CTFR 16/960,691 CTFR 97342 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 Claims 1-3, 5, 9, and 12-19 are currently pending in this application. Election/Restrictions Applicant’s election without traverse of Group I, claims 1-11, in the reply filed 10/12/23 is acknowledged. Claims 12-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Claims 1-3, 5, and 9 are considered on the merits and all arguments have been fully considered. Benefit of Priority 02-10 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 pre-AIA 35 U.S.C. 112, except for the best mode requirement. 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. US 63/615,727, 62/668,966, and PCT/US/2019/13011, each fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for any of the instant claims due to the “restricted to occur during meiosis.” Therefore the earliest effective filing date of the instant claims is Jul. 8, 2020. Previous Rejections Status of the rejections: a) The previous claim rejections under AIA Section 33(a) are withdrawn in view of the amendment to claim 1. b) The previous claim rejections under 35 USC 112 are withdrawn in view of the claim amendments except as maintained below. 07-30-03-h AIA Claim Interpretation In claim 1, the limitation that “wherein the genetically modified mammal is a mouse” only strictly applies to said genetically modified mammal recited in the preamble and not to every recitation of a mammal in the claim ( see 112(a) and 112(b) rejections below). In claim 1, the term “driving” is interpreted to mean the copying and insertion of the element into a genomic site in a cell(s) of a rodent (e.g., germline cells) or of rodents of a population (e.g., a strain), and possibly continued insertion activities in the progeny of such rodents. In claims 1-2, the term “allele” is interpreted to encompass allele loci with eliminated gene function (e.g., a complete gene deletion of all copies when diploid). Claim Rejections - 35 USC § 112(a), New Matter (new) 07-30-01 AIA 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, and 9 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 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 wherein the activity of the Cas9-mediated split gene-drive system is “restricted to occurring during meiosis.” This lacks support in the application as filed and thus constitutes new matter; however, there may be support for expression “restricted to the germline,” which although highly similar is not synonymous to restricted to meiosis ( see instant [0080] regarding mitotic germline cells). 37 CFR 1.118(a) states “No amendment shall introduce new matter into the disclosure of an application after the filing date of the application”. In the instant case, the recitation of the limitation “the activity of the Cas9-mediated split gene-drive system is restricted to occurring during meiosis” (Claim 1) is considered new matter. Upon review of the instant specification, examiner could not find explicit or implicit support for this limitation in the instant filing or in any priority document. Thus, at the time the application was filed, an Artisan of skill would not recognize from the disclosure that Applicant was in possession of such a meiosis restricted promoter or expression system, with description instead only of germline-specific expression ([0072], [0081], Example 2, FIG. 8-9 (e.g., due to Vasa or Stra8)). MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph-written description requirement”. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981) teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed…If a claim is amended to include subject matter, limitation or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application. MPEP 2163.06 further notes, “When an amendment is filed in reply to an objection or rejection based on U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendment made to the disclosure”. Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence. Claim Rejections - 35 USC § 112(a), Written Description (modified) 07-30-01 AIA 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. 07-31-01 Claims 1-3, 5, and 9 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. When claim 1 is analyzed in light of the specification, the instant invention is directed to a method of (1) genetic engineering a first mammal to make a transgenic mammalian strain A having genetic element A (allele-gRNA-at- TYR ), (2) genetic engineering a second mammalian strain B having a genetic element B-Cas9 (any location), and (3) mating the transgenic mammalian strains A and B or their progeny together to produce a genetically modified mouse C expressing, at least during meiosis I, a split gene-drive system (A-gRNA and B-Cas9) in trans whereby genetic element A is driven to be mobilized and inserted at a TYR locus by the activity of Cas9-gRNA during meiosis I in the mammal C and/or its offspring (strain C) thereby accomplishing a Cas9-mediated split-gene drive system in a genetically modified mouse/mice. M.P.E.P. §2163 states “To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g ., Moba, B.V. v. Diamond Automation, Inc ., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar , 935 F.2d at 1563, 19 USPQ2d at 1116.” In the instant case, claim 1 broadly encompasses strains of the genus of mammal, which encompasses some 6,400 species (including humans), distributed in about 1,200 genera, 152 families and up to 46 orders (en.wikipedia.org/wiki/Mammal, last visited August 31, 2022), such as Rodentia, Chiroptera, and Eulipotyphla, as well as diverse types, such as undomesticated mammals, egg-laying mammals, marsupials and whales. Claim 1 is also broad in that the strain A mammal and strain B mammal are not necessarily the same species of mammal while their crossing must produce a species of mouse. In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described. In the instant case, the specification describes in detail only how to make a transgenic mammal of a single mouse species, Mus musculus (Example 2, e.g., B6J.129 and Tyr CopyCat mice backgrounds), which relies on crossing males expression a meiosis- specific Cre transgene. There is only prophetic language at high generality for applying the claimed method to other species of mice. Thus, the written description for the genus of mammal or any mouse species consists merely of an invitation to figure it out based on the Mus musculus examples made by the method described in instant Example 2. Therefore, the instant specification purports at the earliest effective filing date it was within the scope of skills of the ordinary artisan to cross non-mice mammals together to produce a mouse or to cross any strain of mouse species together to obtain a viable/fertile mouse species (e.g., interspecies hybrid from interbreeding). Claim 1 is also broad in that if all the mammals in the claim are limited to a mouse species, the strain A mouse species and strain B mouse species are not necessarily the same species of mouse. As the prior art teaches certain mouse species cannot interbreed such as due to having different chromosome numbers and/or genetic incompatibilities, e.g., Mus spretus with Mus musculus domesticus (El Yakoubi and Akera, Nature 623: 347-55 (2023)) applicant has the burden to show with evidence that at the effective filing date this was possible, e.g., breeding a strain of African pygmy mouse with a strain of deer mouse. The instant application has no such evidence. Thus, the skilled artisan cannot envision how to apply the claimed method as described in the instant application across the scope of the entire genus of mammals or all mouse species. Critically, the specification fails to describe enough representative species of methods and fails to provide the related guidance to adapt the representative method described to mammalian or mouse species that have never been genetically engineered before, especially if requiring multiple different strain creation (e.g., expression-limited Cre variants) and multiple genetic crosses based on controlled matings to generate the requisite heterozygotes. In conclusion, there is a lack of evidence in the instant specification as filed that the inventors were in possession of a method of making a genetically engineered split-gene drive system active in meiosis I over the entire scope of non-mouse mammals as encompassed by the instant claims requiring a “crossing” of mammalian strains, or even crossing incompatible mouse species together. 35 USC § 112(a) – Scope of Enablement (modified) 07-30-01 AIA 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, and 9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification while being enabling for wherein the strain A mammal and strain B mammal are both a species of mouse capable of interbreeding and only a single gene is actively edited in the genetically modified mouse; does not enable any person skilled in the art, to which it pertains or with which it is most nearly connected to, to perform the claimed methods on the entire genus of mammals as encompassed by the claims. Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below. Nature of the invention : The claims are directed to methods of creating (1) a genetically modified mammal strain A having an exogenous genetic construct (element A) inserted at the TYR gene and comprising a recombinant allele and gRNA; (2) a genetically modified mammal strain B having an exogenous genetic construct (element B) encoding a Cas9 endonuclease; and producing (3) a genetically modified mouse progeny of the aforementioned comprising a Cas9-mediated split gene-drive system comprising both a stable insertion of element A and genetic element B wherein both the gRNA and Cas9 are expressed during at least meiosis I while being restricted to meiosis generally. Breadth of the claims The claims are broadly directed to wherein the genetically modified mouse (3) is a product of crossing the two strains (1-2) that any species of mammal (strain A mammal A and strain B mammal). The state of the art : The prior art teaches a method of generating genetically modified rodents and non-rodent mammals (rabbits) comprising a desired allele inserted into the TYR gene by editing the TYR gene in rabbits using CRISPR/Cas9 and a sgRNA expressed from an injected plasmid (Honda et al ., Exp Anim 64: 31-7 (2014) at Abstract; Fig. 1-3). The prior art also teaches methods of producing genetically modified mammals, the method comprising using a split Cas9-mediated gene-drive system to specifically insert into a target genome sequence a desired allele due to the gRNA(s) and Cas9 sources (e.g., transgenic elements) being located on different chromosomes and when combined by mating strains leads to autocatalytic copying of a first transgenic element (element A) to a sister chromosome (Bier (WO 2017049266 A2) at [00280], [00392], ([00341], [00349], [00413], [0013], [0015], [00339]-[00340], [00415]; Examples 3-4 and 10; FIG. 4-6, 19-21, 31-32). However these methods do not specify how to cross any non-mouse mammal strain with another strain (whether mouse or not) to produce a mouse. Thus, this aspect must be shown to a reasonable extent over the scope of said strains of any mammal species so that one of the ordinary skills in the art would be able to practice the invention without any undue or unreasonable burden being on such an Artisan. The amount of direction and guidance and working examples provided by Applicant : The instant application provides working examples only in a laboratory Mus musculus mouse strain (C57BL/6J) using either Vasa-Cre or Stra8-Cre mouse strains whereby conditional Cas9 expression is driven in germ cells Example 2, FIG. 1-6) ( id .). In these working example, males carrying a genetic element A (heterozygous for Tyr CopyCat and U6-Tyr4a gRNA) and the Cre transgene were crossed to females carrying a genetic element B (homozygous H11:LSL-Cas9) and then crossed to Tyr Ch homozygotes resulting in up to 78.6% gene drive of the Tyr CopyCat of element A in the F4 generation as determined by conversion of the Tyr Ch chinchilla phenotype to Tyr null, which is predicted to occur naturally at a lower frequency of 4.7×10 −5 (Example 2; FIG. 8; Table 7). The instant specification notes that Tyr locus mosaicism observed in progeny when males carrying genetic element B were crossed to females carrying element A indicates Cas-9 mediated split gene drive activity outside of meiosis, perhaps due to promoter leakiness ([0081]; Table 6). Regarding claims 3 and 5, the instant specification lacks a working example of any method comprising multiple gRNAs actively targeting two or more genes for genomic editing yet the claims encompasses wherein the function of several genes is eliminated in the genetically modified mouse. The instant specification provides guidance in detail only how to make a transgenic mammal of a single species of mouse, Mus musculus (Example 2, e.g., C57BL/6J or B6J.129). In the working examples, the method relies on a human U6 snRNA promoter to drive expression of the gRNA and a germline-specific promoter system to drive expression of Cas9 during meiosis. However no ready-made germline promoter mouse line was available, so first another transgenic Mus musculus line was constructed comprising a floxed mutant Cas9 transgene at Rosa26/LSL2 and crossed with an already available Vasa-Cre or Stra8-Cre mouse line to obtain transgenic mammal B before moving on to perform the method recited in claim 1. Of the over 30 species of mouse, most lack any genetically engineered strains or technologies, such as for expressing Cre, as well as no operational knowledge of reliable germline promoter technologies. Thus, the instant method requires for each application to a new mouse species the identification of a meiosis-specific promoter or even a germline-permissive constitutive promoter to either drive Cas9 directly or, as per the working examples, to be engineered via an additional cross after setting up de novo a loxP Cre system in each new mouse species. There is only prophetic language at high generality for applying the claimed method to other mouse species other than Mus musculus , which is not predictable to work for all mouse species in the same manner. There is no specific guidance how to adapt this single mouse species example and apply it to all 36 or so other species of mice. While Cas9-gRNA editing likely works in all mouse species and all mice probably have a Tyr locus, a U6 promoter, and Vasa or Stra8 promoter; it is not predictable from the prior art how to breed non-mouse mammal strains to obtain the progeny of the cross of strain A and strain B that is a mouse. Further, the creation of strain B for many mouse species may require the creation of two additional new mouse strains, (1) a floxed inactivated Cas9 and (2) germline promoter Cre strain, but this is not recited in any of the claims. Furthermore, it is not predictable from the prior art how to breed any mouse species with any other mouse species to obtain a viable/fertile progeny of a cross as some mouse strains are known to be incompatible for interbreeding, e.g., Mus spretus with Mus musculus domesticus (El Yakoubi and Akera, Nature 623: 347-55 (2023)). The quantity of experimentation needed to make and/or use the invention : Extensive experimentation would be required to determine how to create the scope of transgenic mammals of each species comprising genetic element A or element B and breed them into a single mouse, across the breadth of any mammal. The field of genetic engineering has not evolved such that, without guidance or working examples in the specification, the artisan could predictably perform the method of claim 1 using each mammalian species without undue and/or unreasonable experimentation. Extensive experimentation would also be required to determine how to create the scope of transgenic mouse specie strains comprising genetic element A or element B and breed them, across the breadth of any mouse species. The field of genetic engineering has not evolved such that, without guidance or working examples in the specification, the artisan could predictably perform the method of claim 1 using each mouse species without undue and/or unreasonable experimentation. Thus, there is no evidence provided in the application that transgenic mammals carrying an element A and others of the same species carrying an element B can be made and crossed with each other to produce a split gene-drive system with gRNA-guided Cas9 activity during meiosis I wherein the strains of mammal encompasses any type of mammal or even any species of mouse. Given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims with regard to any mammal and requiring at least one controlled “crossing” or mating step producing viable/fertile progeny, undue and unreasonable experimentation would have been required for one skilled in the art to use the claimed methods to produce the recited result across the breadth of the claims (i.e., regarding the genus of mammal and the genus of mouse of any species). Response to Arguments Applicant's arguments filed 5/13/26 regarding the previous 112(a) rejections (pg. 9) have been fully considered but not found persuasive regarding enablement. As noted previously, the working examples are only in a laboratory mouse strain ( Mus musculus ), and Applicant appears to agree with this in their remarks. While the claimed invention is enabled for more than just one species of mouse (e.g., Mus musculus), it is the opinion of this office action that it is not enabled for wherein the species of strain A and B do not match, i.e., any species of mouse. Previously, the Examiner assumed in the written description rejection of 3/18/26 that claim 1 logically implied the species of mammal of strain A and strain B must be the same species but not in the previous enablement rejection. This claim interpretation is withdrawn as indicated above and aligned across both current written description and enablement rejections set forth herein. Note, it would be at least partially remedial to amend the claims to recite “restricted to the germline” as is inherently the case for the Vasa promoter profile with the understanding the term “restricted” is not absolute due to promoter leakiness ( see instant [0080] regarding mosaicism and uncertainty regarding the timing of Cas9 activity). It would be at least partially remedial to amend the claims to recite “wherein the strain A mammal and the strain B mammal are the same species of mouse” or, alternatively, “wherein all mammals are laboratory (inbred) strains of Mus musculus .” Claim Rejections - 35 USC § 112(b) 07-30-02 AIA 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. 07-34-01 AIA Claim s 1-3, 5, and 9 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 pre-AIA the applicant regards as the invention. Claim 1 recites “wherein the genetically modified mammal is a mouse” where the only precise antecedent for this term is in the preamble describing the result of performing this method of making and thus other recitations of “the mammal” referring back to the same. As the claim also recites “a strain A mammal” and “a strain B mammal,” the claim is ambiguous as to whether these mammals are also limited to mouse. Claims 2-3 and 5 each recites the same ambiguous language as well. Thus, claims 1-3 and 5 are indefinite regarding the scope of the term a [strain] mammal or the [strain] mammal. Claim 9 is included in this rejection for depending from indefinite claims 1 and 2. Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 1-2 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Grunwald (Grunwald et al., bioRxiv. doi:https://doi.org/10.1101/362558 (2018)) in view of Burkhardt (Burkhardt et al., Curr Biol 26: 678-85 (2016)) . Grunwald teaches a method of producing a genetically modified mouse, the method comprising introducing into a mouse a Cas9-mediated gene-drive system to actively edit a genome sequence of a mammal via super-Mendelian inheritance wherein the system is “split” due to the gRNA and Cas9 sources (e.g., transgenic elements) being located on different chromosomes of different mouse lines but when combined by mating results in autocatalytic copying of a transgenic element (e.g., a first genetic element A CopyCat allele inserted into the Tyrosinase gene locus and encoding the gRNA) to a sister chromosome lack genetic element A due to activity of the Cas9 during female meiosis (encoded by the second element B “ H11-Cas9” ) (abstract, Fig. 1-3). Regarding claims 1-2, Grunwald does not teach how to “restrict” the gene drive activity solely to meiosis, instead relying on germline expression generally via Vasa-Cre or Stra8-Cre transgenes, which may provide Cas9 activity during meiosis and prior. However Grunwald teaches the goal of restricting CRISPR/Cas9 activity to meiosis during development of the germline to favor HDR over NHEJ (pg. 4). Furthermore, Burnhardt teaches mouse meiosis restricted promoters driving transgenes, such as Rec8 or Spo11 promoters (Fig. 2-3). It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing in light of teachings in Burnhardt to modify the system of Grunwald to use a Rec8 or Spo11 promoter to restrict Cas9 expression to meiosis. One of ordinary skill in the art would be motivated by Grunwald teaching the advantages of such restriction when gene editing via chromatid DSB and favoring HDR for siter chromatid repair (pg. 4). Regarding claim 9, Grunwald teaches using an element A comprising an inserted transgenic element expressing the fluorescent mCherry marker (mCherry-CMV), which readily distinguish transgenic from unmodified (pg. 3, Fig. 1). Thus, the claimed invention as a whole is prima facie obvious before the earliest effective filing date in the absence of evidence to the contrary. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00. 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 on 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. /ERIC J ROGERS/Examiner, Art Unit 1638 /KEVIN K HILL/Primary Examiner, Art Unit 1638 Application/Control Number: 16/960,691 Page 2 Art Unit: 1638 Application/Control Number: 16/960,691 Page 3 Art Unit: 1638 Application/Control Number: 16/960,691 Page 4 Art Unit: 1638 Application/Control Number: 16/960,691 Page 5 Art Unit: 1638 Application/Control Number: 16/960,691 Page 6 Art Unit: 1638 Application/Control Number: 16/960,691 Page 7 Art Unit: 1638 Application/Control Number: 16/960,691 Page 8 Art Unit: 1638 Application/Control Number: 16/960,691 Page 9 Art Unit: 1638 Application/Control Number: 16/960,691 Page 10 Art Unit: 1638 Application/Control Number: 16/960,691 Page 11 Art Unit: 1638 Application/Control Number: 16/960,691 Page 12 Art Unit: 1638 Application/Control Number: 16/960,691 Page 13 Art Unit: 1638 Application/Control Number: 16/960,691 Page 14 Art Unit: 1638 Application/Control Number: 16/960,691 Page 15 Art Unit: 1638 Application/Control Number: 16/960,691 Page 16 Art Unit: 1638 Application/Control Number: 16/960,691 Page 17 Art Unit: 1638 Application/Control Number: 16/960,691 Page 19 Art Unit: 1638 Application/Control Number: 16/960,691 Page 20 Art Unit: 1638 Application/Control Number: 16/960,691 Page 21 Art Unit: 1638
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