68-70 are pending and under examination herein.
Withdrawn Rejections
Applicant’s amendment to claims 48, and 65-66 to require that the “complementary RNA sequence comprised by the single-stranded RNA molecule is 71 to 260 nucleotides in length,” is sufficient to overcome the § 103 rejections raised in the prior action over Woolf, Wettengel, and Turunen, and Woolf, Wettengel, and Turunen in further view of Schneider. The length of the complementary RNA sequence comprised by the single-stranded RNA molecule taught by Woolf, which was relied upon in the previous rejections, falls outside of the instantly claimed range. These rejections are withdrawn, accordingly. The grounds over which the non-statutory double patenting rejections over U.S. Patent No. 11,661,596 B2 and co-pending Application No. 18/684,082 were raised are also overcome by this amendment. These rejections are withdrawn as they were presented in the previous action, accordingly.
Applicant’s remarks and amendments have been thoroughly considered but are not persuasive to place the claims in condition for allowance for the reasons that follow. Any rejection or objection not reiterated herein has been overcome by amendment.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. PCT/CN2018/110105, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, PCT/CN2018/110105 does not disclose the limitation “wherein the single-stranded RNA molecule comprises a mismatch directly opposite the target adenosine in the target RNA, wherein the mismatch is located at least 20 nucleotides away from the 5' end of the complementary RNA sequence comprised by the single-stranded RNA molecule and at least 5 nucleotides away from the 3' end of the complementary RNA sequence comprised by the single-stranded RNA molecule” recited in claims 48, and 65-66. The first disclosure of this limitation is in Application No. PCT/CN2019/082713. See paragraph [0087], and embodiment 4, pg. 48. The effective filing date of all claims under examination is April 15, 2019, accordingly.
Claim Rejections - 35 USC § 102 – Katrekar
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 48, 52, 54, 58-62, 65-66, and 68-70 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information). The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Claims 48 and 65-66 are interpreted as requiring the introduction of either “a single-stranded RNA molecule” or a “construct encoding the single-stranded RNA molecule.” The single-stranded RNA molecule is interpreted as an RNA molecule which is not duplexed (i.e., the molecule is not hybridized to a separate, complementary strand), “is exogenous to the host cell,” “does not comprise an ADAR-recruiting domain comprising a stem-loop structure” (e.g., a GluR-2, or 5HT2C domain, or a stem-loop structure of a CRISPR/Cas gRNA), and “does not comprise any chemically modified nucleotide.” The specification also provides that the RNA molecule “do[es] not comprise crRNA, tracrRNA, or gRNA used in the CRISPR/Cas system” (specification, [0057]). This term is not interpreted as excluding single-stranded RNA molecules which form intramolecular stem-loops or duplexed regions, generally, because, as evidenced by secondary structure prediction software, RNA molecules described in the specification may form such structures. See Appendix I (of record), which shows secondary structures predicted by VectorBuilder (VectorBuilder, https://en.vectorbuilder.com/tool/dna-secondary-structure.html, accessed 12 September 2025; of record) for SEQ ID NOs: 341-342 described in Example 17. The construct is interpreted as a nucleic acid (i.e., DNA or RNA) which comprises a sequence encoding the single-stranded RNA molecule ([00130]).
The single-stranded RNA molecule must hybridize to an endogenous target RNA “in the host cell” (i.e., not prior to introduction to the host cell), via a complementary RNA sequence, form a double-stranded RNA, which thereby, must recruit an ADAR to deaminate a target adenosine in the target RNA. The single-stranded RNA molecule must comprise a mismatch directly opposite the target adenosine, wherein the mismatch is located at least 20-nts away from the 5’ end, and at least 5-nts away from the 3’ end, of the complementary RNA sequence. Finally, the complementary RNA sequence comprised by the single-stranded RNA molecule is 71 to 260 nucleotides in length.
Regarding claims 48, 54, 65-66, and 68-70, Katrekar teaches a method of editing a target RNA comprising a target adenosine, for example, a target adenosine within an early stop codon, in order to reverse the early stop codon (“in vivo sequence-specific RNA base editing via adenosine deaminases acting on RNA (ADAR) enzymes with associated ADAR guide RNAs (adRNAs),” pg. 239; Fig. 1; Supp. Fig. 6; Supp. Fig. 10). Katrekar teaches the method comprises introducing a construct encoding a single-stranded RNA molecule into a eukaryotic host cell (“U6-transcribed adRNAs and chemically synthesized adRNAs were both an effective format… adRNAs bearing long antisense domains, both with and without GluR2 domains, sufficed to recruit exogenously expressed ADARs and, to a degree, endogenous ADARs to enable efficient RNA editing” pg. 239; “RNA editing via constructs using the full-length ADAR2 and an engineered adRNA derived from the GluR2 transcript…,” Fig. 1, Supp. Fig. 2, Supp. Fig. 5; Supp. Table 1). Katrekar teaches that the target RNA is deaminated in the host cell by endogenous ADAR following introduction of the construct encoding the single-stranded RNA molecule (“Adenosine-to-inosine RNA editing… is catalyzed by ADAR enzymes. Inosine is a deaminated form of adenosine,” pg. 239; see working examples throughout, e.g., Fig. 1, Supp. Fig. 6). Katrekar teaches that the deamination restores expression or activity of the target RNA, or the protein encoded by the target RNA (“Immunoblots of the treated muscles… demonstrated 1-2.5% protein restoration,” pg. 240; “we observed a high editing fraction… in the correctly spliced OTC mRNA… and confirmed a reduction in the incorrectly spliced product… confirmed partial… restoration of OTC protein,” pg. 242; Supp. Fig. 13).
Katrekar teaches that the single-stranded RNA molecule comprises a complementary sequence to the target RNA (“antisense domain”), wherein the complementary sequence is 100 nucleotides in length (Fig. 1; Supp. Fig. 6; Supp. Table 1). Katrekar’s single-stranded RNA molecules do not comprise any chemically modified nucleotides (“U6-transcribed adRNAs,” pg. 239), and do not comprise an ADAR-recruiting domain comprising a stem-loop structure (“in one version, they bear zero… ADAR-recruiting domains,” pg. 239). Katrekar teaches the single-stranded RNA comprises a cytidine mismatch directly opposite the target adenosine in the target RNA (“a mismatched cytidine opposite the target adenosine,” pg. 239; Supp. Table 1). Katrekar teaches exemplary such RNA molecules, wherein the cytidine mismatch is at least 5 nucleotides away from the 3’ end of the complementary RNA sequence and at least 2- nucleotides away from the 5’ end of the complementary RNA sequence (see Supp. Table 1).
Regarding claim 52, “the ADAR is endogenously expressed by the host cell,” is interpreted as encompassing expression of ADAR from a naturally-occurring genomic copy, or an introduced copy of the naturally-occurring ADAR (“the ADAR is an endogenously encoded ADAR of the host cell, wherein introduction of the ADAR comprises over-expressing the ADAR in the host cell,” [0071]). As described above, Katrekar teaches the ADAR is endogenously expressed by the host cell (“adRNAs bearing long antisense domains, both with and without Gl2 domains, sufficed to recruit… to a degree, endogenous ADARs to enable efficient RNA editing,” pg. 239; endogenous recruitment of these via adRNAs bearing long-antisense domains… presents a very attractive strategy for efficacious RNA editing,” pg. 242).
Regarding claims 58-59, Katrekar teaches the target adenosine is in a “UAG” three-base motif in the target RNA, wherein the single-stranded RNA molecule comprises an adenosine directly opposite the uridine, a cytidine directly opposite the target adenosine, and a cytidine, guanosine, or uridine directly opposite the guanosine in the three-base motif (“RAB7A transcript,” Supp. Fig. 6; “RAB7A (100, 50),” “RAB7A (100, 6),” “KRAS (100, 50),” “CKB (100, 50),” Supp. Table 1).
Regarding claims 60-62, Katrekar teaches the methods in mouse and human host cells (“Mammalian cell culture and transfection. All HEK293T cells (ATCC) or HEK293FT cells,” “All mice were acquired from Jackson Labs… injected into either the gastrocnemius or tibialis anterior muscle,” pg. 243).
Notice to Joint Inventors
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.
Claim Rejections - 35 USC § 103 – Katrekar in view of Mali
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.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) as applied to claims 48, 52, 54, 58-62, 65-66, and 68-70, in view of Mali (Mali et al., US 2022/0010333 A1, effectively filed 15 December 2018). The rejection that follows is new and necessitated by Applicant’s amendments to the claims.
The teachings of Katrekar are described above and applied as to claims 48, 52, 54, 58-62, 65-66, and 68-70 therein. As stated therein, Katrekar teaches that endogenous recruitment of [ADAR1 and ADAR2] via adRNAs bearing long-antisense domains… presents a very attractive strategy for efficacious RNA editing” (pg. 242). Katrekar teaches that long antisense domains, even without ADAR-recruiting domain(s) suffices to recruit endogenous ADARs to enable efficient RNA editing (pg. 239). As stated above, Katrekar teaches complementary RNA sequences 100 nucleotides in length (see Supp. Table 1).
Katrekar does not teach that the complementary RNA sequence comprised by the single-stranded RNA molecule is 111 to 191 nucleotides in length.
Mali teaches substantially identical single-stranded RNAs, and constructs encoding the single-stranded RNAs, for use in substantially identical methods to Katrekar (see at least [0242]-[0259]). Mali teaches the single-stranded RNAs do not comprise an ADAR-recruiting domain (“For adRNAs of lengths over 50 base pairs, when expressed in HEK 293T and HeLa, the adRNAs cells can recruit ADARs even in the absence of the ADAR recruiting domain and enable significant levels of target RNA editing,” [0241]; “no ADAR recruiting domains,” [0244]). Mali teaches single-stranded RNAa comprising a complementary RNA sequence “from about 100 to about 200, base pairs” ([0243]).
MPEP 2144.05 provides that “In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists.”
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the length of the complementary RNA sequence of the single-stranded RNA of Katrekar, to a length within the range taught by Mali and recited in the instant claim. It would have amounted to modifying the length of a known complementary RNA sequence, to another known length which is suitable for use in methods of editing a target adenosine with an endogenous ADAR, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success of modifying the length given the teachings of Katrekar and Mali regarding the suitability of long antisense domains for recruiting endogenous ADAR to edit a target adenosine, and because preparing single-stranded RNAs with a variety of complementary RNA sequence lengths was known in the art. The skilled artisan would have been motivated to modify the length in an effort to prepare additional single-stranded RNAs for the “very attractive strategy for efficacious RNA editing” taught by both Katrekar and Mali.
Claim Rejections - 35 USC § 103 – Katrekar in view of Turunen and Schneider
Claims 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) as applied to claims 48, 52, 54, 58-62, 65-66, and 68-70, in view of Turunen (Turunen et al., 28 December 2017, WO 2017/220751 A1; of record) and Schneider (Schneider et al., 17 April 2014, Nucleic Acids Research, Vol. 42, No. 10, pg. 1-9; of record). The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
The teachings of Katrekar are described above and applied as to claims 48, 52, 54, 58-62, 65-66, and 68-70 therein.
Katrekar does not teach that the complementary RNA sequence comprises one or more guanosines each opposite a non-target adenosine in the target RNA (claim 56); or that the complementary RNA sequence comprises two or more consecutive mismatch nucleotides opposite a non-target adenosine in the target RNA (claim 57).
Turunen teaches substantially identical single-stranded RNAs for use in substantially identical methods to Katrekar (pg. 5, lines 20-24; pg. 3, line 38 to pg. 4, line 1; pg. 8, line 11-12; pg. 4, lines 13-29; pg. 8, lines 10 to pg. 9, line 2; pg. 18, lines 37-39). Turunen teaches that RNA molecules with additional “series of nucleotides that are not fully complementary… preferably two or three consecutive mismatching and/or wobble base pairs and/or bulges” are “tolerable, and in some cases preferable” (pgs. 8-9). Turunen teaches the presence of additional mismatches and or wobble base pairs may add to the RNA editing efficiency (pg. 4, lines 16-19). Turunen teaches that guanosine sterically clashes with an amino acid side chain of ADAR, and is disfavorable for editing (pg. 15, lines 26-35).
Schneider teaches modifications to RNA molecules which improve ADAR-mediated RNA editing efficiency at a target adenosine “in neighborhood of other adenosines” (pg. 2, right col.). Schneider teaches that “RNA editing can lead to off-site editing in adenosine-rich sequences” (pg. 4, right col.). Schneider demonstrates that editing selectivity at a target adenosine can be efficiently controlled by placing a guanosine mismatch opposite a non-target adenosine (pg. 4, right col.; Fig. 3; pg. 8, left col.). Schneider teaches that a guanosine mismatch protects a non-target adenosine from deamination, even when the non-target adenosine is separated by only a single intervening base from the target adenosine (pg. 4, right col.; Fig. 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the guanosine mismatch technique taught by Schneider, to a nucleotide which was directly opposite a non-target adenosine, and adjacent to the target adenosine within a single-stranded RNA molecule used in the method of Katrekar. It would have amounted to applying a known technique to a known single-stranded RNA, by known means, with the predicted effect of reducing deamination at non-target adenosines in the neighborhood of the target adenosine within the target RNA. The skilled artisan would have been capable of applying the guanosine mismatch technique taught by Schneider, because as evidenced by the prior art, it was well within the capabilities of the skilled artisan to prepare RNA molecules with a desired sequence, including those with guanosine mismatches opposite non-target adenosines. The skilled artisan would have had a reasonable expectation of success in reducing deamination at non-target adenosines by applying the guanosine mismatch technique because Schneider and Turunen both teach that guanosine mismatches hamper ADAR editing, and Schneider demonstrates that guanosine mismatches protect non-target adenosines from deamination, even when the non-target adenosines are separated from the target adenosine by only a single intervening base. The skilled artisan would have been motivated to apply the technique of Schneider in an effort to reduce editing at the non-target adenosines adjacent to the target adenosine in Katrekar’s method.
Regarding claim 57, as stated above, Turunen teaches that additional “series of nucleotides that are not fully complementary… preferably two or three consecutive mismatching and/or wobble base pairs and/or bulges” are “tolerable, and in some cases preferable” (pgs. 8-9). Turunen teaches the presence of additional mismatches and or wobble base pairs may add to the RNA editing efficiency (pg. 4, lines 16-19).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the guanosine mismatch technique taught by Schneider, to two or more consecutive nucleotides directly opposite non-target adenosines, and adjacent to the target adenosine, within a single-stranded RNA molecule used in the method of Katrekar. It would have amounted to applying a known technique to a known single-stranded RNA molecule, by known means, with the predicted effect of reducing deamination at non-target adenosines in the neighborhood of the target adenosine within the target RNA. The skilled artisan would have been capable of applying the guanosine mismatch technique taught by Schneider, because as evidenced by the prior art, it was well within the capabilities of the skilled artisan to prepare RNA molecules with a desired sequence, including those with guanosine mismatches opposite non-target adenosines. The skilled artisan would have had a reasonable expectation of success in reducing deamination at two or more non-target adenosines in the target RNA by applying the guanosine mismatch technique, because Schneider and Turunen both teach that guanosine mismatches hamper ADAR editing, Turunen teaches that additional “series of nucleotides that are not fully complementary… preferably two or three consecutive mismatching and/or wobble base pairs and/or bulges” are “tolerable, and in some cases preferable” and increase editing efficiency, and Schneider demonstrates that guanosine mismatches protect non-target adenosines from deamination. The skilled artisan would have been motivated to apply the technique of Schneider to two or more consecutive nucleotides in the RNA molecule in an effort to reduce editing at the non-target adenosines adjacent to the target adenosine in Katrekar’s method.
Claim Rejections - 35 USC § 103 – Katrekar in view of Turunen
Claims 63-64 are rejected under 35 U.S.C. 103 as being unpatentable over Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) as applied to claims 48, 52, 54, 58-62, 65-66, and 68-70, in view of Turunen (Turunen et al., 28 December 2017, WO 2017/220751 A1; of record). The rejections that follow are new, and necessitated by Applicant’s amendments to the claims.
The teachings of Katrekar are described above and applied as to claims 48, 52, 54, 58-62, 65-66, and 68-70 therein.
Katrekar does not teach that the method is carried out in an isolated cell from an individual ex vivo, wherein the individual has a disease or condition.
Turunen teaches their substantially identical method may be carried out in an isolated cell from an individual ex vivo, wherein the individual has a disease or condition (“The invention is particularly suitable for modifying sequences in cells, tissues or organs implicated in a diseased state of a (human) subject… In some embodiments cells are treated ex vivo and are then introduced into a living organism (e.g., re-introduced into an organism from whom they were originally derived)… The cell to be treated will generally have a genetic mutation.”, pg. 21, lines 1-24).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have applied the method of Katrekar to an isolated cell from an individual with a disease or condition as taught by Turunen. It would have amounted to applying a known method to a known cell type, by known means to yield predictable results. A skilled artisan would have had a reasonable expectation of success in applying the method to an isolated cell from an individual with a disease or condition because Katrekar and Turunen teach substantially identical RNA molecules, used in substantially identical methods of deaminating a target adenosine in human cells, and because the prior art teaches the method has therapeutic implications in the treatment of genetic disease caused by mutations. The skilled artisan would have been motivated to apply the method to an isolated cell from an individual with a disease or condition because Katrekar and Turunen both teach that the method will have therapeutic applications, including in treatment of human genetic disease (see for example, Katrekar, pg. 240, left col., pg. 242, left col.; Turunen, pg. 5, lines 1-18).
Response to Remarks - 35 USC § 103
Applicant’s remarks with respect to the § 103 rejections raised in the prior action have been considered, but are moot because the new grounds of rejection do not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Nonstatutory 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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 11,661,596 B2
Claims 48, 52, 54, 56-58, 60-61, 65-66, and 68-70 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,661,596 B2 in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Patented claim 1 recites “A method for editing a target RNA comprising a target adenosine in a host cell, comprising introducing a construct comprising a nucleic acid encoding the dRNA into the host cell, wherein: (1) the dRNA comprises a targeting RNA sequence that is at least partially complementary to the target RNA, (2) the dRNA is capable of recruiting an adenosine deaminase acting on RNA (ADAR), and (3) the dRNA forms a circular RNA within the host cell, wherein the circular RNA recruits an ADAR to deaminate a target adenosine in the target RNA; wherein the dRNA further comprises: (i) a 3′ ligation sequence and a 5′ ligation sequence; or (ii) a 3′ twister ribozyme sequence linked to the 3′ end of the nucleic acid encoding the dRNA and a 5′ twister ribozyme sequence linked to the 5′ end of the nucleic acid encoding the dRNA.”
Regarding claims 66 and 70, the patented method of claim 1 does not explicitly recite that “the [dRNA] does not comprise any chemically modified nucleotide.” However, in order for the method of targeted editing to take place following “introducing a construct comprising a nucleic acid encoding the dRNA into the host cell,” the dRNA must necessarily be expressed by the cell, prepared using naturally-occurring nucleotides, and therefore, would not comprise any chemically modified nucleotide.
The patented method of claim 1 also does not explicitly recite a single-stranded RNA molecule, which is interpreted as an RNA molecule which is not duplexed, i.e., the molecule is not hybridized to another, complementary strand. However, a dRNA molecule which is transcribed from a construct must necessarily be single-stranded, because transcription produces a single-stranded complementary transcript to a template sequence.
The patented method of claim 1 also does not explicitly recite that “the RNA molecule does not comprise an ADAR-recruiting domain comprising a stem-loop structure.” The phrase is interpreted as requiring that the RNA molecule be without a stem-loop structure that “binds at high affinity to ADAR” (e.g., a GluR-2, or 5HT2C domain), or “binds to a binding partner fused to ADAR in an engineered ADAR construct” (e.g., a stem-loop structure of a gRNA)(specification, [0083]; [00110]). MPEP 2131.02(III) provides that “A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.” Based on the prior art, the ordinarily skilled artisan would understand that the genus of “arRNA” includes RNA molecules with ADAR-recruiting domains comprising a stem-loop structure (e.g., those described by Turunen in review of the prior art, pgs. 1-2; and Zhang, US 11,618,896 B2, 4 April 2023; both of record), and those without ADAR-recruiting domains comprising a stem-loop structure (e.g., those taught by prior art Woolf, Turunen, Katrekar, and Mali). Thus, although the patented claims do not expressly spell out the limitation “the RNA molecule does not comprise an ADAR-recruiting domain comprising a stem-loop structure,” the limitation is at once envisaged by the ordinary skilled artisan given the limited number of configurations in the genus of ADAR-recruiting RNA molecules.
Similarly, the patented claim does not explicitly recite that the target RNA is endogenous to the host cell, and the RNA molecule is exogenous to the host cell. The ordinarily skilled artisan would understand that the genus of RNA molecules and target RNAs includes those exogenous to, and endogenous to, the host cell. Thus, although the patented claims do not expressly recite that the RNA molecule is exogenous to the host cell, and the target RNA is endogenous to the host cell, the limitation is at once envisaged by the skilled artisan given the limited types in the genus.
Patented claim 1 does not recite that the RNA molecule comprises a mismatch directly opposite the target adenosine, wherein the mismatch is at least 20-nts away from the 5’ end of the complementary RNA sequence, and at least 5-nts away from the 3’ end of the complementary RNA sequence, or that the complementary RNA sequence comprised by the RNA molecule is 71 to 260, or 111 to 191 nucleotides in length.
The teachings of Katrekar are described above and applied hereinafter.
Regarding the features of the RNA molecule, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the RNA molecule of the patented claims in view of the design features of Katrekar. It would have amounted to applying known design features to a known RNA molecule, by known means to yield predictable results. The skilled artisan would have been capable of applying the cytidine mismatch location and complementary RNA sequence lengths disclosed by Katrekar to the RNA molecule of the patented claims, because as evidenced by the prior art it was well within the capabilities of one of ordinary skill to prepare RNA molecules with a desired sequence and length, including those with a cytidine mismatch directly opposite a target adenosine, at virtually any location within the RNA molecule (e.g., centrally as in some examples in Katrekar). Based on the successful examples of Katrekar, the skilled artisan could have applied the design features to the RNA molecule of the patented claims with a reasonable expectation that the resulting RNA molecules would be functional. The skilled artisan would have been motivated to do so in an effort to produce RNA molecules for use in the patented methods, which are substantially identical to those of Katrekar.
Patented claim 1 does not recite that the method is used for “restoring expression or activity of a target RNA comprising a target adenosine or a protein encoded by the target RNA.”
The teachings of Katrekar are described above and applied hereinafter.
Regarding instant claims 48 and 68, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the patented method to restore expression or activity of a target RNA comprising a target adenosine as taught by Katrekar. It would have amounted to applying a known, patented method by known means, to yield predictable results. The skilled artisan would have had a reasonable expectation of success in using the patented method to restore expression or activity of a target RNA comprising a target adenosine because Katrekar teaches a substantially identical method to that of the patented method, which is used for this purpose. The skilled artisan would have been motivated to use the patented method to restore expression or activity of a target RNA comprising a target adenosine because Katrekar demonstrates a successful, working example substantially identical to the patented method, and teaches that the method has therapeutic applications for genetic disease.
Patented claim 1 also does not recite that the method is used for “reversing an early stop codon in a target RNA comprising a target adenosine.”
The teachings of Katrekar are described above and applied hereinafter.
Regarding instant claims 65 and 69, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the patented method to reverse an early stop codon in a target RNA comprising a target adenosine as taught by Katrekar. It would have amounted to applying a known, patented method by known means, to yield predictable results. The skilled artisan would have had a reasonable expectation of success in using the patented method to reverse an early stop codon in a target RNA comprising a target adenosine because Katrekar teaches a substantially identical method to that of the patented method, which is used for this purpose. The skilled artisan would have been motivated to use the patented method to reverse an early stop codon in a target RNA comprising a target adenosine because Katrekar demonstrates a successful, working example substantially identical to the patented method, and teaches that the method has therapeutic applications for genetic disease.
Patented claim 10 meets the limitations of instant claim 52. Patented claim 11 meets the limitations of instant claims 54, 56-58. Patented claim 16 meets the limitations of instant claims 60-61. These claims are also obvious over the patented claims in view of Katrekar.
Claim 49 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,661,596 B2 in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) and Mali (Mali et al., US 2022/0010333 A1, effectively filed 15 December 2018). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. The rejection that follows is new and necessitated by Applicant’s amendments to the claims.
The obviousness of arriving at a complementary RNA sequence comprised by the patented RNA molecule which is in the claimed range based on Katrekar and Mali is described above in paragraph 16 and applied hereinafter.
Claim 59 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,661,596 B2 in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) and Schneider (Schneider et al., 17 April 2014, Nucleic Acids Research, Vol. 42, No. 10, pg. 1-9; of record). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. The rejection that follows is new and necessitated by Applicant’s amendments to the claims.
Regarding instant claim 59, the patented claims do not recite the three-base motif in the RNA molecule which is opposite the three-base motif UAG in the target RNA. The teachings of Schneider are described above and applied hereinafter. Schneider teaches that deamination at UAG “strictly require[s] a matching base pair at the 5’-site” and demonstrates that the “optimal” RNA molecule architecture opposite the UAG is ACC (see Fig. 4, top panel and description; pg. 8, left col.).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have designed the RNA molecule of the patented method to comprise the three-base motif ACC opposite the target RNA three-base motif UAG as taught by Schneider. It would have amounted to applying the known, optimal architecture to the patented RNA molecule, by known means to yield predictable results. The skilled artisan would have been motivated to apply the optimal architecture to the patented RNA molecule, and with a reasonable expectation of success because preparing RNA molecules with a desired sequence was well within the purview of the ordinarily skilled artisan as evidenced by Schneider, and because Schneider teaches the design principles which lead to optimal editing at the three-base motif UAG, from which the skilled artisan would expect to achieve optimal editing as evidenced by Schneider.
Claims 62-64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,661,596 B2 in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) and Turunen (Turunen et al., 28 December 2017, WO 2017/220751 A1; of record). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Regarding instant claims 62-64, the teachings of Turunen are described above, and in the prior actions, and applied hereinafter. The obviousness of substituting the generic mammalian cell of the patented claims for a human cell, or applying the patented method to an isolated cell from an individual ex vivo, wherein the individual has a disease or condition, is described in paragraphs 27-28 of the action dated April 25, 2025 and applied here.
Co-pending Application No. 18/684,082
Claims 48, 52, 54, 58-59, 65-66, and 68-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-15, 18, 29, 63, 69, and 74 of co-pending Application No. 18/684,082 (reference application) in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Co-pending claim 1 recites “A method for editing a target adenosine in a target RNA in a host cell, comprising introducing a deaminase-recruiting RNA (dRNA) or a construct comprising a nucleic acid sequence encoding the dRNA into the host cell, wherein: (1) the dRNA comprises a targeting RNA sequence that is capable of hybridizing to the target RNA to form a duplex RNA, wherein the duplex RNA comprises a bulge comprising a non-target adenosine in the target RNA; and (2) the dRNA is capable of recruiting an adenosine deaminase acting on RNA (ADAR).”
Regarding claims 66 and 70, the co-pending claim does not explicitly recite that “the [dRNA] does not comprise any chemically modified nucleotide.” However, in order for the method of targeted editing to take place following “introducing… a construct comprising a nucleic acid sequence encoding the dRNA into the host cell,” the dRNA must necessarily be expressed by the cell, prepared using naturally-occurring nucleotides, and therefore, would not comprise any chemically modified nucleotide.
The co-pending claim also does not explicitly recite a single-stranded RNA molecule, which is interpreted as an RNA molecule which is not duplexed, i.e., the molecule is not hybridized to another, complementary strand. However, a dRNA which is transcribed from a construct must necessarily be single-stranded, because transcription produces a single-stranded complementary transcript to a template sequence.
The co-pending claim also does not explicitly recite that “the RNA molecule does not comprise an ADAR-recruiting domain comprising a stem-loop structure.” The phrase is interpreted as requiring that the RNA molecule be without a stem-loop structure that “binds at high affinity to ADAR” (e.g., a GluR-2, or 5HT2C domain), or “binds to a binding partner fused to ADAR in an engineered ADAR construct” (e.g., a stem-loop structure of a gRNA)(specification, [0083]; [00110]). MPEP 2131.02(III) provides that “A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination.” Based on the prior art, the ordinarily skilled artisan would understand that the genus of “arRNA” includes RNA molecules with ADAR-recruiting domains comprising a stem-loop structure (e.g., those described by Turunen in review of the prior art, pgs. 1-2; and Zhang, US 11,618,896 B2, 4 April 2023; both of record), and those without ADAR-recruiting domains comprising a stem-loop structure (e.g., those taught by prior art Woolf, Turunen, Katrekar, and Mali). Thus, although the co-pending claim does not expressly spell out the limitation “the RNA molecule does not comprise an ADAR-recruiting domain comprising a stem-loop structure,” the limitation is at once envisaged by the ordinary skilled artisan given the limited number of configurations in the genus of ADAR-recruiting RNA molecules.
The co-pending claim also does not explicitly recite that the target RNA is endogenous to the host cell, and the RNA molecule is exogenous to the host cell. The ordinarily skilled artisan would understand that the genus of RNA molecules and target RNAs includes those exogenous to, and endogenous to, the host cell. Thus, although the co-pending claims do not expressly recite that the RNA molecule is exogenous, and the target RNA is endogenous to the host cell, the limitation is at once envisaged by the skilled artisan given the limited types in the genus.
The co-pending claim does not recite that the RNA molecule comprises a mismatch directly opposite the target adenosine, wherein the mismatch is at least 20-nts away from the 5’ end of the complementary RNA sequence, and at least 5-nts away from the 3’ end of the complementary RNA sequence, or that the complementary RNA sequence comprised by the RNA molecule is 71 to 260, or 111 to 191 nucleotides in length.
The teachings of Katrekar are described above and applied hereinafter.
Regarding the features of the RNA molecule, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the RNA molecule of the co-pending claims in view of the design features of Katrekar. It would have amounted to applying known design features to a known RNA molecule, by known means to yield predictable results. The skilled artisan would have been capable of applying the cytidine mismatch location and complementary RNA sequence lengths disclosed by Katrekar and Mali to the RNA molecule of the co-pending claims, because as evidenced by the prior art it was well within the capabilities of one of ordinary skill to prepare RNA molecules with a desired sequence and length, including those with a cytidine mismatch directly opposite a target adenosine, at virtually any location within the RNA molecule (e.g., centrally as in some examples in Katrekar). Based on the successful examples of Katrekar, the skilled artisan could have applied the design features to the RNA molecule of the co-pending claims with a reasonable expectation that the resulting RNA molecules would be functional. The skilled artisan would have been motivated to do so in an effort to produce RNA molecules for use in the co-pending methods, which are substantially identical to those of Katrekar.
Co-pending claim 1 does not recite that the method is used for “restoring expression or activity of a target RNA comprising a target adenosine or a protein encoded by the target RNA.”
The teachings of Katrekar are recited above and applied hereinafter.
Regarding instant claims 48 and 68, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the co-pending method to restore expression or activity of a target RNA comprising a target adenosine as taught by Katrekar. It would have amounted to applying a known, co-pending method by known means, to yield predictable results. The skilled artisan would have had a reasonable expectation of success in using the co-pending method to restore expression or activity of a target RNA comprising a target adenosine because Katrekar teaches a substantially identical method to that of the co-pending method, which is used for this purpose. The skilled artisan would have been motivated to use the co-pending method to restore expression or activity of a target RNA comprising a target adenosine because Katrekar demonstrates a successful, working example substantially identical to the co-pending method, and teaches that the method has therapeutic applications for genetic disease.
Co-pending claim 1 does not recite that the method is used for “reversing an early stop codon in a target RNA comprising a target adenosine.”
The teachings of Katrekar are recited above and applied hereinafter.
Regarding instant claims 65 and 69, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the co-pending method to reverse an early stop codon in a target RNA comprising a target adenosine as taught by Katrekar. It would have amounted to applying a known, co-pending method by known means, to yield predictable results. The skilled artisan would have had a reasonable expectation of success in using the co-pending method to reverse an early stop codon in a target RNA comprising a target adenosine because Katrekar teaches a substantially identical method to that of the co-pending method, which is used for this purpose. The skilled artisan would have been motivated to use the co-pending method to reverse an early stop codon in a target RNA comprising a target adenosine because Katrekar demonstrates a successful, working example substantially identical to the co-pending method, and teaches that the method has therapeutic applications for genetic disease.
Regarding instant claims 52, 54, and 58-59, the teaching of Katrekar are described above and applied hereinafter.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the obvious methods above in view of the design features of Katrekar. It would have amounted to applying known design features to known methods, by known means to yield predictable results. The skilled artisan would have been capable of modifying the obvious method above so as to arrive at the methods of claims 52, 54, and 58-59, because as evidenced by the prior art it was well within the capabilities of one of ordinary skill to prepare RNA molecules as required of the instant claims, and to use them to edit a target adenosine via endogenously expressed ADAR. Based on the successful examples of Katrekar, the skilled artisan would have been motivated to apply the design features to the obvious methods with a reasonable expectation that the resulting methods would be functional.
Claim 49 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-15, 18, 29, 63, 69, and 74 of co-pending Application No. 18/684,082 (reference application) in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) and Mali (Mali et al., US 2022/0010333 A1, effectively filed 15 December 2018). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejection that follows is new and necessitated by Applicant’s amendments to the claims.
The obviousness of arriving at a complementary RNA sequence comprised by the co-pending RNA molecule which is in the claimed range based on Katrekar and Mali is described above in paragraph 16 and applied hereinafter.
Claims 56-57 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-15, 18, 29, 63, 69, and 74 of co-pending Application No. 18/684,082 (reference application) in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information), Turunen (Turunen et al., 28 December 2017, WO 2017/220751 A1; of record), and Schneider (Schneider et al., 17 April 2014, Nucleic Acids Research, Vol. 42, No. 10, pg. 1-9; of record). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
The obviousness of arriving at a co-pending RNA molecule comprising the features recited in claims 56-57 based on Katrekar, Turunen, and Schnieder is described above in paragraphs 21 and 23 and applied hereinafter.
Claims 60-64 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5-15, 18, 29, 63, 69, and 74 of co-pending Application No. 18/684,082 (reference application) in view of Katrekar (Katrekar et al., 8 February 2019, Nature Methods, 16, pg. 239-242, and Supplemental Information) and Turunen (Turunen et al., 28 December 2017, WO 2017/220751 A1; of record). Although the claims at issue are not identical, they are not patentably distinct from each other for the reasons that follow. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. The rejections that follow are new and necessitated by Applicant’s amendments to the claims.
Regarding claims 60-64, the teachings of Turunen are described above, and in the prior actions, and applied hereinafter. The obviousness of applying the co-pending method to an isolated human cell from an individual ex vivo, wherein the individual has a disease or condition, is described in paragraph 28 of the action dated April 25, 2025 and applied here.
Response to Remarks – Nonstatutory Double Patenting
Applicant’s remarks regarding the nonstatutory double patenting rejections raised in the prior action have been thoroughly considered. The remarks are not found persuasive to overcome the rejections described above because the alleged distinguishing features referred to by Applicant are addressed in the new rejections above, which are necessitated by Applicant’s amendments. The instant claims remain indistinct from the patented and co-pending claims in view of the prior art. No terminal disclaimers have been filed. The nonstatutory double patenting rejections over U.S. Patent No. 11,661,596 and co-pending Application No. 18/684,082 remain outstanding.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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