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. Election/Restrictions Applicant’s election without traverse of a gNA targeting sequence of SEQ ID NO:321 and of an NLS sequence of SEQ ID NO:167 in the reply filed on 10/02/2025 is acknowledged. Claims Status Claims 3-10, 12-27, 30-40, 42-45, 48-51, 53-64, 66-78, 80, 82-83, 85-92, 94, 96-111, 113-114, 116-146, 148-192 is/are cancelled. Claims 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 9395, 112, 115, 147, 193 is/are currently pending. Claims 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 9395, 112, 115, 147, 193 is/are under examination. Claim Interpretation Claim 193 recites “[a] composition for use in a method of treating a chromosome 9 open reading frame 72 (C9orf72) -related disorder in a subject in need thereof” (lines 1-2). While the preamble of the claim recites that the invention is the composition, the claim, when taken as a whole, including the recited steps comprised in the method, is interpreted to be drawn to the method of treating a C9orf72-related disorder in a subject in need thereof . As such, claim 193 is examined as a process claim, and not a product claim. Claim Objections Claim s 41 and 46 are objected to because of the following informalities : Claim 41 recites “a N-terminus” in line 25 . For grammatical correctness, this should be rewritten as “an N-terminus”. Claim 46 recites “Cas X”, whereas all other claims recite “ CasX ”. “Cas X” should be rewritten as “ CasX ”. Appropriate correction is required. Claim Rejections - 35 USC § 112 112(b): 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 41 , 47, and 193 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. The term “ near ” in claim 41, lines 24-25, is a relative term which renders the claim indefinite. The term “ near ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification, paragraph [0265], teaches that “near” can mean “within 50 amino acids of”; however, this is not a limiting definition, as it is presented as an example of a definition of “near” (“e.g.”). It is thus unclear what the metes and bounds of claim 41 are. Regarding claim 47, the phrase "including" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). “Including”, in the present context, is considered to be exemplary claim language. The term “ having identity ” in claim 52 is a relative term which renders the claim indefinite. The term “ having identity ” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. “Having identity” is interpreted to mean “having a degree of sequence similarity”. However, claim 52 does not define the degree of sequence similarity required for two sequences to “have identity”, and an artisan would not be able to determine the required degree of sequence similarity. As such, the metes and bounds of claim 52 are unclear, and claim 52 is rendered indefinite. The preamble of claim 193 recites both a product and a method (“A composition”, “a method of treating”). Claim 193 is indefinite because it fails to distinctly claim the subject matter which is regarded as the invention—i.e., the “composition” or the “method of treating”. 112(d): The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claim 46 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 46 recites “The system of claim 1, wherein the Cas X variant protein is capable of forming a ribonuclear protein complex (RNP) with the gNA .” Claim 46 depends on claim 1. Claim 1 recites “A system comprising a CasX variant protein and a guide nucleic acid ( gNA )…wherein the CasX variant protein is capable of forming a ribonuclear protein complex (RNP) with the gNA ” (lines 1-2, 5-6) . As all of the limitations of claim 46 are required by claim 1, on which claim 46 depends, claim 46 fails to further limit claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. 112(a): 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. Written Description: Claim s 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147, 193 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. 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. Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaff v. Wells Eiees ., Inc., 525 U.S. 55, 68, 119 S.Ct . 304, 312, 48 USPQ2d 1641,1647 (1998); Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F. 2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it”). According to the MPEP § 2163, "The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutsch land GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")." Claim s 1 and 79 recite CasX variant proteins comprising sequences at least 70% identical to SEQ ID NO:138. This creates an enormous genus of proteins. Claim s 1 and 79 recite gNAs comprising target sequences “complementary to a target nucleic acid sequence comprising a chromosome 9 open reading frame 72 ( C9orf72 ) gene” (lines 7-8), but do not recite a degree of complementarity required, creating an enormous genus of gNA targeting sequences ranging from 1-100% complementary to a target sequence. Claim 11 recites a gNA comprising a sequence at least 65% identical to SEQ ID NOs:309-343, 363-2100, or 2295-21835, which does not sufficiently further describe the genus of targeting sequences of claim 1. Claim 11 recites a scaffold sequence comprising at least 1 mismatch relative to SEQ ID NO:32, creating an enormous genus of scaffold sequences comprising no sequence identity to SEQ ID NO:32. Claim 11 also recites that the gNA is chemically modified, but does not recite any particular chemical modifications, creating an enormous genus of possible chemical modifications. 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 by their complete structure. In the instant case, the only species of variant CasX proteins described comprise SEQ ID NOs:72, 94, 113, 130-138, 141-144, 239, 277, or 280 (paragraph [0201]); the only species of gNA targeting sequences are SEQ ID NOs:309-343, 363-2100, and 2295-21835 (paragraph [0101]); the only species of scaffold stem loop sequences are SEQ ID NOs:14, 32, or 33, or SEQ ID NO:5 comprising the modifications C18G, G55, U1 deletion, A99 deletion, or G64U substitution (paragraph [0110]) , or any of the modifications taught in Table 2, starting on page 37 . The specification does not provide any description of any species of chemical modification of a gNA . While the genera encompass a large number of variant proteins and gNA sequences that have the same activity (RNA-guided DNA-targeting and cleaving activity of variant CasX proteins, CasX - and DNA-binding activity of variant gNA sequences) and the genera encompass large numbers of variants and molecules that have different structures, the specification does not describe the complete structures of representative numbers of species of the large genera of variant CasX proteins and variant and chemically-modified gNA sequences. Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than amino acid or nucleotide sequence, or chemical modification), specific features and functional attributes that would distinguish different members of the claimed genera. In the instant case, the only other identifying characteristic of the variant CasX proteins is that they “exhibit at least one improved characteristic compared to the reference CasX protein” (paragraph [0172]), wherein the at least one improved characteristic can be, but is not limited to, “improved folding of the variant, improved binding affinity to the gNA , improved binding affinity to the target DNA, altered binding affinity to one or more PAM sequences, improved unwinding of the target DNA, increased activity, improved editing efficiency, improved editing specificity, increased activity of the nuclease, increased target strand loading for double strand cleavage, decreased target strand loading for single strand nicking, decreased off-target cleavage, improved binding of the non-target strand of DNA, improved protein stability, improved protein:gNA complex stability, improved protein solubility, improved protein:gNA complex solubility, improved protein yield, improved protein expression, and improved fusion characteristics” (paragraph [0175]). T he only other identifying characteristic of the variant gNAs is that they “have one or more improved functions or characteristics, or add one or more new functions when the variant gNA is compared to a reference gRNA”, including, but not limited to, “improved stability; improved solubility; improved transcription of the gNA ; improved resistance ot nuclease activity; increased folding rate of the gNA ; decreased side product formation during folding; increased productive folding; improved binding affinity to a CasX protein; improved binding affinity to a target DNA when compexed with a CasX protein; improved gene editing when complexed with a CasX protein; improved specificity of editing when complexed with a CasX protein; and improved ability to utilize a greater spectrum of one or more PAM sequences, including ATC, CTC, GTC, or TTC, in the editing of target DNA when complexed with a CasX protein” (paragraph [0111]). The specification also teaches that the gNA targeting sequence must target a portion of the C9orf72 gene or an associated regulatory sequence (paragraphs [0099]-[0100]). Such functional limitations cannot be identifying characteristics for the claimed diverse genera of molecules since by Applicant’s definition of variant CasX proteins and gNAs , all members of the claimed genera will have these characteristics. Further, no identifying characteristics of the modified CasX proteins and gNAs are disclosed. The inventions of claims 2, 28-29, 41, 46-47, 52, 65, 81, 84, 93, 95, 112, 115, 147, 193 require the use of the inventions of claims 1, 11, and 79 and are likewise rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. Enablement: 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 s 95, 112, 115, and 193 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 a method of modifying a C9orf72 gene in vitro , does not reasonably provide enablement for a method of modifying a C9orf72 gene in vivo or for a method of treating a disease associated with C9orf72 . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. The breadth of the claims: With respect to claim breadth, the standard under 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. As such, the broadest reasonable interpretation of the claimed method s is that they encompass methods of modifying a C9orf72 gene sequence in a population of cells in vitro or in vivo , and of treating a disorder associated with C9orf72 (see claim 193) , by administering a CasX-gNA system, wherein the gNA targets any sequence comprising a C9orf72 gene sequence, encompassing a gNA targeting any target sequence anywhere in human chromosome 9 or in any vector or construct comprising a C9orf72 gene sequence . A skilled artisan would not know how to use the method with a reasonable expectation of success based solely on what is disclosed in the specification. The amount of direction provided by the inventor and the level of predictability in the art: The specification teaches FILLIN \* MERGEFORMAT that the intended use of the claimed methods of modifying a C9orf72 gene in vivo is in a method of treating amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (paragraphs [0003]-[0006]) . The art at the time of filing provided enabling guidance for expected therapeutic efficacy of Cas9-gRNA systems in the treatment of C9orf72 -related ALS and FTD, wherein the gRNA targets the promoter region controlling expression of C9orf72 ( Krishnan, 2020 ), or wherein the gRNAs target two sequences within the C9orf72 gene and flanking the GC-rich expansion region ( Pribadi , 2016 ) . However, the prior art did not provide enabling guidance for methods of treating C9orf72 -related diseases ALS and FTD using gRNA targeting any other sequence within the C9orf72 gene sequence or a C9orf72 expression control region, or any sequence not in the C9orf72 gene or expression control region. T he specification as filed does not provide guidance that overcomes this unpredictability within the art. The existence of working examples: What is enabled by the working examples is narrow in comparison to the breadth of the claims: The specification discloses working examples in vitro wherein the CasX-gNA systems are shown to be capable of targeting and cleaving a C9orf72 gene sequence ( paragraphs [0533]-[0548] ). The specification provides prophetic examples of methods of treating animal models of C9orf72 -related neurodegeneration; however, the disclosure teaches gNA targeting the promoter region, Exon 1, and Intron 1, including HRE, of C9orf72 ( see Fig. 22 ) . The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the nature of the invention encompasses in vivo treatment of any C9orf72 -related disease using a gNA targeting any sequence anywhere within any nucleic acid comprising a C9orf72 gene (including all of human chromosome 9) , a person having ordinary skill in the art would have to perform multiple further experiments, in human clinical trials or in animal models that are predictive of treatment, using a representative number of gNAs targeting a representative number of sequences comprised in any nucleic acid comprising a C9orf72 gene , in order to demonstrate the invention could be used with a reasonable expectation of success. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation in order to use the method with a reasonable expectation of successfully treating any CNS disorder or neurodegenerative disease. Therefore, Claims 95, 112, 115, and 193 are rejected under 35 U.S.C. 112, first paragraph, for failing to meet the enablement requirement. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Section 33(a) of the America Invents Act reads as follows: Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism. Claim 147 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability , 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 147 is drawn to “[a] population of cells”, wherein the cells are neurons. Claims 95 and 112 are drawn, in part, to methods of modifying populations of cells in vivo in humans. As such, it is evident that “a population of cells” in the instant application encompasses cells in a human body. As such, Claim 147 is, in part, drawn to a population of cells in a human body, and thus drawn to a human organism. Double Patenting The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer . The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer . US 11535835 B1 : Claim s 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147 rejected on the ground of nonstatutory double patenting a s being unpatentable over claims 1-3, 8-9, 11, 13-15, 20, 22-2 6 of U.S. Patent No. 11535835 B1 in view of Cowan ( WO 2017109757 A1 ) . The issued claims are drawn to a system comprising a variant CasX protein of SEQ ID NO:138 ( 100 % identical to instant SEQ ID NO:138) and a gRNA having a scaffold sequence at least 70% identical to SEQ ID NO:2238 ( 100 % identical to instant SEQ ID NO:2238) (claim 19). The issued claims recite that the system comprises a first and a second gRNA, wherein the second gRNA has a targeting sequence complementary to a different or overlapping portion of the target gene compared to the targeting sequence of the first gRNA (claim 13). The issued claims recite that the CasX comprises one or more NLS (claim 15). The specification of the issued patent describes the structure of an NLS sequence as comprising SEQ ID NOs:176-213 (col. 164 line 18-col. 165 line 15). Furthermore, issued claim 15 encompasses NLS sequences positioned anywhere within the CasX protein, including at or “near” the C- or N-terminus. As the variant CasX protein and gRNA sequences of the issued claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics and qualities recited in the instant claims as inherent qualities. The issued claims recite nucleic acids and vectors encoding the CasX and gRNA (claims 23-25). The AAV vector of issued claim 25 is considered to encompass any AAV serotype. The issued claims recite cells comprising the CasX:gRNA complex, including human cells (claim 26). However, the issued claims do not recite that the target sequence is comprised in a nucleic acid comprising a C9orf72 gene, as required by the instant claims. Cowan teaches a Cas9:gRNA system targeting C9orf72 . Regarding claim 1, Cowan teaches a system comprising a CRISPR endonuclease and two guide RNAs, wherein the guide RNAs target C9orf72 “in or near” the first exon, first intron, or second exon of C9orf72 (claims 1, 58-62). Regarding claim 2, Cowan teaches that the target C9orf72 gene comprises an expanded hexanucleotide repeat (claims 1, 7, 13, 18, 25), and that the expanded hexanucleotide repeat can comprise more than 30 GGGGCC repeats (paragraph [00181]). Regarding claim 11, Cowan teaches that the targeting sequence of one gRNA is SEQ ID NO:3357 (SEQ ID NO:3357 is 100% identical to instant SEQ ID NO:321, see alignment below) (page 155) . Regarding claim 28, Cowan teaches that the system comprises two gRNAs, wherein both gRNAs target sequences within the C9orf72 gene, and the first and second gRNAs target different sequences (claims 1, 58-62). Regarding claim 29, Cowan teaches that the first and second gRNAs target a 5’ double-stranded break (DSB) locus and a 3’ DSB locus which flank the expanded hexanucleotide repeat (claims 58-63). Regarding claim 79, Cowan teaches a nucleic acid encoding the Cas9 endonuclease (paragraph [0049]) and gRNA (paragraph [00448]). Regarding claims 81 and 84, Cowan teaches that the Cas9-gRNA system is encoded in an AAV6 viral vector (claims 67, 71). Regarding claim 93, Cowan teaches that the Cas9-gRNA system is introduced into HEK293T cells (paragraph [00742]). Regarding claim 95, Cowan teaches a method of modifying a C9orf72 gene in a population of cells, the method comprising the steps of: introducing into the population of cells the Cas9-gRNA system; modifying the C9orf72 gene in the population of cells, wherein the modifying comprises: introducing a DSB in the C9orf72 gene and introducing a deletion in the C9orf72 gene (claims 1-3, 7). Regarding claims 112 and 115, Cowan teaches that the population of cells is a population of spinal cord motor neurons, glia, astrocytes, motor cortex neurons (paragraph [00225]). Regarding claim 147, Cowan teaches that the population of cells is modified by administering the Cas9-gRNA system (paragraph [00225]). Cowan teaches that the expanded hexanucleotide repeat in the C9ORF72 gene in the cells is corrected (claim 1). Cowan teaches that the population of cells are a population of spinal cord motor neurons, glia, astrocytes, or motor cortex neurons (paragraph [00225]). It would have been obvious to an artisan that the compositions and methods of the issued claims could be modified, by modifying the targeting sequences of the guide RNAs, to target the CasX -gRNA complex of the issued claims to different genes whose modification were desired. Cowan teaches that CRISPR endonuclease-mediated editing of the C9ORF72 gene was known in the art and useful in the study of amyotrophic lateral sclerosis and frontotemporal degeneration (as taught by Cowan). Given the teachings of Cowan, the compositions and methods of the instant claims are derived from obvious modifications of the issued claims. US 11613742 B2: Claim s 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147 are rejected on the ground of nonstatutory double patenting a s being unpatentable over claims 1, 8, 12-14, 18, 22, 24-25 of U.S. Patent No. 11613742 B2 in view of Cowan ( WO 2017109757 A1 ) . The issued claims are drawn to a system comprising a variant CasX protein of SEQ ID NO:126 (100% identical to instant SEQ ID NO:138) and a gRNA having a scaffold sequence at least 70% identical to SEQ ID NO:2238 ( 100 % identical to instant SEQ ID NO:2238) (claim s 1, 13, 22, 25 ). The issued claims recite that the system comprises a first and a second gRNA, wherein the second gRNA has a targeting sequence complementary to a different or overlapping portion of the target gene compared to the targeting sequence of the first gRNA (claim 12 ). The issued claims recite that the CasX comprises one or more NLS (claim 14 ). The specification of the issued patent describes the structure of an NLS sequence as comprising SEQ ID NOs:176-213 (col. 16 1 line 20 -col. 16 2 line 17 ). Furthermore, issued claim 1 4 encompasses NLS sequences positioned anywhere within the CasX protein, including at or “near” the C- or N-terminus. As the variant CasX protein and gRNA sequences of the issued claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics and qualities recited in the instant claims as inherent qualities. The issued claims recite nucleic acids and vectors encoding the CasX and gRNA (claims 2 2, 24 ). The AAV vector of issued claim 2 4 is considered to encompass any AAV serotype. However, the issued claims do not recite that the target sequence is comprised in a nucleic acid comprising a C9orf72 gene, as required by the instant claims. Cowan teaches a Cas9:gRNA system targeting C9orf72 . Regarding claim 1, Cowan teaches a system comprising a CRISPR endonuclease and two guide RNAs, wherein the guide RNAs target C9orf72 “in or near” the first exon, first intron, or second exon of C9orf72 (claims 1, 58-62). Regarding claim 2, Cowan teaches that the target C9orf72 gene comprises an expanded hexanucleotide repeat (claims 1, 7, 13, 18, 25), and that the expanded hexanucleotide repeat can comprise more than 30 GGGGCC repeats (paragraph [00181]). Regarding claim 11, Cowan teaches that the targeting sequence of one gRNA is SEQ ID NO:3357 (SEQ ID NO:3357 is 100% identical to instant SEQ ID NO:321, see alignment below) (page 155). Regarding claim 28, Cowan teaches that the system comprises two gRNAs, wherein both gRNAs target sequences within the C9orf72 gene, and the first and second gRNAs target different sequences (claims 1, 58-62). Regarding claim 29, Cowan teaches that the first and second gRNAs target a 5’ double-stranded break (DSB) locus and a 3’ DSB locus which flank the expanded hexanucleotide repeat (claims 58-63). Regarding claim 79, Cowan teaches a nucleic acid encoding the Cas9 endonuclease (paragraph [0049]) and gRNA (paragraph [00448]). Regarding claims 81 and 84, Cowan teaches that the Cas9-gRNA system is encoded in an AAV6 viral vector (claims 67, 71). Regarding claim 93, Cowan teaches that the Cas9-gRNA system is introduced into HEK293T cells (paragraph [00742]). Regarding claim 95, Cowan teaches a method of modifying a C9orf72 gene in a population of cells, the method comprising the steps of: introducing into the population of cells the Cas9-gRNA system; modifying the C9orf72 gene in the population of cells, wherein the modifying comprises: introducing a DSB in the C9orf72 gene and introducing a deletion in the C9orf72 gene (claims 1-3, 7). Regarding claims 112 and 115, Cowan teaches that the population of cells is a population of spinal cord motor neurons, glia, astrocytes, motor cortex neurons (paragraph [00225]). Regarding claim 147, Cowan teaches that the population of cells is modified by administering the Cas9-gRNA system (paragraph [00225]). Cowan teaches that the expanded hexanucleotide repeat in the C9ORF72 gene in the cells is corrected (claim 1). Cowan teaches that the population of cells are a population of spinal cord motor neurons, glia, astrocytes, or motor cortex neurons (paragraph [00225]). It would have been obvious to an artisan that the compositions and methods of the issued claims could be modified, by modifying the targeting sequences of the guide RNAs, to target the CasX -gRNA complex of the issued claims to different genes whose modification were desired. Cowan teaches that CRISPR endonuclease-mediated editing of the C9ORF72 gene was known in the art and useful in the study of amyotrophic lateral sclerosis and frontotemporal degeneration (as taught by Cowan). Given the teachings of Cowan, the compositions and methods of the instant claims are derived from obvious modifications of the issued claims. 17641426: Claim s 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 169, 174-177, 179-195 of copending Application No. 17641426 in view of Cowan ( WO 2017109757 A1 ). The copending claims are drawn to a system comprising a variant CasX protein of SEQ ID NO:126 (100% identical to instant SEQ ID NO:138) and a gRNA having a scaffold sequence at least 70% identical to SEQ ID NO:2238 (100% identical to instant SEQ ID NO:2238) (claims 169, 175, 181 ). The copending claims recite that the system comprises a first and a second gRNA, wherein the second gRNA has a targeting sequence complementary to a different or overlapping portion of the target gene compared to the targeting sequence of the first gRNA (claim 174 ). The copending claims recite that the CasX comprises one or more NLS at or near the N- or C-terminus of the CasX protein (claim 176 ). The copending specification describes the structure of an NLS sequence as comprising SEQ ID NOs: 145-182 ( paragraph [00317] ). As the variant CasX protein and gRNA sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics and qualities recited in the instant claims as inherent qualities. The copending claims recite nucleic acids and vectors encoding the CasX and gRNA (claims 183-184 ). The AAV vector of copending claim 184 is considered to encompass any AAV serotype. The copending claims recite a population of cells modified by the CasX -gRNA system (claims 185-190, 192). However, the copending claims do not recite that the target sequence is comprised in a nucleic acid comprising a C9orf72 gene, as required by the instant claims. Cowan teaches a Cas9:gRNA system targeting C9orf72 . Regarding claim 1, Cowan teaches a system comprising a CRISPR endonuclease and two guide RNAs, wherein the guide RNAs target C9orf72 “in or near” the first exon, first intron, or second exon of C9orf72 (claims 1, 58-62). Regarding claim 2, Cowan teaches that the target C9orf72 gene comprises an expanded hexanucleotide repeat (claims 1, 7, 13, 18, 25), and that the expanded hexanucleotide repeat can comprise more than 30 GGGGCC repeats (paragraph [00181]). Regarding claim 11, Cowan teaches that the targeting sequence of one gRNA is SEQ ID NO:3357 (SEQ ID NO:3357 is 100% identical to instant SEQ ID NO:321, see alignment below) (page 155). Regarding claim 28, Cowan teaches that the system comprises two gRNAs, wherein both gRNAs target sequences within the C9orf72 gene, and the first and second gRNAs target different sequences (claims 1, 58-62). Regarding claim 29, Cowan teaches that the first and second gRNAs target a 5’ double-stranded break (DSB) locus and a 3’ DSB locus which flank the expanded hexanucleotide repeat (claims 58-63). Regarding claim 79, Cowan teaches a nucleic acid encoding the Cas9 endonuclease (paragraph [0049]) and gRNA (paragraph [00448]). Regarding claims 81 and 84, Cowan teaches that the Cas9-gRNA system is encoded in an AAV6 viral vector (claims 67, 71). Regarding claim 93, Cowan teaches that the Cas9-gRNA system is introduced into HEK293T cells (paragraph [00742]). Regarding claim 95, Cowan teaches a method of modifying a C9orf72 gene in a population of cells, the method comprising the steps of: introducing into the population of cells the Cas9-gRNA system; modifying the C9orf72 gene in the population of cells, wherein the modifying comprises: introducing a DSB in the C9orf72 gene and introducing a deletion in the C9orf72 gene (claims 1-3, 7). Regarding claims 112 and 115, Cowan teaches that the population of cells is a population of spinal cord motor neurons, glia, astrocytes, motor cortex neurons (paragraph [00225]). Regarding claim 147, Cowan teaches that the population of cells is modified by administering the Cas9-gRNA system (paragraph [00225]). Cowan teaches that the expanded hexanucleotide repeat in the C9ORF72 gene in the cells is corrected (claim 1). Cowan teaches that the population of cells are a population of spinal cord motor neurons, glia, astrocytes, or motor cortex neurons (paragraph [00225]). It would have been obvious to an artisan that the compositions and methods of the copending claims could be modified, by modifying the targeting sequences of the guide RNAs, to target the CasX -gRNA complex of the copending claims to different genes whose modification were desired. Cowan teaches that CRISPR endonuclease-mediated editing of the C9ORF72 gene was known in the art and useful in the study of amyotrophic lateral sclerosis and frontotemporal degeneration (as taught by Cowan). Given the teachings of Cowan, the compositions and methods of the instant claims are derived from obvious modifications of the copending claims. This is a provisional nonstatutory double patenting rejection. 17829206: Claim FILLIN "Pluralize \“Claim\” if necessary, insert \“is\” or \“are\” as appropriate, and insert the claim number(s) which are under rejection." s 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 171, 174, 176-178, 180, 182-190 of copending Application No. 17829206 in view of Cowan ( WO 2017109757 A1 ) . The copending claims are drawn to a system comprising a variant CasX protein of SEQ ID NO:1 38 (100% identical to instant SEQ ID NO:138) and a gRNA having a scaffold sequence at least 70% identical to SEQ ID NO:2238 (100% identical to instant SEQ ID NO:2238) (claims 171, 176, 178, 180, 182 ). The copending claims recite that the system comprises a first and a second gRNA, wherein the second gRNA has a targeting sequence complementary to a different or overlapping portion of the target gene compared to the targeting sequence of the first gRNA (claim 175 ). The copending claims recite that the CasX comprises one or more NLS at or near the N- or C-terminus of the CasX protein (claim 177 ). The copending specification describes the structure of an NLS sequence as comprising SEQ ID NOs:145-182 (paragraph [ 00289 ]). As the variant CasX protein and gRNA sequences of the copending claims fulfill the required structural limitations of the instant claims, they are considered to exhibit the improved characteristics and qualities recited in the instant claims as inherent qualities. The copending claims recite nucleic acids and vectors encoding the CasX and gRNA (claims 184-185 ). The AAV vector of copending claim 185 is considered to encompass any AAV serotype. However, the copending claims do not recite that the target sequence is comprised in a nucleic acid comprising a C9orf72 gene, as required by the instant claims. Cowan teaches a Cas9:gRNA system targeting C9orf72 . Regarding claim 1, Cowan teaches a system comprising a CRISPR endonuclease and two guide RNAs, wherein the guide RNAs target C9orf72 “in or near” the first exon, first intron, or second exon of C9orf72 (claims 1, 58-62). Regarding claim 2, Cowan teaches that the target C9orf72 gene comprises an expanded hexanucleotide repeat (claims 1, 7, 13, 18, 25), and that the expanded hexanucleotide repeat can comprise more than 30 GGGGCC repeats (paragraph [00181]). Regarding claim 11, Cowan teaches that the targeting sequence of one gRNA is SEQ ID NO:3357 (SEQ ID NO:3357 is 100% identical to instant SEQ ID NO:321, see alignment below) (page 155). Regarding claim 28, Cowan teaches that the system comprises two gRNAs, wherein both gRNAs target sequences within the C9orf72 gene, and the first and second gRNAs target different sequences (claims 1, 58-62). Regarding claim 29, Cowan teaches that the first and second gRNAs target a 5’ double-stranded break (DSB) locus and a 3’ DSB locus which flank the expanded hexanucleotide repeat (claims 58-63). Regarding claim 79, Cowan teaches a nucleic acid encoding the Cas9 endonuclease (paragraph [0049]) and gRNA (paragraph [00448]). Regarding claims 81 and 84, Cowan teaches that the Cas9-gRNA system is encoded in an AAV6 viral vector (claims 67, 71). Regarding claim 93, Cowan teaches that the Cas9-gRNA system is introduced into HEK293T cells (paragraph [00742]). Regarding claim 95, Cowan teaches a method of modifying a C9orf72 gene in a population of cells, the method comprising the steps of: introducing into the population of cells the Cas9-gRNA system; modifying the C9orf72 gene in the population of cells, wherein the modifying comprises: introducing a DSB in the C9orf72 gene and introducing a deletion in the C9orf72 gene (claims 1-3, 7). Regarding claims 112 and 115, Cowan teaches that the population of cells is a population of spinal cord motor neurons, glia, astrocytes, motor cortex neurons (paragraph [00225]). Regarding claim 147, Cowan teaches that the population of cells is modified by administering the Cas9-gRNA system (paragraph [00225]). Cowan teaches that the expanded hexanucleotide repeat in the C9ORF72 gene in the cells is corrected (claim 1). Cowan teaches that the population of cells are a population of spinal cord motor neurons, glia, astrocytes, or motor cortex neurons (paragraph [00225]). It would have been obvious to an artisan that the compositions and methods of the copending claims could be modified, by modifying the targeting sequences of the guide RNAs, to target the CasX -gRNA complex of the copending claims to different genes whose modification were desired. Cowan teaches that CRISPR endonuclease-mediated editing of the C9ORF72 gene was known in the art and useful in the study of amyotrophic lateral sclerosis and frontotemporal degeneration (as taught by Cowan). Given the teachings of Cowan, the compositions and methods of the instant claims are derived from obvious modifications of the copending claims. This is a provisional nonstatutory double patenting rejection. 17641404 : Claim FILLIN "Pluralize \“Claim\” if necessary, insert \“is\” or \“are\” as appropriate, and insert the claim number(s) which are under rejection." s 1-2, 11, 28-29, 41, 46-47, 52, 65, 79, 81, 84, 93, 95, 112, 115, 147 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 14, 21, 31, 35, 40, 46, 60, 64, 73, 97-98, 117-118, 120-121, 184, 191, 211, 215-216 of copending Application No. 17641404 in view of Cowan ( WO 2017109757 A1 ). The copending claims are drawn to a system comprising a variant CasX protein of SEQ ID NO:138 (100% identical to instant SEQ ID NO:138) and a gRNA having a scaffold sequence at least 70% identical to SEQ ID NO:2238 (100% identical to instant SEQ ID NO:2238) (claims 1, 14, 31, 40, 211, 216). The copending claims recite that the system comprises a first and a second gRNA, wherein the second gRNA has a targeting sequence complementary to a different or overlapping portion of the target gene compared to the targeting sequence of the first gRNA (claim 14). The copending claims r