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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 10, 2026 has been entered.
Application Status and Withdrawn Rejections
Applicant’s amendment filed March 10, 2026, amending claims 1, 3, 11, 45, 76-77, 105, 126-128 and 134-136, 164 and 181 is acknowledged. Claims 1, 3, 11-14, 19, 26, 45, 48, 73, 76-77, 84, 105, 125-128, 134-136, 158, 164, 181 are pending. Claims 45, 48, 73, 76-77, 84, 125-127, 135, 158, 164 and 181 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim.
Claims 1, 3, 11-14, 19, 26, 105, 128, 134 and 136 are under examination.
The amendment to claims 1, 3, 105, 128 and 136 overcomes the §102, §103 and nonstatutory double patenting (NSDP) rejection over copending application 18744175s of record, as Maianti does not teach a base editor with an H122A alteration in SEQ ID NO 130 (i.e., ppAPOBEC-1).
Any other rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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) 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 35 U.S.C. 112 (pre-AlA). 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. 62/893638 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) for one or more claims of this application. The application fails to provide support for the claims under examination, since there is no disclosure therein of an H122A alteration in SEQ ID NO 130 (i.e., ppAPOBEC-1), SEQ ID NO 126 (i.e., RrA3F from Rhinopithecus roxellana), SEQ ID NO 127 (i.e., amAPOBEC-1 from Alligator mississippiensis), or SEQ ID NO 136 (i.e., ssAPOBEC-2 from Sus scrogfa). The first evidence of support for the above sequences and/or amino acid substitutions is in PCT Application PCT/US20/48510, filed August 28, 2020. As such, the effective filing date for claims 1, 3, 14, 19, 26, 105, 128, 134 and 136 is August 28, 2020.
Claims 11 and 13 require the deaminase to be the adenosine deaminase domain. Application No. 62/893638 discloses SEQ ID NO 23 (i.e., TadA7.10) with at least one of each of the substitutions recited in claim 1. Thus claims 11 and 13 are limited to the adenosine deaminase and do not include the limitations directed to the unsupported cytidine deaminases. Claim 12 requires the guide polynucleotide to target either SEQ ID NO 1 or SEQ ID NO 2. Application No. 62/893638 discloses guides with SEQ ID Nos 1 and 2 (page 253, Table 7). Although claim 12 depends from claim 1 and does not explicitly require the adenosine deaminase domain, Application No. 62/893638 discloses that guide polynucleotides with SEQ ID NOs 1 and 2 require an adenosine deaminase base editor (page 253, Table 7). Thus, the method of claim 12 would be limited to an adenosine deaminase and not include the limitations directed to the unsupported cytidine deaminases. As such, the effective filing date for claims 11-13 is August 29, 2019.
Claim Objections
Claim 12 is objected to because of the following informalities:
Claim 12 depends from claim 1 and recites “wherein the guide polynucleotides target one of the following sequences SEQ ID NO 1 or SEQ ID NO 2”. Claim 12 is silent as to the targeted gene, splice site, or stop codon that would be targeted by the SEQ ID NOs, and by the type of base editor that would be used by guide polynucleotides targeting the SEQ ID NOs. However, according to the Specification, the recited SEQ ID NOs target a pathogenic TA>CT mutation in the SBDS gene, and require an adenosine base editor for correction (page 298, Table 11). Claim 1 recites both specific cytidine deaminases, which are not supported in the provisional Application 62/893638, and specific adenosine deaminases, which are given the earlier priority date (see previous paragraph). To be complete, it is suggested that claim 12 be amended to include limitations as to the type of base editor given their different priority dates above. For instance: “The method of claim 1, where the base editor is an adenosine base editor (ABE) comprising the adenosine deaminase domain, and wherein the guide polynucleotides target one of the following sequences…”. Alternatively, claim 12 could be amended to depend from claim 11.
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, 14, 19, 26, 105, 128, 134, 136 are rejected under 35 U.S.C. 103 as being unpatentable over Yuan (Yuan et al., Molecular Cell (2018), 27: 1364-1371, of record), in view of Rommens (US 20060110734 A1; of record), Liu (US 20190225955 A1, published July 25 2019; of record), Yu (Yu et al., Nature Communications (2020), 11:2052, published April 28, 2020) and dbSNP2 rs113993993, https://www.ncbi.nlm.hin.gov/snp/ rs113993993 [retrieved August 14, 2025]; of record).
The Yu reference cited below was published within one year of the effective filing date of the claimed invention (see ¶ 9 above). One author in the Yu reference, Luis Barrera, is an inventor on the examined application. However, Yu names 8 additional authors that are not inventors. Therefore, Yu qualifies as prior art under § 102(a)(1).
Regarding claims 1, 3, 14 and 19, Yuan teaches using CRISPR-guided cytidine deaminase to correct mutations associated with aberrant splicing in human diseases (Abstract). Yuan teaches contacting a polynucleotide encoding OS9 with a dCas9-AID (i.e., a programmable DNA binding domain and a cytidine deaminase domain) and guide RNAs to target the dCas9-AID to edit a C>T splice site on the non-coding strand to include Exon 13 in the OS9 mRNA (Fig 5; page e3, ¶3). Yuan teaches the C> T alteration introduces a slice acceptor site (Fig 5A and E). Yuan also teaches editing a splicing donor site can be used to inhibit translation of a pathogenic form of the dystrophin protein (Fig 5). Yuan also teaches editing a splice donor nucleotide to define an intron (Fig 4A). Yuan also teaches editing a splice donor nucleotide to define an exon (Fig 1A). Yuan teaches that dCas9-AID is an efficient and versatile means of modulating splicing (page 391, ¶1). Yuan teaches the window for efficient G>A (i.e., C>T) editing is 12-20 upstream of the PAM sequence (Fig S7J; page 392, ¶4). Yuan teaches that dCas9-AID should be able to target over 80% of all human exons (page 392, ¶4). Yuan teaches the PAM sequence for dCas9 is "NGG" or "NAG" (Figure S7(K), legend).
Yuan does not teach using the method to affect or create a splice site in SBDS associated with Shwachman Diamond Syndrome (SDS). Yuan does not teach a cytidine deaminase domain having at least 90% identity to SEQ ID NO 126, 127, 130 or 136.
Rommens teaches that mutations in the SBDS gene are associated with SDS (Abstract). Rommens teaches that a 258+2T>C mutation results in an 8bp deletion and a premature truncation of the protein by a frameshift ([0124]). Rommens teaches the 258+2T>C is predicted to disrupt the donor splice site of intron 2 ([0124], FIG 2a,b). Rommens teaches the T>C change corresponds to an invariant T of the donor splice site, which results in the use of an alternative splice site ([0033]). Rommens teaches the sequence of the wild type and 258+2T>C mutations (FIG 2a, b).
Liu teaches cytidine base editors comprising dCas9 fused to a cytidine deaminase (FIG 11). Liu teaches one such mutation that can be targeted using the base editors with Cas9 and/or Cas9 variants with expanded PAMs is the C.258 + 2T>C SNP in the SBDS gene (Table 6). Liu teaches that deamination occurs at positions 4-8 in the protospacer sequence, which is 13-17 nucleotides 5’ of the PAM site (Figs 12-13).
Yu teaches next generation cytosine base editors (CBEs) using Rr3AF displayed comparable on-target editing frequencies as other CBEs, but had greatly reduced off-target DNA deamination (Abstract; Fig 2). Yu teaches that compared to CBEs with rAPOBEC1, a CBE with Rr3AF had just as high cis deamination (i.e., on target) activity, but only half as much trans deamination (i.e., off target) activity (Fig 2). Yu teaches the amino acid sequence of Rr3AF (Supp Table 1, page 25), which is 100% identical to SEQ ID NO 126 (See OA Appendix). Yu teaches deamination occurs on the non-targeted strand (Fig 1b).
dbSNP2 teaches the rs113993993 SNP is a splice donor variant (page 1). dbSNP2 teaches the SNP is "likely pathogenic" and is associated with Shwachman syndrome (page 5). dbSNP2 teaches the SNP is located at the 5' end of an intron the SBDS gene (page 10). dbSNP2 teaches the flanking sequence of the rs113993993 SNP (page 8).
Regarding claims 1, 3, 14 and 19, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used Yuan's splice site introduction method for editing the splice site mutation caused by the 258+2T>C rs113993993 SNP in the SBDS gene using a dCas9-Rr3AF base editor comprising SEQ ID NO 126. It would have amounted to 1) the simple substitution of one mammalian cytidine deaminase domain for another and 2) applying a known method for correcting and/or introducing a splice donor site by known means to yield predictable results. First, the skilled artisan would predict that RrAF3 could be used in the method because Yu demonstrates a CBE with Rr3AF can deaminate at over 30 genomic sites in human cells. The skilled artisan would have been motivated to make the substitution to use Rr3AF because of its reduced off-target deamination activity compared to earlier-developed CBEs.
Second, the skilled artisan would have expected that Yuan's method could be used to edit the "C" nucleotide on the noncoding SBDS strand thus restoring the splice donor site because such editing would follow the known parameters of cytidine base editing as follows: The SBDS rs113993993 sequence as deduced from dbSNP2 and Rommens is below: SNP (mutated splice donor site) = lowercase and bolded; PAM sequence for Cas9 = bolded and underlined; protospacer sequence with C13 in predicted Cas9-APOBIC1 window = underlined
5'-TTAGCTATGCTGCAGCTGTTACCCgCCTGCTTACAGATTTCAGT
AATCGATACGACGTCGACAATGGGcGGACGAATGTCTAAAGTCA-5' (coding strand)
The skilled artisan would have expected that the C on the coding strand could be edited using dCas9-Rr3AF, because the targeted C is in position 13 from the PAM with CAG (i.e., 5'-NAG) as the PAM sequence, which Liu teaches is in the editing window for cytidine base editors using CBEs. The skilled artisan would have been motivated to use a dCas9-Rr3AF base editor to target the C in the known splice-donor SNP mutation because Yuan teaches targeting the splice donor sites using CRISPR-cytidine deaminases to define the length of an exon and intron. The skilled artisan would have been motivated to apply Yuan's method to the 258+2T>C SNP in the SBDS gene because Liu teaches CRISPR-mediated cytidine deamination can be used to correct the SNP.
Regarding claim 26, Liu teaches using xCas9 variants that have altered PAM specificity, including 5’-NNG ([0342]).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used a Cas9 with altered PAM specificity in the method rendered obvious above. It would have amounted to substituting known Cas9 variants for the dCas9 in Yuan by known means to yield predictable results. The skilled artisan would have predicted another Cas9 variant could be use because Liu teaches using the Cas9 variants in base editing methods including for altering splice sites. One would have been motivated to do so do adjust the editing window for the Rr3AF deaminase.
Regarding claim 105, the teachings of Yuan, Rommens, Liu, Yu and dbSNP2 and the obviousness of applying Yuan's method to correcting a splice-site mutation in SBDS is recited above as for claims 1, 3, 14 and 19. Yuan teaches splice site editing can be performed in induced pluripotent cells (iPSCs) derived from patient's cells (page 388, ¶7-8). Yuan teaches differentiating the iPSCs into cardiomyocytes (i.e., a desired cell type).
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have editing iPSCs derived from SBDS patient cells using the method of editing the SBDS splice site mutation rendered obvious above. It would have amounted to using known cells amenable to base-editing genome modification methods. The skilled artisan would have expected that iPSCs with the 258+2T>C SNP could be edited using dCas9-Rr3AF because Yuan demonstrates editing a different site in iPSCs and differentiating the edited cells. The skilled artisan would have been motivated to do so in order to replace a patient's SBDS-mutated cells with cells comprising the corrected SNP.
Regarding claims 128, 134 and 136, the teachings of Yuan, Rommens, Liu, Yu and dbSNP2 and the obviousness of applying Yuan's method to correcting a splice-site mutation in SBDS, including in cells derived from an SDS patient is recited above as for claims 1, 3, 14, 19 and 105.
Response to Arguments - §103
Applicant’s arguments with respect to the obviousness rejections have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
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.
Claim 1, 3, 11-13, 19 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-11, 14, 24, 39, 60, 64-65, 67, 69 and 111 of copending Application No. 17430672. Claims 3, 11-12 and 19 are rejected in view of Lee (Lee et al., Molecular Therapy (2019), 27: 1364-1371; published August 7, 2019; of record), Rommens (US 20060110734 A1; of record) and dbSNP1 (rs113993991, https://www.ncbi.nlm.hin.gov/snp/ rs113993991 [retrieved August 14, 2025]; of record).
Copending claim 1 recites A method of treating a neurological disorder ... the method comprising: administering to the subject (i) an adenosine base editor or a nucleic acid sequence encoding the adenosine base editor and (ii) a guide polynucleotide or a nucleic acid sequence encoding the guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain and an adenosine deaminase domain, wherein the adenosine deaminase domain comprises a V82S alteration at amino acid position 82 as numbered in SEQ ID NO: 2 or a corresponding position thereof, and wherein the guide polynucleotide directs the adenosine base editor to effect an A-to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder in the subject, thereby treating the neurological disorder in the subject. Copending claim 8 recites where the SNP encodes an IDUA polypeptide with W402X (i.e., a premature stop codon). Copending claim 60 recites a method of editing a target gene or regulatory element thereof associated with a neurological disorder ... the method comprising contacting the target gene or regulatory element thereof with (i) an adenosine base editor and (ii) a guide polynucleotide, wherein the adenosine base editor comprises a programmable DNA binding domain and an adenosine deaminase domain ... wherein the guide polynucleotide directs the adenosine base editor to effect an A to-G nucleobase alteration in a target gene or a regulatory element thereof associated with the neurological disorder. Copending claim 65 recites wherein the A-to-G nucleobase alteration changes the SNP associated with the neurological disorder to a wild type nucleobase. SEQ ID NO 2 of the copending application is 92% identical to the SEQ ID NO 23 of the examined application (See OA Appendix, page 3). Therefore, the copending claims recite a method of editing a polynucleotide to alter a stop codon using a base editor comprising a guide RNA, programmable DNA domain and an adenosine deaminase domain having at least 90% identity to SEQ ID NO 23 and comprising a V82S alteration. Therefore, the copending claims anticipate examined claim 1.
The copending claims do not recite the disorder is SDS and the gene is SBDS. The copending claims do not recite altering a stop codon such that it creates a missense mutation. The copending claims do not recite the guide RNA sequences targeting SBDS. The copending claims do not recite the base editor has 5’-NGC or 5NGG-3’ PAM specificity
Lee teaches a method called "CRISPR-PASS" for editing premature stop codons (Abstract). Lee teaches contacting a polynucleotide encoding EGFP that contains a premature stop codon with the adenosine base editor, ABEMax (Figure 2). Lee teaches ABEMax comprises xCas9 (i.e., a polynucleotide programmable DNA binding domain) fused to an adenosine deaminase domain called ABE7.10 (page 1364, ¶2). Lee teaches the xCas9 has been engineered to expand the PAM specificity of Cas9 (page 1364, ¶2). Lee teaches delivering ABEMax and a guide RNA directed to a premature stop codon, created a missense mutation in EGFP allowing bypass of the premature stop codon and allowing the expression of EGFP (Figure 2C-G, Supp Fig 2, Supp Table 4). Lee also teaches editing a premature stop codon in the XPC gene in cells derived from patients having xeroderma pigmentosum (Figure 3). Lee teaches the premature stop codon (i.e., nonsense mutation) causes xeroderma pigmentosum. Lee teaches the method was able to restore expression by of XPC (Fig 3). Lee teaches the CRISPR-Pass method is a relevant approach for rescuing the nonsense-associated diseases with higher editing efficiencies than using homology directed repair (page 1377, ¶2). Lee teaches the ABEMax base editor can edit A nucleotides at the 7th and 8th position relative to the 5' end of the sgRNA on the strand that does not hybridize to the guide RNA (Fig 1A and Fig 2E). Lee teaches that adenines at positions 4-8 of the protospacer from the end distal to the PAM sequences of NGG, NRG, NG, or NAR can be targeted using adenosine base editors known in the art (Fig 1C; page 1368, ¶5). Lee also teaches that Cas9 variants that can recognize sequences with a 5' - NG PAM sequences can also be used in adenosine base editors (page 1365, ¶1). Lee teaches that adenines outside of the targeted window are also edited to guanines, albeit at low frequencies, including at positions 10 and 15 (Fig 3B).
Rommens teaches that mutations in the SBDS gene are associated with SDS (Abstract). Rommens teaches that the 183-184 TA➔ CT mutation causes a premature stop codon (i.e., introduces a stop codon) at residue K62, resulting in a K62X nonsense mutation, which is associated with SDS (Table 1).
dbSNP1 teaches the rs113993991 SNP is located in the SBDS gene and results in the formation of a stop codon in the SBDS coding sequence (page 1). dbSNP1 teaches the SNP is "pathogenic" and is associated with Shwachman syndrome (page 3). dbSNP1 teaches the flanking sequence of the 183-184 TA➔ CT SNP (page 8). dbSNP1 teaches the SNP was discovered at least as early as 2010 (page 5).
Regarding claims 3 and 11-13, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the copending method to treating SDS by editing a premature stop codon in the SBDS gene using Lee's CRISPR-Pass method with xCas9 and the copending adenosine deaminase domain comprising the V82S substitution. It would have amounted to applying the copending method to editing a known premature stop codon by known means to yield predictable results. The skilled artisan would have expected that using the copending method could be used to edit the "A" nucleotide on the noncoding SBDS strand thus changing the "TAA'' codon to "GAA'' because such editing follows Lee's parameters of adenosine base editing as follows: The SBDS rs113993991 sequence as deduced from dbSNP and Rommens is below: SNP = lowercase; premature stop codon= bolded; PAM sequence for xCas9 = bolded and underlined; protospacer sequence with A8 in predicted Cas9-ABE window = Underlined.
5'-TTCCTTTTTGGCAACCTGACCTTagGAAACATTTACAAACACTGAG
AAGGAAAAACCGTTGGACTGGAAtcCTTTGTAAATGTTTGTGACTC-5' (coding strand)
The skilled artisan would have expected that the A on the non-coding strand could be edited using the copending adenosine deaminase because the targeted A is in position 8 using the AAA (i.e., 5'-NAR'3') PAM sequence, which Lee teaches is in the editing window, and 2) the A is on the non-target strand.
Regarding the guide RNA sequences in claim 12, it also would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have used a guide RNA with SEQ ID NO 2 to edit the AA on the coding strand to produce the codon TGG, which codes for tryptophan and is a missense mutation. The claimed sgRNA targeting sequence with the flaking sequence of the SNP is below: SNP = lowercase; premature stop codon= bolded; PAM sequence for xCas9 = bolded and underlined; sgRNA with SEQ ID NO protospacer = underlined with As in the positions 11 and 12 (A11 and A12).
5'-TTCCTTTTTGGCAACCTGACCTTagGAAACATTTACAAACACTGAG
AAGGAAAAACCGTTGGACTGGAAtcCTTTGTAAATGTTTGTGACTC-5' (coding strand)
The skilled artisan would have expected that the A on the coding strand could be edited using the copending adenosine base editor because the targeted As are in positions 11 and 12, which Lee teaches will be edited at low, but detectable frequencies, and 2) the AA is on the non-target strand. The skilled artisan would have been motivated to use the copending base editor to target the A in the SNP because Lee teaches targeting an A on the non-coding strand for deaminase base editing such that the TAA stop codon will become a CAA codon on the coding strand (i.e., a missense mutation). The skilled artisan would have been motivated to apply the copending method to the rs113993991 SNP in the SBDS gene because Lee teaches the method can be applied to gene rescuing of pathogenic premature stop codon SNPs.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 3, 14, 19, 26, 105, 128, 134 and 136 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-11, 14, 24, 39, 60, 64-65, 67 and 69 of copending Application No. 18744175 in view of Yuan (Yuan et al., Molecular Cell (2018), 27: 1364-1371), Rommens (US 20060110734 Al), Liu (US 20190225955 A1, published July 25 2019), Yu (Yu et al., Nature Communications (2020), 11:2052, published April 28, 2020) and dbSNP2 rs113993993, https://www.ncbi.nlm.hin.gov/snp/ rs113993993 [retrieved August 14, 2025]; of record). This is a new rejection necessitated by amendment.
Copending claim 1 recites A method of editing a nucleobase of a survival of motor neuron 2 (SMN2) polynucleotide, the method comprising contacting the SMN2 polynucleotide with a guide polynucleotide and a base editor comprising a fusion protein or a protein complex comprising a nucleic acid programmable DNA binding protein (napDNAbp) domain and a deaminase domain, wherein said guide polynucleotide targets said base editor to effect an alteration of the nucleobase of the SMN2 polynucleotide. Copending claim 8 recites wherein alteration of the nucleobase is associated with an increase in full-length polynucleotides encoding the SMN2 polypeptide transcribed from the SMN2 polynucleotide; and/or wherein alteration of a nucleobase in the SMN2 polynucleotide results in an increase in the number of transcripts transcribed from the SMN2 polynucleotide that include Exon 7. Copending claim 9 recites wherein the altered nucleobase in the SMN2 polynucleotide is associated with an alteration in splicing. Copending claim 11 recites wherein the napDNAbp domain comprises a variant of SpCas9 having an altered PAM specificity and the deaminase is an APOBEC deaminase domain.
The copending claims do not recite a specific SEQ ID NO or origin from the APOBEC deaminase domain. The copending claims do not recite the disorder is SDS, the gene is SBDS, or the SNP is rs113993993 in the SBDS gene. The copending claims do not recite induced pluripotent cells.
The teachings of Yuan, Rommens, Liu, Yu and dbSNP2 are recited above in paragraphs 17, 19-22, 25, 27 and 29 and incorporated here.
It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to have modified the copending method for treatment of SDS by editing the mutated splice donor site in the SBDS gene using Yuan's method of modulating splice sites and substituting generic APOBEC deaminase domain for the Rr3AF deaminase taught in Yu, which is 100% identical to SEQ ID NO 126. It would have amounted to 1) substituting a known APOBEC domain that can be used for base editing for a generic one, and 2) applying the copending method to editing a mutated splice site by known means to yield predictable results. The skilled artisan would predict that human APOBEC1 could be used in the method because Yu teaches that Rr3AF is a deaminase that can be used in Cas9-derived base editors and has low off-target activity. The skilled artisan would have expected that the copending method could be applied to editing the "C" nucleotide in the SBDS gene thus restoring the "GT" donor site following Yuan's parameters because such editing would follow the known parameters of cytidine base editing as indicated above in paragraphs 23-24. The skilled artisan would have expected that the C on the non-coding strand could be edited using the copending dSpCas9-Rr3AF, because the targeted C is in the predicted window using the known dCas9 PAM (i.e., 5'-NAG). The skilled artisan would have been motivated to apply the copending method of editing the mutated splice site in SBDS using Yuan's method because Yuan teaches the method can be used to define exons and introns.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments - NSDP
Applicant’s arguments with respect to the NSDP rejections have been fully considered. Regarding the rejection over the ‘175 Application, the arguments are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. Applicant does not provide any arguments rebutting the rejection over the ‘672 Application other than to say the amendments overcome the rejections. However, the claim amendments only limited the CBE, not the ABE. Therefore, the claims encompassing an ABE are still rejected for NSDP over the claims in the ‘672 application which require the instantly claimed ABE sequences.
Applicant also argues that the ‘175 co-pending application has a later US filing date than the present application and the NSDP rejection over the ‘175 should be withdrawn (Remarks, page 19, last ¶). Examiner agrees that the ‘175 co-pending application has a later US filing date. However, MPEP 804.I.B.1.(b).(i) makes clear that a provisional double patenting rejection should be made and maintained by the examiner until the rejection has been overcome by amendment or the rejection is the only rejection remaining in an application having the earlier patent term filing date. Because the claims are still rejected under § 103 and another provisional NSDP rejection over an application with an earlier US filing date, the rejection for nonstatutory double patenting over the copending ‘175 application is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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