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 .
Applicant’s election without traverse of Group I Claims 1-4, 6-9, 11, 22-23, and 26-27 in the reply filed on 12/10/2025 is acknowledged.
Claims 13, 15-18, and 20-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/10/2025.
Priority
This application claims the benefit of priority to U.S. Provisional Patent Application Number 63030222. Acknowledgement is made of Applicants’ claim for benefit to prior filed US Provisional Application 63030222 filed on 05/26/2020.
This application claims the benefit of priority to Patent Application PCT/US2021/034107. Acknowledgement is made of Applicants’ claim for benefit to prior filed to Patent Application Number PCT/US2021/034107, filed on 05/25/2021.
Information Disclosure Statement
The Information Disclosure Statements filed 11/21/2022, 10/18/2023, 04/15/2025, 12/10/2025, and 05/05/2026 have been considered by the Examiner.
Status of Claims
Claims 1-4, 6-9, 11, 22-23 and 26-27 are under examination.
Claims 13, 15-18 and 20-21 are withdrawn.
Claims 5, 10, 12, 14, 19, 24-25, and 28 are cancelled.
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.
Claims 1-4, 6 ,11, 22-23, and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Crisanti et al. (WO-2019243840-A1) in view of Ali et al. (Scientific Reports, 2017).
Regarding claim 1, Crisanti et al. teach a gene editing system comprising (a) a Cas endonuclease (page 64, claim 13), (b) Crisanti et al. teach a regulatory sequence that substantially restricts expression of the second nucleotide sequence to germline cells of the arthropod (page 28, lines 33-35), (c) Crisanti et al. teach the CRISPR-based gene drive genetic construct which hybridizes to the intron-exon boundary of the doublesex (dsx) gene, the first gRNA (page 31, lines 22-28). (d) Crisanti et al. teach a gene drive genetic construct, wherein the first promoter is a polymerase III promoter, optionally a U6 promoter (page 65, claim 16).
Crisanti et al. do not teach a guide polynucleotide targeting a male sterility genomic sequence that is required for male-specific fertility, or a complementary sequence of the guide polynucleotide, or a polynucleotide expressing the guide polynucleotide, wherein the guide polynucleotide targets a gene active during spermatogenesis optionally selected from PTubulin 85D (PTub), fuzzy onions (fzo), protamine A (ProtA), or spermatocyte arrest.
Ali et al. teach a genetically enhanced sterile insect technique against the fruit fly utilizing double-stranded RNAs (page 1, abstract). Ali et al. teach in spermatogenesis occurs at a sex-specific stage to promote male dominant characteristics, which requires the male-specific sequence of the gene double sex male (dsxM) (page 2, paragraph 2). Ali et al. teach Zero Population growth (Zpg) plays a very important role in producing spermless males (page 2, paragraph 2). Ali et al. teach feeding genetically engineered-bacteria that express the target gene dsRNA. Ali et al. teach five testis-specific genes (boul, Zpg, dsxM, fzo and gas8) and their efficacy was assessed (page 5, discussion). Ali et al. teach the most effective gene combinations were boul + zpg, boul + dsxM and zpg + dsxM for pest management applications. Ali et al. teach their method achieved up to 85.40% male sterility. Ali et al. teach highly selective genes involved in spermatogenesis and environmentally friendly approach (page 5, Discussion). Ali et al. teach a silencing effect and male sterility in the target pests in response to target gene dsRNA (page 7, paragraph 2). Ali et al. teach their method provides greater efficiency and a significant reduction in spermatozoa. Ali et al. teach that the selection of target genes is very important. (page 7, paragraph 2).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have combined the teachings of Crisanti et al. for a gene editing system with the teachings of Ali et al. for the genes to target for the silencing effect and in male sterility in the target pest. Ali et al. provide motivation by teaching that their method provides greater efficiency and a significant reduction in spermatozoa, further teaching that the selection of the proper target gene is important (page 7, paragraph 2). One of skill in the art would have had a reasonable expectation of success at combining Crisanti et al. and Ali et al. because they both teach methods of insect population control.
Regarding claim 2, Crisanti et al. teach a genetically modified insect (page 63, claim 2) or insect egg (page 36, lines 11-12). Crisanti et al. teach the species could be selected from Ceratitis capitata, or Drosophila (page 5, lines 6-12).
Regarding claims 3 and 4, Crisanti et al. teach the insect egg or insect comprises (a) Crisanti et al. teach an insect egg which comprises a polynucleotide encoding an endonuclease which is Cas9 endonuclease (page 64, claim 13). (b) Crisanti et al. teach a regulatory sequence that substantially restricts expression of the second nucleotide sequence to germline cells of the arthropod (page 28, lines 33-35), (c) Crisanti et al. teach the CRISPR-based gene drive genetic construct which hybridizes to the intron-exon boundary of the doublesex (dsx) gene, the first gRNA (page 31, lines 22-28). (d) Crisanti et al. teach the gene drive genetic construct according to, wherein the first promoter is a polymerase III promoter, optionally a U6 promoter (page 65, claim 16). Ali et al. teach a genetically enhanced sterile insect technique against the fruit fly utilizing double-stranded RNAs (page 1, abstract). Ali et al. teach in spermatogenesis occurs at a sex-specific stage to promote male dominant characteristics, which requires the male-specific sequence of the gene double sex male (dsxM) (page 2, paragraph 2). Ali et al. teach Zero growth Population (Zpg) plays a very important role in producing spermless males (page 2, paragraph 2). Ali et al. teach feeding genetically engineered-bacteria that express the target gene dsRNA. Ali et al. teach five testis-specific genes (boul, Zpg, dsxM, fzo and gas8) and their efficacy was assessed (page 5, discussion). Ali et al. teach the most effective gene combinations were boul + zpg, boul + dsxM and zpg + dsxM for pest management applications. Ali et al. teach their method achieved up to 85.40% male sterility. Ali et al. teach highly selective genes involved in spermatogenesis and environmentally friendly approach (page 5, Discussion). Ali et al. teach a silencing effect and male sterility in the target pests in response to target gene dsRNA (page 7, paragraph 2). Ali et al. teach their method provides greater efficiency and a significant reduction in spermatozoa. Ali et al. teach that the selection of target genes is very important. (page 7, paragraph 2). Therefore, Chrisanti et al. and Ali et al. make obvious an engineered insect egg or insect or a progeny thereof which was modified by a gene editing system that targeted genes for a silencing effect and male sterility in target pests.
Regarding claim 6, (a) Crisanti et al. teach an insect egg which comprises a polynucleotide encoding an endonuclease which is Cas9 endonuclease (page 64, claim 13). (b) Crisanti et al. teach a regulatory sequence that substantially restricts expression of the second nucleotide sequence to germline cells of the arthropod (page 28, lines 33-35), (c) Crisanti et al. teach the CRISPR-based gene drive genetic construct which hybridizes to the intron-exon boundary of the doublesex (dsx) gene, the first gRNA (page 31, lines 22-28). (d) Crisanti et al. teach a gene drive genetic construct, wherein the first promoter is a polymerase III promoter, optionally a U6 promoter (page 65, claim 16). (f) Crisanti et al. teach introduction of the polynucleotide to a host cell (page 19, lines 7-10). Crisanti et al. teach the nuclease gene is inserted within its own recognition sequence in the genome such that a chromosome containing the nuclease gene cannot be cut, but chromosomes lacking it are cut. Crisanti et al. teach when an individual contains both a nuclease-carrying chromosome and an unmodified chromosome, heterozygous for the gene drive, the unmodified chromosome is cut by the nuclease (page 46, lines 15-20).
Ali et al. teach a genetically enhanced sterile insect technique against the fruit fly utilizing double-stranded RNAs (page 1, abstract). Ali et al. teach in spermatogenesis occurs at a sex-specific stage to promote male dominant characteristics, which requires the male-specific sequence of the gene double sex male (dsxM) (page 2, paragraph 2). Ali et al. teach Zero growth Population (Zpg) plays a very important role in producing spermless males (page 2, paragraph 2). Ali et al. teach feeding genetically engineered-bacteria that express the target gene dsRNA. Ali et al. teach five testis-specific genes (boul, Zpg, dsxM, fzo and gas8) and their efficacy was assessed (page 5, discussion). Ali et al. teach the most effective gene combinations were boul + zpg, boul + dsxM and zpg + dsxM for pest management applications. Ali et al. teach their method achieved up to 85.40% male sterility. Ali et al. teach highly selective genes involved in spermatogenesis and environmentally friendly approach (page 5, Discussion). Ali et al. teach a silencing effect and male sterility in the target pests in response to target gene dsRNA (page 7, paragraph 2). Ali et al. teach their method provides greater efficiency and a significant reduction in spermatozoa. Ali et al. teach that the selection of target genes is very important. (page 7, paragraph 2). Therefore, Chrisanti et al. and Ali et al. make obvious an engineered insect egg or insect or a progeny thereof which was modified by a gene editing system that targeted genes for a silencing effect and male sterility in target pests.
Regarding claim 11, Crisanti et al. teach there is no reduction in fitness in females with only one copy of the target gene (page 48, lines 2-5). Regarding claim 22, Crisanti et al. teach suppressing a wild type arthropod population (page 37, lines 4-5). Crisanti et al. teach a method of progressively reducing the egg production to the point of total population collapse (page 59, lines 11-14).
Regarding claim 23, Crisanti et al. teach a method of producing (1) a genetically modified insect egg (page 69, claim 36), (2) a genetically modified insect (page 69, claim 37), (3) a population comprising the genetically modified insect egg or the genetically modified insect (page 69, claim 41). Crisanti et al. teach introducing gene drive genetic construct capable of disrupting an intron/exon boundary of the female specific splice form of doublesex gene in an arthropod. Crisanti et al. when the gene-drive construct is expressed the arthropod exhibits a suppressed reproductive capacity (page 69, claim 37).
Regarding claim 26, Crisanti et al. teach a composition comprising a carrier of the gene driver system (page 45, lines 26-30).
Regarding claim 27, Crisanti et al. teach a method/provide instructions for progressively reducing the egg production to the point of total population collapse (page 59, lines 11-14), which are the components of a kit.
Claims 7-9, are rejected under 35 U.S.C. 103 as being unpatentable over Crisanti et al. (WO 2019/243840) in view of Ali et al. (Scientific Reports, 2017) as applied to claims 1-6 and 8 above, and further in view of Nandy et al. (Plant Direct, 2019).
Crisanti et al. and Ali et al. make obvious a genetically modified insect or insect egg, where a gene active during spermatogenesis was targeted. Crisanti et al. make obvious that the species could be selected from Ceratitis capitata, or Drosophila.
Regarding claims 7-9, Crisanti et al. and Ali et al. teach the insect population with a Cas9 endonuclease.
Crisanti et al. and Ali et al.do not teach expression of the endonuclease is not activated and the insect egg or the insect or the insect population or a progeny of each thereof of is kept under a permissive temperature of the regulatory sequence of (b)regulatory sequence directing the endonuclease expression in a cell, optionally wherein the cell is an insect germline cell, optionally wherein the regulatory sequence is temperature-sensitive, and further optionally wherein the regulatory sequence comprises a heat-shock protein 70B (Hsp70Bb)promoter.
Nandy et al. teach a heat-shock-inducible CRISPR/Cas9 system. Nandy et al. teach sequences ending with noncanonical PAMs such as NAG can also be targeted by Cas9, and while chromatin structure plays a marginal role in targeting, the secondary structures in the target DNA and the sgRNA could allow significant pairing, in spite of the mismatches at the PAM end. Nandy et al. teach in mammalian cells, higher concentrations or the constitutive expression of sgRNA:Cas9 reportedly induced a high rate of off‐target mutations (page 11, paragraph 1). Nandy et al. teach inducible expression systems can be argued as more versatile transient expression systems, provided they generate low or undetectable background expression and a high‐induced expression. Nandy et al. teach heat‐shock promoters have been successfully used in applications where their proper regulation was critical (page 11, paragraph 2). Nandy et al. teach a HS‐inducible CRISPR/Cas9 system which is generally suppressed at the ambient room temperature and activated by the heat‐shock treatment. Nandy et al. teach the heat‐shock‐induced genome editing is efficient at producing heritable targeted mutations, while curbing the off‐target mutations. Nandy et al. teach HS‐CRISPR/ Cas9 is a promising genome editing tool that can provide temporal control toward improving the precision of the CRISPR/Cas9 activities (page 12, paragraph 2).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to have modified the teachings of Crisanti et al. and Ali et al. for the modified insect population utilizing an endonuclease with the teachings of Nandy et al. for a heat-shock-inducible CRISPR/Cas9 system. Nandy et al. provide motivation by teaching that teach the heat‐shock‐induced genome editing is efficient at producing heritable targeted mutations, while curbing the off‐target mutations. One of skill in the art would have had a reasonable expectation of success at combining Crisanti et al., Ali et., and Nandy et al. because both utilize CRISPR/Cas9 for gene modification.
Response to Arguments
Applicant's arguments filed 06/10/2026 have been fully considered but they are not persuasive.
Applicant’s arguments: Applicant argues a person of skill in the art would not have been motivated to modify Ali to arrive at the claimed gene editing system. Specifically, there is no motivation to select fzo from the combination of genes taught by Ali or to modify Ali to arrive at the claimed invention.
Ali discloses an “effective sterile insect technique (SIT)” for long-term B. dorsalis management by feeding adult animals double-stranded RNAs. The SIT of Ali discloses an RNAi-based technique, not a CRISPR-based gene editing system comprising an endonuclease, guide polynucleotides, and regulatory sequences directing expression of those guide polynucleotides.
Ali discloses RNAi-mediated single and double mutants using five different genes. The five genes knockdown by Ali are boul, Zpg, dsxM , fzo and gas8. Ali discloses that boul, Zpg, and dsxM RNAi-knockdown showed significant sterility in B. dorsalis individually. Specifically, the deletion of fzo only displayed 19.96% reduction in egg hatching, gas8 displayed 16.40% in egg hatching, while deletion of boul, zpg and dsxM produced substantially higher male sterility rates (67.59%, 64.84%, and 58.57%, respectively). See Ali, page 2 and Fig. 3. Furthermore, the combination of boul + zpg, boul + dsx M , and zpg+ dsx M ) respectively achieved 85.40%, 77.39%, 74.17% male sterility compared to control.
Based on these results, a person of ordinary skill in the art would not have been motivated by Ali to select fzo, one of the least effective knockout gene disclosed in Ali, to arrive at the claimed invention. Furthermore, modifying Ali to arrive at the claimed invention would have rendered Ali’s disclosure unsatisfactory for its intended purpose of generating an effective sterile insect technique (SIT) for long-term B. dorsalis management.
Examiner’s response: Cristanti already teaches the use of dsx, one of the genes taught by Ali with significant reductions in expressions after oral dsRNA administration (page 1, Abstract). Ali et al. teach all of the examined genes severely impaired gene efficiency (page 5, Discussion). Ali et al. teach the lack of a significant reduction in egg hatching rate for fzo compared with the control may be due to an inappropriate concentration or to the development of resistance to the dsRNA (page 7, paragraph 1). The lack of proper dosing of the RNAi or resistance to the dsRNA of the fertility related fzo would not have any impact on the gene drive genetic construct of Crisanti. Furthermore Ali et al. do not teach the fertility gene fzo, should not be used, they only teach fzo alone was not fully effective for the RNAi based sterile insect technique (SIT) utilized by Ali. Ali et al. teach to enhance the sterility effect, target gene dsRNA combinations can be made (page 2, Effects of a combination of different genes on male sterility). Ali et al. teach boul, zpg, gas8, fzo and dsx are highly expressed in the testis (page 2, Selection of testis specific genes). Therefore Ali et al. provide motivation to choose a secondary testis-specific fertility gene target to bolster sterility.
Applicant’s arguments: Ali teaches away from selecting fzo among the five disclosed and tested genes because the fzo was the one of “least effective” knockout genes as discussed above. For these reasons, under MPEP § 2143.01, one of ordinary skill in the art would have been discouraged from selecting fzo as the male sterility target gene (19.96% reduction in egg hatching) given the superior results obtained with knocking down boul, Zpg, dsxM (85.40%, 77.39%, and 74.17% male sterility, respectively).
Examiner’s response: Ali et al. teach data demonstrates significant reductions in the target genes expressions (boul, zpg, dsxM, fzo and gas8) after oral dsRNA administration (page 1 , Abstract). Ali et al. teach all of the examined genes severely impaired gene efficiency (page 5, Discussion). Ali et al. do teach all of target gene dsRNAs displayed a significant silencing effect and egg hatching rates were highly reduced, except with the two genes, fzo and gas8 (page 7, paragraph 1). Ali et al. teach the lack of a significant reduction in egg hatching rate compared with the control may be due to an inappropriate concentration or to the development of resistance to the dsRNA (page 7, paragraph 1). The lack of proper dosing of the RNAi of the fertility related fzo would not have any impact on the gene drive genetic construct of Crisanti. Therefore the secondary fertility target would not be the only gene replied upon.
Applicant’s arguments: Ali also does not use a system comprising an endonuclease. The sterile insect technique (SIT) disclosed in Ali is an RNAi-mediated gene knockdown technique, not a CRISPR-based genome editing system comprising an endonuclease, guide polynucleotides, and regulatory sequences. As such, the SIT of Ali is not directed to the same technological field. Thus, Ali does not supply the missing structural features of the claims or the reasoned basis for modifying Crisanti to include them.
Examiner’s response: While the method to get the desired effect is different the desired effect is the same. Both Ali and Crisanti are concerned with suppressing insect populations, therefore the target genes would overlap. Both methods are concerned with decreasing the expression of fertility genes to induce sterility.
Applicant’s arguments: Nandy does not cure the deficiencies of Crisanti and Ali because Nandy also does not teach or suggest all elements of claims 1-4 and 6, 11, 22-23, and 26-27, as discussed above. Nandy is relied upon only for allegedly disclosing a temperature-inducible CRISPR/Cas9. Claims 7-9 depend from claim 2, which depends from claim 1. Therefore, claims 7-9 still require the gene editing system of claim 1, including at least the female-essential guide polynucleotide and its regulatory sequence of elements 1(c) and 1(d), and the male-sterility guide polynucleotide and its regulatory sequence of elements 1(e) and 1(f). Nandy does not provide the necessary motivation to select fzo, one of the least effective knockout genes disclosed in Ali (19.96% reduction in egg hatching vs 85.40%, 77.39%, and 74.17% male sterility for boul, Zpg, dsx M , respectively), to arrive at the claimed invention.
Examiner’s response: The motivation to select fzo is provided by Ali and not required by Nandy.
Conclusion
THIS ACTION IS MADE FINAL. 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 Catherine L McCormick whose telephone number is (703)756-5659. The examiner can normally be reached Monday-Friday, 8:30 am-5:30 pm.
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, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.L.M./Examiner, Art Unit 1638
/Anna Skibinsky/
Primary Examiner, AU 1635
Prosecution Insights