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
This action is written in response to applicant’s correspondence received 20 February 2026. Claims 1, 3, 6, 10, 14-18, 23-25, 34, 37, 45-46, 67, 68, 76, 101, 102, 110-112, and 122 are currently pending. Claims 6, 14, 23-25, 76, 101, 102, 110-112, and 122 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1, 3, 10, 15-18, 34, 37, 41, 45-47, and 67-68 are examined herein. The restriction requirement mailed 10 September 2025 is still deemed proper. Applicant's elected Group I, claims 1, 3, 8, 10, 15-18, 34, 37, 41, 45-47, and 67-68, alongside the species of CD117, Y256C, guide CC128, and SEQ ID NO: 574 without traverse in the reply filed 28 October 2025. Because claims 1 and 15 no longer encompass a Y256C mutation as elected previously, the search for the species of mutations has been extended to a D419G mutation as recited in the claims.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Interpretation
Regarding claims 1 and 15, for the purposes of examination the claims are interpreted as claiming that the CD117 sequence is not limited to the claimed SEQ ID NO: 35. Rather, the claims are interpreted as encompassing a CD117 protein sequence that comprises one of the claimed mutations that are present at an equivalent position when compared to the claimed SEQ ID NO: 35.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3, 10, 15-18, 34, 37, 45-46, and 67-68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 15, the claim recites “[…] wherein the at least one amino acid substitution is referenced to SEQ ID NO: 35 and is selected from [specific amino acid positions and mutations]”. The claimed SEQ ID NO: 35 does not comprise at least one of the claimed amino acids listed in the claim. The claimed SEQ ID NO: 35 does not comprise a threonine at position 13 (i.e., as encompassed by the claimed T13A mutation) and instead comprises a valine at position 13. Therefore, it is unclear if the claimed T13A mutation was claimed in error (i.e., a typographical error) or if the claimed CD117 cell surface protein is intended to comprise a threonine at position 13.
Regarding claims 3, 10, 16-18, 34, 37, 45-46, and 67-68, as the claims are ultimately dependent on claims 1 and 15 and do not rectify the currently outstanding 35 USC 112(b) rejections of record, the claims are rejected under 35 USC 112(b).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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(s) 1, 3, 10, 15-16, 34, 37, and 45-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (PG Pub No. US 2019/0169639 A1, published 6 June 2019, filed 24 January 2019) in view of Gaudelli (Nature 551.7681 (2017): 464-471), Reshetnyak ("The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer." Molecular cell 57.1 (2015): 191-201), and Miyata ("Two types of amino acid substitutions in protein evolution." Journal of molecular evolution 12.3 (1979): 219-236).
Regarding claims 1 and 15, as discussed above, for the purposes of examination the claims are interpreted as claiming that the CD117 sequence is not limited to the claimed SEQ ID NO: 35. Rather, the claims are interpreted as encompassing a CD117 protein sequence that comprises one of the claimed mutations that are present at an equivalent position when compared to the claimed SEQ ID NO: 35.
Regarding claims 1 and 15-16, Zhang is drawn towards an invention concerned with editing a target nucleic acid with a Cas9 molecule/gRNA complex (Abstract). Zhang teaches a) a method of modifying a hematopoietic stem cell ([1407]-[1408]; see Table VII-10) via the expression of a Cas9 molecule alongside a gRNA (i.e., a napDNAbp) that can be used to manipulate the cell in order to target a nucleic acid of interest to increase cell engraftment ([1409]). Zhang teaches that b) one or more target genes may be manipulated via the introduction of a mutation ([1406]), and that CD117 (i.e., also known as proto-oncogene c-Kit or cytosine-protein kinase Kit) is a gene that could be targeted and upregulated by the Cas9 molecule via its guide RNA in order to increase the efficiency of the engraftment of the cells ([1410]-[1413]). Zhang teaches that the method can be utilized to treat hemoglobinopathies in a target cell from a subject ([1442], [1562]-[1564]).
Zhang does not teach or suggest that the napDNAbp comprises a deaminase (Claims 1 and 15). Zhang does not teach or suggest that the mutation results in an amino acid substitution D419G (Claims 1 and 15).
Gaudelli is drawn to a study concerned with programmable base editing of target DNA without DNA cleavage via the use of a catalytically impaired Cas9 fused to a deaminase (Abstract). Gaudelli teaches that the fusion constructs can introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than Cas9 nuclease-based methods, and can install disease-correcting or disease-suppressing mutations in human cells (Abstract). Gaudelli teaches that the fusion construct is directed towards a target genomic DNA via the use of a guide RNA that complexes with the Cas9 in order to recruit a TadA*7.10 adenosine deaminase to the target genomic DNA and induce A:T to G:C conversion (i.e., the fusion construct can induce a conversion of an adenosine to a guanine) (pg. 470; see Figure 5).
Reshetnyak is drawn towards a study concerned with the introduction of mutations into oncogenic KIT and how they affect KIT functions (Abstract). Reshetnyak teaches that introducing a D419A mutation into the KIT molecule (i.e., a D419 mutation as referenced to the claimed SEQ ID NO: 35) resulted in a high basal tyrosine kinase activity and sensitized stem cell factor stimulation in comparison to ligand stimulation of WT KIT (pg. 199).
Miyata is drawn towards a study concerned with how tolerated certain amino acid substitutions are in proteins (Abstract). Miyata teaches the calculation of a value, termed pair distance "d" that quantitatively classifies the physico-chemical properties of amino acids including polarity, volume, and composition (pg. 220). Miyata teaches that substitutions between amino acids that have similar physico-chemical properties, and have been calculated to have a pair distance of less than 1.0, may not result in any significant change of tertiary structure over almost all variable sites in the protein (i.e., Miyata teaches that amino acids with a pair distance of less than 1.0 could be substituted for one another, and that substitution is tolerated by the protein such that it would not result in the change of the protein's tertiary structure or resulting function derived from the tertiary structure) (pg. 232). Miyata teaches that alanine and glycine have a pair distance of 0.91 (pg. 222; see Table 1).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the Cas9 of Zhang for a fusion construct comprising a catalytically impaired Cas9 fused to a deaminase, as described by Gaudelli. Because Gaudelli teaches the use of a fusion protein for the purpose of editing a target nucleic acid (i.e., the same purpose that the Cas9 of Zhang was utilized for), it would have been predictable to have utilized the fusion protein of Gaudelli in order to upregulate the activity of CD117. Further, because Gaudelli teaches that utilizing the fusion protein resulted in less off-target activity than Cas9 alone, one would have been motived to have substituted the Cas9 of Zhang for the fusion protein of Gaudelli.
Additionally, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have mutated the CD117 protein sequence of Zhang with a D419A mutation through the use of the fusion protein because it would have merely amounted to a combination of prior art elements according to known methods to yield predictable results. Because Reshetnyak teaches that the claimed mutational position resulted in the increased activity of KIT (i.e., a similar result compared to the beneficial upregulation of CD117 present in Zhang), then one of ordinary skill in the art would have been motivated to have mutated the CD117 with a D419A mutation in order to further increase the engraftment of the cells. Further, because Reshetnyak teaches the mutation of KIT for the same purpose as Zhang (i.e., the upregulation of CD117 activity), then one would have had a reasonable expectation of success in mutating the CD117 of Zhang with a D419A mutation and achieving an upregulation of the CD117 activity.
Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the alanine at position D419 for a glycine because it would have merely amounted to and a simple substitution of one known amino acid for another that has similar properties. Because Miyata teaches that alanine and glycine have similar biochemical properties that are tolerated by proteins, then one of ordinary skill in the art would have expected that the conservative substitution would not alter the improved activity of the CD117 protein as seen with the D419A mutation rendered obvious above because substituting a glycine with an alanine is not expected to alter a proteins tertiary structure.
Regarding claim 3, Zhang teaches that a hemoglobinopathy that can be treated by the method is sickle cell anemia ([1584]).
Regarding claim 10, Zhang teaches that multiple, independent, guide RNA molecules may be utilized in the invention to target two genes of interest ([1110]). Zhang teaches that CXCR4 can also be targeted by the Cas9 molecule via its guide RNA in order to increase the efficiency of the engraftment of the cells ([1410]-[1411]).
Regarding claim 16, Gaudelli teaches that the deaminase domain is an adenosine deaminase (pg. 465-466; see Figures 1-2).
Regarding claim 34, Zhang teaches that the target gene may encode a CD117 receptor that can bind to an SCF ligand ([1412]).
Regarding claim 37, for the purposes of examination the claim is interpreted as claiming the generation of an D419G mutation through the conversion of an adenosine to a guanine. Gaudelli teaches that the fusion construct is directed towards a target genomic DNA via the use of a guide RNA that complexes with the Cas9 in order to recruit a TadA*7.10 adenosine deaminase to the target genomic DNA and induce A:T to G:C conversion (i.e., the fusion construct can induce a conversion of an adenosine to a guanine) (pg. 470; see Figure 5). The obviousness of introducing a D419G mutation is discussed above as applied to claims 1 and 15.
Regarding claim 45, Zhang teaches that the method can be utilized to treat hemoglobinopathies in a target cell ([1562]-[1564]).
Regarding claim 46, Zhang teaches that a hemoglobinopathy that can be treated by the method is sickle cell anemia ([1584]).
Claim(s) 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (PG Pub No. US 2019/0169639 A1, published 6 June 2019, filed 24 January 2019) in view of Gaudelli (Nature 551.7681 (2017): 464-471), Schlessinger (PG Pub No. WO 2015/050959 A1), Schlessinger sequence alignment (accessed 15 June 2026), and Reshetnyak ("The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer." Molecular cell 57.1 (2015): 191-201) as applied to claims 1, 3, 10, 15-16, 34, 37, and 45-46 above, and further in view of Joung (PG Pub No. US 2020/0308571 A1, earliest effective filing date of 4 February 2019).
Regarding claims 17-18, Zhang in view of Gaudelli, Schlessinger, and Reshetnyak renders obvious claims 1, 3, 10, 15-16, 34, 37, and 45-46 as described above.
For the purposes of examination, it is noted that Applicant has defined TadA*8 variants in Table 10 on pg. 293-294 in the instant specification. One such variant, TadA*8.4, is defined as a TadA*7.10 with a V82S mutation (see Table 10 on pg. 293-294).
Zhang in view of Gaudelli, Schlessinger, and Reshetnyak does not teach or suggest the use of a TadA*8 variant (Claim 17) selected from TadA*8.4 (Claim 18).
Joung is drawn towards a study concerned with engineered adenine base editor variants (Abstract). Joung teaches the use of a TadA*7.10 that can comprise a mutation at position V82 that is a substitution with any other amino acid other than the wild-type amino acid ([0066]-[0067]; see Table A). Joung teaches that the mutation is predicted to cause an RRE phenotype in the TadA*7.10 ([0067]). Joung teaches that the RRE phenotype allows for the TadA*7.10 to have reduced RNA editing activity while maintaining DNA editing activity (i.e., the mutated TadA*7.10 has an increased specificity for target DNA) ([0006]). Joung teaches that the TadA may be successfully mutated at multiple positions of interest in order to generate a TadA with an RRE phenotype and its activity levels measured ([0151]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to try to mutate the TadA*7.10 of Zhang in view of Gaudelli such that it comprised a V82S mutation (i.e., arriving at a TadA*8.4 variant). Because a need for increased specificity of the TadA*7.10 was identified, then one of ordinary skill in the art would have identified that mutating the TadA*7.10 at position V82 would have been a predicable solution to achieve the increased specificity. Further, because there are 20 amino acids total, one of ordinary skill in the art would have found that there were a finite number of predictable potential solutions that would arrive at a TadA*7.10 with increased DNA specificity. A person of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success because Joung teaches that the activity levels of potential variants of TadA*7.10 could be tested.
Claim(s) 47 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (PG Pub No. US 2019/0169639 A1, published 6 June 2019, filed 24 January 2019) in view of Gaudelli (Nature 551.7681 (2017): 464-471), Schlessinger (PG Pub No. WO 2015/050959 A1), Schlessinger sequence alignment (accessed 15 June 2026), and Reshetnyak ("The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer." Molecular cell 57.1 (2015): 191-201) as applied to claims 1, 3, 10, 15-16, 34, 37, and 45-46 above, and further in view of Forget (Annals of the New York Academy of Sciences 850.1 (1998): 38-44).
Regarding claim 47, Zhang in view of Gaudelli, Schlessinger, and Reshetnyak renders obvious claims 1, 3, 10, 15-16, 34, 37, and 45-46 as described above.
Zhang in view of Gaudelli, Schlessinger, and Reshetnyak does not teach or suggest that the cell is from a subject having HPFH (Claim 47).
Forget is drawn towards a study concerned with the molecular basis of hereditary persistence of fetal hemoglobin (i.e., HPFH) (Abstract). Forget teaches that HPFH is a hemoglobinopathy that is characterized by the presence of a substantial elevation of fetal hemoglobin in red blood cells of heterozygotes (pg. 38). Forget teaches that identifying cells from subjects having HPFH can be utilized in order to provide therapeutic measures to subjects suffering from HPFH (pg. 43-44; Conclusion).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the cell from a subject who suffers from a hemoglobinopathy, as described by Zhang in view of Gaudelli, Schlessinger, and Reshetnyak, for a cell from a subject suffering from HPFH (i.e., a known hemoglobinopathy), as described by Forget. Because Forget teaches the treatment of hemoglobinopathies in a similar manner as Zhang in view of Gaudelli, Schlessinger, and Reshetnyak (i.e., treatment through the administration of a therapeutic agent), then one of ordinary skill in the art would have had a reasonable expectation of success in treating HPFH via the administration of the nucleobase editor polypeptide.
Claim(s) 67-68 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (PG Pub No. US 2019/0169639 A1, published 6 June 2019, filed 24 January 2019) in view of Gaudelli (Nature 551.7681 (2017): 464-471), Schlessinger (PG Pub No. WO 2015/050959 A1), Schlessinger sequence alignment (accessed 15 June 2026), and Reshetnyak ("The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer." Molecular cell 57.1 (2015): 191-201) as applied to claims 1, 3, 10, 15-16, 34, 37, and 45-46 above, and further in view of Andre (PG Pub No. US 2011/0009286 A1) and Andre sequence alignment (accessed 15 June 2026) as evidenced by Simon (Clinical cancer research 10.1 (2004): 178-183).
Regarding claim 47, Zhang in view of Gaudelli, Schlessinger, and Reshetnyak renders obvious claims 1, 3, 10, 15-16, 34, 37, and 45-46 as described above. Zhang further teaches that guide RNA molecules can be designed in order to target nucleic acids of interest ([0811]-[0814]).
Zhang in view of Gaudelli, Schlessinger, and Reshetnyak does not teach or suggest that the guide RNA comprises the claimed SEQ ID NO: 391 (Claim 67). Zhang in view of Gaudelli, Schlessinger, and Reshetnyak does not teach or suggest that the target sequence is selected from the claimed SEQ ID NO: 574 (Claim 68).
Andre is drawn towards an invention concerned with polynucleotide probes that can hybridize with a gene of interest (Abstract). Andre teaches that a portion of a KIT gene is a known target sequence that can be targeted by the probes and comprises a target sequence having 100% identity to the claimed SEQ ID NO: 391 and 574 ([0184]; see SEQ ID NO: 2984 in previously attached sequence alignment).
Simon is drawn towards a study concerned with CD117 and its role in breast cancer (Abstract). Miettinen teaches that CD117 is a gene that is also referred to as KIT and encodes a type III receptor tyrosine kinase (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the nucleic acid sequence targeting a CD117 gene as described by Zhang in view of Gaudelli for a nucleic acid sequence having 100% identity to the claimed SEQ ID NO: 391 that can target a nucleic acid molecule to a CD117 gene, as described and evidenced by Andre and Simon. Because Andre and Simon teach the targeting of a CD117 gene via a similar method described by Zhang in view of Gaudelli, Schlessinger, and Reshetnyak (i.e., the use of a nucleic acid molecule that can bind to a CD117 target sequence), then one of ordinary skill in the art would have expected that the sequence of Andre and Simon, when present within the nucleobase editor polypeptide, to have successfully targeted the polypeptide to a CD117 gene.
Response to Arguments
Applicant's arguments filed 20 February 2026 have been fully considered but they are not persuasive.
Applicant alleges that none of the cited references teach the use of an amino acid substitution as referenced to the claimed SEQ ID NO: 35 (Remarks; pg. 14).
This argument is not found persuasive because Applicant’s amendment’s necessitated the newly filed rejections above. Because Applicant has not provided any arguments pertaining to the newly recited references, the arguments are not found persuasive.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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