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. Claims 1-3, 5-6, 8, 10-11, 13-16, 18, 20-22, and 24-25 are pending as amended 7/29/24, and are considered herein. Formalities: Applicant’s priority is noted to be a 371 to PCT/GB2022/051600, filed 6/23/22, and back to GB 2109133.5, filed 6/24/21, which has been supplied by the international authority in the present Application. The IDS of 12/21/23 has been considered, and the references therein, and a signed copy of the same is supplied, herewith. The drawings of 12/21/23 are accepted. The specification, as amended on 12/21/23, is accepted. 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 appl icant regards as his invention. Claim s 2-3, 6, 8, 11, 14-16, and 22 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. Claim 2 recites the term “preferably” for the NLS to be linked to the Acr protein. The specification fails to define the embodiments which are preferable for this, and thus, it is not clear what is meant. Claim 3 recites “the NLS-tagged Acr protein”, in Claim 1. The limitation lacks antecedent basis. Claim 3 recites “or a fragment or a variant thereof”. While a fragment appears to be mean any two sequential amino acids of the sequence, it is not clear how variant relates to this sequence. I.e., does this include sequences which are not substantially set out in SEQ ID NO: 11? How much is it allowed to vary to and still be a variant? The metes and bounds of the claim are not clear. Claim 6 recites “or a fragment or a variant thereof”. While a fragment appears to be mean any two sequential amino acids of the sequence, it is not clear how variant relates to these sequences? How much is it allowed to vary to and still be a variant? The metes and bounds of the claim are not clear. Claim 6 recites the promoter may be of a Markush which includes SEQ ID NO: 10, being vasa2, as well as fragments, and variants, and then states “optionally wherein the promoter sequence is vasa2”. It is not clear what is meant here? Is this meaning SEQ ID NO: 10, or can it be a different vasa2? Does it refer to more fragments and variants? The scope is not clear. Claim 8 recites “the NLS-tagged Acr protein”, in Claim 1, twice. The limitation lacks antecedent basis. Claim 11 recites that the sequence is substantially set out in SEQ ID NO: 21, or a fragment or variant thereof. While it is clear that fragment means any two bases in sequence, it is not clear what a variant is, in this context. Is it required to have any sequence in common with SEQ ID NO: 21? The scope is not clear. Claim 11 recites SEQ ID NO: 22, or a fragment or variant thereof. While fragment means any two bases in common, it is not clear what a variant is. Does this require any sequence to be in common? The scope is not clear. Claim 14 recites “substantially as set out in any one of SEQ ID NO: 2, 3, and 4, or a fragment or variant thereof”. While fragment appears to indicate any two bases in the same sequence in common with one of the sequences, in the same context, variant appears to mean that there need be absolutely relation to these sequences. And thus, it is not clear what the claimed scope is. Claim 15: similar to the above, while the term “fragment” appears to encompass any two bases in common with the claimed sequences, variant appears to have no relation at all given the claiming of fragment and the sequence itself. Thus, the scope of variant is unclear. Claim 16 recites, in the alternative that the drive construct is a CRISPR-Cpfi or -Cas9 based, and then says again, optionally, it may be Cas9 based. It is not clear why the Cas9 option is provided twice. Was something else meant? Claim 22 recites “preferably wherein the insect is a mosquito”, “more preferably … anophelinae”, and “even more preferably [Markush of species]”. The specification fails to define the embodiments where it is so “ preferably ” , “ more preferabl y” , and “ even more preferabl y” . As such, the claim is not clear. Claim 22 provides an embodiment of Anopheles gambiae, then later recites “optionally wherein the arthropod is Anopheles gambiae”. In reciting this the second time, it is not clear if another option was meant, as that option had already been recited. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1-3, 5-6, 8, 10-11, 13-16, 18, 20-22, and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. As indicated in Claim 2, the claims are generic for NLS signals not operably linked to the Acr protein , as well as NLS signals not being present . Claim 8 is currently also included in this, as it is not clear the NLS-tagged Acr protein is the Acr of Claim 1 (See also, rejection for antecedent basis, above) , and the indication that it may be separated from the Acr protein, by way of an attB or attP integrase site, which would cause them to be not operably linked, once integrated. The specification provides antecedent basis for the same (e.g., p. 5, paragraph 8), however, it is taught that the NLS tags a protein for import into the cell nucleus by nuclear transport (e.g., pp. 5-6, paragraph bridging). Further, it is taught that the Acr proteins inhibit gene-editing activities in cells (e.g., p. 4, paragraph 3). All of this is in the context of the specification’s teaching of counteracting the spread of gene-drives (e.g., p. 1, paragraph 2). Specifically, it is recognized that gene drives, used for conferring desired properties on populations, e.g., insects, but there is a need to counteract the spread of gene drives, as a risk mitigation/management approach, in the cases of unintended consequences or unintended releases (e.g., p. 1 paragraph 4). Thus, it is object of the invention is to provide a genetic tool to counteract CRISPR-based gene drives (e.g., p. 2, paragraph 2). The Art recognizes that the genes of eukaryotic cells are in the nucleus, while the CRISPR enzymes and RNAs, as well as Acr proteins, are derived of prokaryotes and bacteriophages, respectively, and do not have to enter a nucleus to act on genetic material (Official Notice). However, it is well known that to utilize the CRISPR enzymes and RNAs in gene editing, such as for a gene drive, they need to target the nucleus, to edit the genetic material. If it is not in the nucleus, it cannot so-edit the genetic material. E.g., Taxiarchi, et al. (2021) “A genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression”, Nature Communications, 12: 3977, 8 pages long (cited by Applicant). Taxiarchi is Applicant’s publication and is published one day after the priority date, and it recognizes that it is required to enter the nucleus to have these activities (e.g., p. 2, col. 2, paragraph 1). Given that the activity of the CRISPR gene is required to act in the nucleus, the lack of any other purpose provided for the NLS as claimed, and t hat t he Acr is a bacterial protein, it would require that the Acr protein is linked to an NLS, or else it would not reach the nucleus, and inhibit the action of the gene drive. Thus, the Artisan would not have understood Applicant to have been in possession of the generic invention, where there is no operably linked NLS to the Acr. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1-3, 6, 8, 10-11, 13-16, 18, 20-22, and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. As indicated by dependent Claim 5, the claims are generic for germline-specific promoters that do not substantially restrict expression to germline cells. The application teaches several germline specific promoters in insects (e.g., p. 39 and Figure 1), however, it provides no germline specific promoters that work in more than just germline cells. Further, the Art recognizes that germline specific promoters are those that are only expressed in the germline cells (e.g., Zheng and Baum (2008) “Evaluation of promoters for use in tissue-specific gene delivery”, Methods in Molecular Biology, 434: 205-19, ABSTRACT, provided as an NIH Public Abstract Manuscript, 13 pages long). Given the lack of identification of any promoters that are germline specific and also expressed outside of germline cells, and the recognition in the Art that germline specific promoters are restricted to expression in germline cells, the Artisan would not recognize Applicant to be in possession of the claims as presently considered. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claim 18, 20-22 and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Claim 18 is generic to a genetically modified arthropod, where the arthropod is introduced with an anti-crispr construct encoding an Acr protein, which may be the construct of Claim 1. This indicates that the arthropod may simply carry a generic construct encoding Acr, with no functionality for that Acr encoding sequence (promoters, etc for expression), in a generic cell(s) of the arthropod (not even required to affect the germline cells, by a generic method of introduction. Claim 20 is generic for the same aspects, as well as any cells of the arthropod carrying the gene. Claims 24-25 are generic for the arthropod used for the same reasons. The specification teaches that the invention lies in the counteracting of a gene drive construct in a population (e.g., p. 1). What happens to counteract the gene drive, is the Acr is expressed and binds to the Cas9 or other CRISPR nuclease, thereby inhibiting the gene editing (e.g., p. 4, paragraph 2). Moreover, while the specification fails to describe where the gene drive is acting to provide its function to the population, it is also well known that the gene drive acts on the population by providing modified individuals to the population, that breed to provide the progeny that then carry the gene further to new progeny (e.g., Taxiarchi, et al. (2021) “A genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression”, Nature Communications, 12: 3977, 8 pages long , ABSTRACT). In each instance, the gene drive needs to be selected for in the gametes of the next population, either through homing or interference techniques. The result is, the drive is active in the germline cells. Thus the Acr protein needs to be transfected into the germline cells it is acting in, which is difficult, as it occurs over time, or the organism may be also transgenic, carrying the Acr gene integrated into the genome , and express it at the right time by being transcribed in the germline. The Art fails to provide any reason to provide an Acr protein to any cell of an organism, aside from Applicant’s disclosure for counteracting a gene drive. Thus the only reason to do so, is to make the protein for research, or seeing what happens to the cells of the organism. These are not patentable utilities, much less adequate description for possession. Therefore, unless the Acr is expressed in germline cells, it cannot act to counteract a gene drive. Also, if it does not introduced into germline cells, it is also not possessed, as it would not even reach germline cells to counteract a gene drive. Further, if the arthropod did not have the genes integrated into the cells, it would not be expressed by the germline cells, which means the construct must have elements to integrate into the genome, and must so-integrate into the genome of the organism, in particular in its germline cells. (For clarity, as the rejection was difficult to write due to the complexity of the subject, the Acr must be linked to a germline promoter, as well as integrating sequences so that it becomes integrated, and the germline cells have to be transfected, otherwise, the gene drive could not be counteracted.) Therefore the artisan would not have understood Applicant to have been in possession of the invention as presently claimed. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1-3, 5-6, 8, 10-11, 13-16, 18, 20-22, and 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The claims are generic for Acr fragments and variants, as seen from Claim 3. The specification provides for variants and fragments, as having 40% or more sequence identity (e.g., p. 36, paragraph 6). Examples of these variants and fragments are not provided. However, Applicant supplies a table listing many Acr proteins, and the Cas type and organism they are associated with. The art teaches that Acr proteins are defined based on their action, and the action may differ, including interruption of CRISPR-Cas complexes, target DNA binding, blocking DNA/RNA cleavage, and enzyme modification/degradation of signalling molecules. Thus, given the distinctions, the Acrs do not provide information that can identify the generic structure required to obtain each function type. Choudhary, et al. (2023) “A comprehensive appraisal of mechanism of anti-CRISPR proteins: an advanced genome editor to amend the CRISPR gene editing”, Frontiers in Plant Science, 14: 1164461 (14 pages), e.g., ABSTRACT . Moreover, sequence identity does not mean the same function, and proteins with higher sequence identity can have distinct function (e.g., He, et a. (2008) “NMR structures of two designed proteins with high sequence identity but different fold and function”, Proceedings of the National Academy of Science, USA, 105(38): 14412-17, ASTRACT). Conversely, other proteins have lower identity but have the same function (e.g., Martin, et al. (1998) “Protein folds and functions”, Structure, 6(7): 875-84, ABSTRACT, Conclusions). Thus, given that the Acr proteins are not necessarily structurally related, and the Art shows that proteins with higher identity can have distinct function, and proteins with lower identity can have the same function, the Artisan would not know which of the great many distinct structures encompassed provide for the action of the Acr fragments and variants. Claims Free of the Art The first publication to disclose the anti-gene drives disclosed, is Inventor Cristani and Galizi’s article: Taxiarchi, et al. (2021) “A genetically encoded anti-CRISPR protein constrains gene drive spread and prevents population suppression”, Nature Communications, 12: 3977, 8 pages long. The publication was published one day after Applicant’s foreign priority date. Moreover, as discussed in Txiarchi, several approaches had been considered, but Applicant’s disclosure was the first to use the Acr proteins to inhibit the Cas9/Cpf1-gRNA complex, in the germ line. There was no teaching or motivation in the prior to arrive at the presently-claimed invention. Thus, the claims are free of the Art. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT ROBERT M KELLY whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0729 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT M-F: 8a-5p . 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, FILLIN "SPE Name?" \* MERGEFORMAT Tracy Vivlemore can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 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. FILLIN "Examiner Stamp" \* MERGEFORMAT ROBERT M. KELLY Examiner Art Unit 1638 /ROBERT M KELLY/ Primary Examiner, Art Unit 1638