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 .
Claim Status
1. Claims 1, 4-8, and 13-17 are pending and under examination to the extent of the elected species of Cas12f.4, SEQ ID NO:1, SEQ ID NO:6, and SEQ ID NO:4.
Claims 2-3, 9-12, 18-24, 28, 31, 33-37, 40-42, and 44 are cancelled.
Claims 20-21, 23, 25-27, 29-30, 32, 38-39, and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on March 05, 2026.
Response to Arguments – Objections to the Specification
2. Applicant’s remarks and amendments filed 07/02/2026 have overcome the objections of record.
Response to Arguments – Claim Rejections - 35 USC § 112(b)
3. Applicant’s remarks and amendments filed 07/02/2026 have overcome the objections of record.
Claim 2 is cancelled; therefore, any objections and/or rejections to the claim have been rendered moot.
Response to Arguments – Claim Rejections - 35 USC § 102
4. Applicant’s remarks and amendments filed 07/02/2026 have overcome the objections of record. However, the claims remain rejected under 35 U.S.C. 103.
Response to Arguments – Claim Rejections - 35 USC § 103
5. Applicant’s remarks and amendments filed 07/02/2026 have been carefully considered but are not persuasive and do not overcome the objections of record.
Applicant argues that the amendments to claim 1 require the presence of an amorphic allele prior to the initial contacting with the Cas12F enzyme and that said requirement renders the claims nonobvious in view of the prior art (p. 10).
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Applicant also argues that the Examiner’s motivation analysis regarding the combination of the teachings of Lai and Ricroch is flawed (pp. 11-12). In doing so, Applicant argues that a person of ordinary skill in the art would have known that multiple Cas nucleases that possessed the same advantages for plant promoter editing as a Cas12F nuclease were available at the time of invention (p. 12; see excerpt from p. 12 pasted above). The Examiner appreciates Applicant’s acknowledgement that the use of the recited Cas12F nuclease does not appear to provide any unique advantageous results when compared to the other Cas nucleases known in the art. Furthermore, Applicant explicitly describes Cas12F and other known Cas nucleases as known alternatives of each other (pp. 12-13). MPEP 2143.I provides examples of rationales for supporting a conclusion of obviousness under 35 U.S.C. 103. Because Cas12F and the other Cas nucleases are known alternatives to each other, said nucleases satisfy examples (A), (B), (E), and (F) of the examples listed in MPEP 2143.I.
Applicant argues that Xu fails to teach or suggest targeting the promoter of a functional allele in a plant cell where the genome already comprises a pre-existing amorphic second allele (p. 11). However, this argument is not persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Xu may not teach targeting promoter regions, but Ricroch does; therefore, the combination of the cited references of Lai in view of Ricroch as evidenced by Xu, but not Xu alone, renders the claim limitations obvious.
Accordingly, this rejection is maintained.
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 1, 4-8, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Lai et al. (US-2021/0395784-A1, published 12/23/2021 (Applicant’s IDS)) in view of Ricroch et al., (Emerging Topics in Life Sciences. 2017; 1:169–182 (previously cited)) as evidenced by Xu et al., (Journal of Genetics and Genomics. 2016; 43(8):529-532 (previously cited)).
Regarding claim 1, Lai teaches a method of obtaining a plant cell with altered expression of at least one gene comprising: (i) contacting at least one promoter region of at least a first allele of the gene in the genome of the plant cell with a Cas12F nuclease and at least one guide RNA that targets the promoter region, wherein the first allele of the gene is a hypomorphic (e.g., a loss-of-function mutation), isomorphic (e.g., a silent mutation), or wild-type allele of the gene[0002-0003], [0128], [0146], [0161], [0165-0166], [0173], [0183], [0194], and (ii) selecting a plant cell, plant callus, plant part, or plant comprising at least one first deletion in the promoter region that confers the altered expression of the gene[0132], [0154-0159].
Lai is silent with regard to the structure of the second allele prior to the contacting with the nuclease. However, the initial structure of the second allele is irrelevant to the final structure of said allele after being contacted by the gene editing Cas nuclease. As such, the null allele generated by Lai is not functionally distinguishable from the amorphic allele recited in claim 1.
Ricroch also teaches the use of CRISPR-based gene editing systems to edit wild-type coding and/or promoter sequences to introduce loss-of-function mutations that reduce the expression of target genes in various crop species (Abstract; pp. 171-176, Table 1).
The combination of Lai and Ricroch teaches, suggests, and provides motivation for methods of obtaining a plant cell with altered expression of at least one gene comprising: (i) contacting at least one promoter region of at least a first allele of the gene in the genome of the plant cell with a Cas12F nuclease and at least one guide RNA that targets the promoter region, wherein the first allele of the gene is a wild-type allele of the gene, and (ii) selecting a plant cell, plant callus, plant part, or plant comprising at least one first deletion in the promoter region that confers the altered expression of the gene.
The level of ordinary skill in the plant biotechnology art is high as evidenced by both Lai and Ricroch. It would have been prima facie obvious for one of ordinary skill in the art at time of filing to modify the method of Lai with the teachings of Ricroch to design a CRISPR/Cas12F gene editing system for targeting the promoter and/or coding regions of a gene to introduce deletions into and alter the expression of said gene. One of ordinary skill would have been motivated to do so for several reasons. First, the use and design of CRISPR-Cas constructs and guide RNAs is routine in the art. Second, as demonstrated by Ricroch, it is well-established in the biological arts that the expression level of a gene can be altered by mutating either the coding region or regulatory regions (e.g., a promoter region) of a gene. Third, Lai teaches that Cas12F-based editing systems have advantages over Cas9-based editing systems due to their suitability for multiple gene editing and need for only a single guide RNA, which reduces off-target gene editing. Finally, both Lai and Ricroch teach and suggest that the disclosed CRISPR/Cas editing systems are suitable for editing a variety of crop species with global economic importance. Accordingly, one of ordinary skill in the art would have been motivated to produce the claimed invention with a reasonable expectation of success and without any surprising or unexpected results.
Regarding claim 4, in addition to the teachings discussed above, Lai teaches using CRISPR/Cas12F to create amorphic alleles by knocking out genes[0146]. The Office appreciates Applicant’s acknowledgement of Lai’s teachings regarding the use of Cas12F to create amorphic alleles (see excerpt below from p. 11 of Applicant’s remarks).
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Though Lai is silent regarding the structure of said alleles prior to editing, the initial structure of the second allele is irrelevant to the final structure of said allele after being edited by the Cas nuclease. The placement of the mutation reducing the function of the allele is a simple design choice parameter well within the skill of a person of ordinary skill in the art. Furthermore, Ricroch teaches the use of CRISPR-based gene editing systems to edit coding and/or promoter sequences to reduce the expression of target genes in various crop species (Abstract; pp. 171-176, Table 1).
Regarding claim 5, the combined teachings of Lai and Ricroch are as discussed above. Though Lai is silent to deletions in promoter regions, Ricroch teaches such deletions as discussed above (Abstract; pp. 171-176, Table 1). In view of the combined teachings of Lai and Ricroch, it would be both routine and trivial for one of ordinary skill in the art to select a transformed plant, plant cell, or callus comprising deletions within the promoter regions of both alleles of a target gene; one of ordinary skill in the art is readily capable of breeding a plant and selecting homozygous offspring harboring a trait of interest without any surprising or unexpected results.
Regarding claim 6, in addition to the teachings discussed above, Lai teaches targeting multiple genes[0003], [0174]. Lai is silent to the introduction of multiple guide RNAs.
Ricroch teaches the introduction of several distinct guide RNAs targeting distinct sequences into the plant cell containing the gene of interest to produce a population of plant cells, plant calli, plant parts, or plants comprising distinct deletions in the target site and wherein the plant cell, plant callus, plant part, or plant comprising the allele with the deletion in the promoter region of the first and/or second allele of the gene and/or altered transcription level is selected from the population of plant cells (p. 174, Table 1; see Xu et al., p. 530, Figure 1).
The combination of Lai and Ricroch renders obvious distinct guide RNAs targeting distinct promoter regions of the gene of the plant cell containing the gene to produce a population of plant cells, plant calli, plant parts, or plants comprising distinct deletions in the promoter of the gene and wherein the plant cell, plant callus, plant part, or plant comprising the gene allele with the deletion in the promoter region of the first and/or second allele of the gene and/or altered transcription level is selected from the population of plant cells. Though neither Lai or Ricroch suggest introducing multiple guide RNAs independently, the separate and independent introduction of said guide RNAs would provide no unique or surprising results in comparison to the method taught by Ricroch, wherein distinct guide RNAs are introduced on the same expression vector. Additionally, though Ricroch teaches targeting multiple genes with the distinct guide RNAs, one of ordinary skill in the art immediately understands that said guide RNAs could be designed to target the same target sequence to increase the efficiency of mutating that target sequence.
Regarding claim 7, in addition to the teachings discussed above, Lai teaches Cas12f.4 nuclease[0196-0200].
Regarding claim 8, in addition to the teachings discussed above, Lai teaches a Cas12F nuclease comprising SEQ ID NO:1 (see Lai SEQ ID NO:1; see pp. 01-04 of attached STIC search results).
Regarding claim 13, in addition to the teachings discussed above, Lai teaches wherein the target sequence (i.e., promoter targeting region) is located at the 3’ end of a protospacer adjacent motif (PAM) comprising the sequence 5’-TTN, wherein N is A, G, T, or C[0003], [0089], [0107] (see Figure 3b).
Regarding claim 14, in addition to the teachings discussed above, Lai teaches wherein the at least one guide RNA comprises SEQ ID NO:6 (see Lai’s SEQ ID NO:16; see pp. 05-06 of the attached STIC search results).
Regarding claim 15, in addition to the teachings discussed above, Lai does not teach SEQ ID NO:4. However, a Cas12F nuclease encoded by SEQ ID NO:4 would provide no surprising or unexpected results in comparison to the Cas12F nucleases taught by Lai and is, therefore, prima facie equivalent to the Cas12F nucleases taught by Lai. See MPEP 2183.
Regarding claim 16, in addition to the teachings discussed above, Lai teaches wherein the deletions comprise about 10 to 20 base pairs of DNA in the target region (Figure 3).
Regarding claim 17, in addition to the teachings discussed above, Lai teaches knocking out genes[0146]. Knocking out a gene results in a complete loss of function, which is a greater than 2-fold decrease in expression of the gene in comparison to a control lacking the deletion.
Accordingly, one of ordinary skill in the art would have been motivated to produce the claimed invention with a reasonable expectation of success and without any surprising or unexpected results.
Conclusion
8. No claim is allowed. Applicant's amendment necessitated any 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.
Examiner’s Contact Information
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEQUANTARIUS J SPEED whose telephone number is (703)756-4779. The examiner can normally be reached M-F; 9AM-5PM ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amjad Abraham can be reached on (571)-270-7058. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DEQUANTARIUS JAVON SPEED/Examiner, Art Unit 1663
/Amjad Abraham/SPE, Art Unit 1663
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