CTNF 17/778,192 CTNF 100577 DETAILED ACTION 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. Applicant’s response of 01/27/2026, including replacement drawing sheets and a substitute specification, has been received and entered into the application file. Claims 3, 6, 7, 9, 12, 13, 18, 41-44, 47, 50, 52, 53, 57, 62, 68, and 72-74 were amended in the claim set filed 01/27/2026. Claims 2, 4, 5, 8, 10, 11, 14-16, 19-40, 45, 48, 49, 51, 54-56, 58-61, 63-67, 69, 70, and 75 were canceled in the claim set filed 01/27/2026. New claims 76-89 were added in the claim set filed 01/27/2026. Claims 1, 3, 6, 7, 9, 12, 13, 17, 18, 41-44, 46, 47, 50, 52, 53, 57, 62, 68, 71-74, and 76-89 are pending. All previously withdrawn claims were canceled in the amended claim set filed 01/27/2026. Accordingly, claims 1, 3, 6, 7, 9, 12, 13, 17, 18, 41-44, 46, 47, 50, 52, 53, 57, 62, 68, 71-74, and 76-89 are pending and under consideration. Election/Restrictions Applicant previously elected Group I (claims 1, 3, 6, 7, 9, 12, 13, 17, 18, 41-47, 50, 52, 53, 57, 62, 68, and 71-74) in the reply filed on 08/15/2025. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). 08-06 AIA Claim s 2, 19-21, 24, 25, 29-31, 35, 39, 45, 63, 65, and 66 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/15/2025. These previously withdrawn claims were subsequently canceled in the reply filed 01/27/2026 . Accordingly, claims 1, 3, 6, 7, 9, 12, 13, 17, 18, 41-44, 46, 47, 50, 52, 53, 57, 62, 68, 71-74, and 76-89 are pending and under consideration. Status of Prior Objections/Rejections RE: Specification ►The disclosure was previously objected to for various informalities. The substitute specification filed 01/27/2026 has obviated most, but not all of the objections of record. Those objections not repeated below are hereby withdrawn . RE: Drawings ►The drawings were previously objected to for various informalities. The replacement drawing sheets filed 01/27/2026 has obviated most, but not all of the objections of record. Those objections not repeated below are hereby withdrawn . RE: Nucleotide and/or Amino Acid Sequence Disclosures ►The drawings were previously indicated to contain nucleotide sequences that were not identified by sequence identifiers in accordance with 37 CFR 1.821(d). The amendments reflected in the substitute specification filed 01/27/2026 have obviated the basis of the objection of record, which is hereby withdrawn . However, the Examiner notes that the sequence listing filed 01/30/2026 is defective, as set forth below. RE: Claim Objections ►Claims 3, 12, 41, 50, 57, 68, 72, and 74 were previously objected to for various minor informalities. The amended claim set filed 01/27/2026 has obviated the basis of the objections of record. The objections of record are hereby withdrawn . However, new grounds of objection are set forth below. RE: Claim Rejections - 35 USC § 112 ►Claims 3, 7, 9, 13, 47, 50, 52, 53, 57, 68, and 72 were previously 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 amended claim set filed 01/27/2026 has obviated the basis of the rejections of record. The rejections of record are hereby withdrawn . However, new grounds of rejection necessitated by amendment are set forth below . RE: Double Patenting ►Claims 1, 6, 68, and 72 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39, 47, and 49 of copending Application No. 18/249,865 (corresponds to US 2023/0383272 A1) (reference application) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022). Although the claims at issue are not identical, they are not patentably distinct from each other. ►Claims 1, 3, 6, 7, 41, 68, 72, and 73 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37, 39, 40, 42, and 45-48 of copending Application No. 18/271,684 (corresponds to US 2024/0084332 A1) (reference application) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022). Although the claims at issue are not identical, they are not patentably distinct from each other. ►Claims 1, 3, 6, 7, 9, 13, and 41 were previously provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7, 11, and 19 of copending Application No. 18/276,471 (corresponds to US 2024/0132916 A1) (reference application) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022). Although the claims at issue are not identical, they are not patentably distinct from each other. Applicant’s reply asserts that the cited co-pending applications have a later patent term filing date. Accordingly, where these provisional obviousness-type double patenting rejections are the last remaining rejections, then the provisional rejections should be withdrawn per MPEP § 804(I)(B)(1)(b). In response, the provisional obviousness-type double patenting rejections are not the last remaining rejections (as set forth below). However, in view of Applicant’s traversal of the 35 USC § 103 rejections of record set forth below, new grounds of rejection are set forth below . RE: Claim Rejections - 35 USC § 103 ►Claims 1, 6, 13, 18, 42, 47, 50, 52, and 62 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022). Applicant has traversed the rejection of record, asserting that the disclosure of Bibillo is mischaracterized, specifically that the assertion that “Bibillo discloses a non-naturally occurring or otherwise modified non-LTR retrotransposon (such as R2) fused to another protein, such as the site-specific nuclease Cas9 or a functional variant thereof (paragraphs [0145], [0125], [0158], and [0220])” is demonstrably incorrect. Applicant asserts that while Bibillo does disclose fusion polypeptides, the disclosure of possible fusion partners encompasses a virtually unlimited scope and does not provide motivation to specifically fuse R2 to Cas9 for the purpose of genome editing. In response, this is found persuasive . The rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claims 3, 9, 17, 43, 44, and 46 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) as applied to claim 1 above, and further in view of Christensen and Eickbush, 2005 and Eickbush and Eickbush, 2015. As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claims 3, 9, 17, 43, 44, and 46 all directly or indirectly depend. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claims 68, 71, and 72 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) and Christensen and Eickbush, 2005. Applicant has successfully traversed the rejection of record. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claim 7 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) as applied to claim 1 above, and further in view of Maizels and Davis, 2018. As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claim 7 directly depends. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claim 12 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) as applied to claim 1 above, and further in view of Yang et al., 1999. As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claim 12 directly depends. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claim 41 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) as applied to claim 1 above, and further in view of Kapitonov et al., 2016. As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claim 41 directly depends. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claims 53 and 57 were previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) as applied to claim 52 above, and further in view of Jiang and Doudna, 2017. As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claims 53 and 57 indirectly depend. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claim 73 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) and Christensen and Eickbush, 2005 as applied to claim 68 above, and further in view of WO 2018/111944 A1 (hereinafter Schuijers). As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claim 73 indirectly depends. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . ►Claim 74 was previously rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0071711 A1 (hereinafter Bibillo; as cited in the IDS filed 05/19/2022) in view of US 2012/0042411 A1 (hereinafter Malcuit; as cited in the IDS filed 05/19/2022) and Christensen and Eickbush, 2005 as applied to claim 68 above, and further in view of Jiang and Doudna, 2017. As set forth above, Applicant has persuasively traversed the rejection of independent claim 1, from which claim 74 indirectly depends. Accordingly, the rejection of record is hereby withdrawn . However, new grounds of rejection are set forth below . New/Maintained Grounds of Objection/Rejection Specification 07-29 AIA The disclosure is objected to because of the following informalities: The brief description of Figure 13 (paragraph [0032]) includes a typographical error when stating “the R2bm proteinexhibits reverse transcriptase activity” (bolded emphasis added). It would be remedial to update the language of the instant specification to correct this typographical error by inserting a space to properly separate “protein” and “exhibits.” The brief description of Figure 28 (paragraph [0047]) includes a grammatical and/or linguistic informality when disclosing that Figure 28 “includes results evaluating whether R2tg retrotransposon activity in an assay for pSR125 and pSR126,” which is unclear. The phrase “whether R2tg retrotransposon activity” is nonsensical and does not convey any meaningful information to someone of ordinary skill in the art. It would remedial to update the language of the instant specification to comport with grammatical and/or linguistic conventions, for example by disclosing “whether R2tg exhibits retrotransposon activity…” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting . Appropriate correction is required. 06-31 AIA The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification. Drawings 06-22 AIA The drawings are objected to because : Figure 22 of the replacement drawing sheets filed 01/27/2026 includes a screen capture of image manipulation tools (specifically the icons for altering image size and rotating the image) in the image of HA-GFP-R2. It would be remedial to remove the capture of these tools . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Nucleotide and/or Amino Acid Sequence Disclosures REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; ii) the date of creation; and iii) the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.821 - 1.825. This application contains a “Sequence Listing” as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)). A copy of the "Sequence Listing" in computer readable form (CRF) has been submitted; however, the content of the CRF does not comply with one or more of the requirements of 37 CFR 1.822 through 1.824, as indicated in the "Error Report" that indicates the "Sequence Listing" could not be accepted. Refer to attachment or document "Computer Readable Form (CRF) for Sequence Listing – Defective" dated 01/30/2026. Required response – Applicant must provide: A replacement "Sequence Listing" part of the disclosure, as described above in item 1); together with An amendment specifically directing its entry into the application in accordance with 37 CFR 1.825(b)(2); A statement that the "Sequence Listing" includes no new matter as required by 37 CFR 1.825(b)(5); and A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4). If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide: A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation-by-reference paragraph, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter and An amendment to the specification to remove the “Sequence Listing previously submitted as a PDF file (37 CFR 1.821(c)(2)) or as physical sheets of paper (37 CFR 1.821(c)(3)) If the replacement "Sequence Listing" part of the disclosure is submitted according to item 1) c) or d) above, Applicant must also provide: A CRF in accordance with 1.821(e)(1) or 1.821(e)(2) as required by 37 CFR 1.825(b)(6)(ii); and Statement according to item 2) a) or b) above. Claim Objections Claims 1, 12, 18, 42-44, 57, 62, 78, 81, 82, 84, and 89 are objected to because of the following informalities: Claims 1 and 89 are objected to for reciting a composition and a method (respectively), wherein the components of each are separated by including periods indicating each component or step “a.”, “b.”, “c.”, and so on and so forth. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck , 36 USPQ2d 1211 (D.D.C. 1995)”. It would be remedial to replace “a.”, “b.”, “c.”, etc. with “a)”, “b)”, “c)”, etc. With regard to amended claim 1, various spaces are underlined at components b and c. These underlined spaces do not appear to reflect claim amendments, as these spaces were present in the previously-filed claim set of 08/15/2025. They also do not appear to serve any particular grammatical function in the claim. For purposes of maintaining the integrity of the electronic file, it would be remedial to ensure that the claim set accurately reflects amendments made throughout prosecution. With regard to amended claim 12, which recites “the composition of claim 1, wherein the at least one of: the nuclease domain(s), and/or a homing domain of the non-LTR retrotransposon polypeptide is /are inactivated” (bolded emphasis added) this recitation is replete with grammatical and/or linguistic informalities. It would be remedial to amend the instant claim language such that it comports with standard grammatical and/or linguistic conventions, for example by reciting “the composition of claim 1, wherein at least one of the nuclease domain(s) and/or a homing domain of the non-LTR retrotransposon polypeptide is/are inactivated.” This is merely an example set forth by the Examiner and is not intended to be limiting. Applicant is invited to amend the instant claim language to more clearly convey the subject matter claimed therein. With regard to amended claim 42, which recites “the polynucleotide encoding a the retrotransposon RNA is operably linked to comprises a pol2 promoter, a pol3 promoter, or a T7 promoter” (bolded emphasis added), this recitation is replete with grammatical and/or linguistic informalities. It would be remedial to amend the instant claim language such that it comports with standard grammatical and/or linguistic conventions, for example by reciting “the polynucleotide encoding the retrotransposon RNA is operably linked to or comprises a pol2 promoter, a pol3 promoter, or a T7 promoter” (bolded emphasis added). This is merely an example set forth by the Examiner and is not intended to be limiting. Applicant is invited to amend the instant claim language to more clearly convey the subject matter claimed therein. With regard to amended claim 43, which recites “the composition of claim 7, wherein a the 3’ end of the retrotransposon RNA is complementary to the target nucleotide sequence, specifically to a portion of a the nicked target nucleotide sequence that is exposed upon nicking by the site-specific nuclease polypeptide” (bolded emphasis added), this recitation is replete with grammatical and/or linguistic informalities. It would be remedial to amend the instant claim language such that it comports with standard grammatical and/or linguistic conventions, for example by removing the phrase “a the.” With regard to amended claim 44, which recites “the composition of claim 1, further comprising an RNaseH RNaseH ” (bolded emphasis added), it appears that Applicant unintentionally incorporated a typographical error in reciting RNaseH twice. It would be remedial to amend the instant claim language such that RNaseH is only recited once. With regard to amended claim 57, which recites “the homology sequence [of the composition of claim 52] is on a region on a strand that binds to the guide” (bolded emphasis added), the Examiner notes that the amended limitation of the homology sequence being “on” a strand that binds to the guide is both inconsistent with scientific principles and inconsistent with the claim language of the remainder of the instant claim set. For example, instant claim 53 recites “the homology sequence is of a region on a strand of the target sequence…” (bolded emphasis added), which is consistent with scientific principles and with the reminder of the instant claim set. For purposes of examination and in the interest of compact prosecution, the Examiner has interpreted instant claim 57 to recite “the homology sequence [of the composition of claim 52] is of a region on a strand that binds to the guide” (bolded emphasis added). It would be remedial to amend the instant claim language such that it is clear what Applicant is reciting throughout the instant claim set. With regard to claim 62, which recites “the composition of claim 1, wherein the donor polynucleotidesequence potion of the retrotransposon RNA…” (bolded emphasis added), it appears that Applicant unintentionally incorporated a typographical error by omitting a space between “polynucleotide” and “sequence.” It would be remedial to amend the instant claim language such that there is a space properly separating “polynucleotide” and “sequence.” Furthermore, with regard to claims 18 and 62, both of these claims recite poly-A tails, wherein claim 18 recites a “poly-(A) tail” at line 2 and claim 62 recites “a poly(A) tail” at line 2. For purposes of internal consistency, it would be remedial to recite the claimed poly-A tails consistently. With regard to new claim 78, as set forth regarding amended claim 1 above, a space is underlined at line 2 of new claim 78. However, as claim 78 is a new claim, these underlined spaces cannot be considered to reflect claim amendments, nor do they appear to serve any particular grammatical function in the claim. For purposes of maintaining the integrity of the electronic file, it would be remedial to ensure that the claim set accurately reflects amendments made throughout prosecution. With regard to new claim 81, which recites “ a RNA-DNA duplex” (bolded emphasis added), the article “a” is grammatically improper when preceding words articulated with an initial vowel sound. While “RNA” is spelled such that it recites a consonant letter “R,” the pronunciation of the letter “R” in “RNA” nonetheless begins with a vowel sound. It would be remedial to amend the instant claim language to be grammatically proper. With regard to new claim 82, which recites “the region comprises a sequence of 10 nucleotide from the 3’ side of the RNA-DNA duplex” (bolded emphasis added), this recitation does not comport with standard grammatical conventions. In order to comport with standard grammatical conventions, it would be remedial to amend the instant claim language to recite “10 nucleotide s ” (bolded emphasis added). With regard to new claim 84, which recites a preamble of “the composition of 83…,” this preamble does not invoke a claim from which claim 84 depends. It would be remedial to amend the instant claim language such that claim 84 explicitly recites a preamble of “the composition of claim 83” (bolded emphasis added). Finally, with regard to new claim 89, as set forth regarding amended claim 1 above, various spaces are underlined throughout new claim 89. However, as claim 89 is a new claim, these underlined spaces cannot be considered to reflect claim amendments, nor do they appear to serve any particular grammatical function in the claim. For purposes of maintaining the integrity of the electronic file, it would be remedial to ensure that the claim set accurately reflects amendments made throughout prosecution. Additionally, claim 89 recites components a. through f., wherein each component is separated by either a comma or a semicolon. For purposes of internal consistency, it would be remedial to separate all components with a semicolon, as at instant claim 1. Appropriate correction is required. While the Examiner has noted the informalities that most impact claim interpretation, the list above is not an exhaustive list of every minor informality. It would be remedial to review the entire claim set to ensure the language comports with standard grammatical and/or linguistic conventions. 07-05-05 Applicant is advised that should claim 83 be found allowable, claim 84, which recites identical limitations to that of claim 83, will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). Claim Rejections - 35 USC § 112(a) 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, 6-7, 9, 12-13, 17-18, 41-44, 46-47, 50, 52-53, 57, 62, 68, 71-74, and 76-89 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 1 (from which all other claims directly or indirectly depend or otherwise incorporate all the limitations thereof) is drawn to a non-naturally occurring composition comprising a site-specific nuclease polypeptide (or a polynucleotide comprising a coding sequence thereof) and a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence of a target polynucleotide, among other components. The rejected claims thus comprise a set of site-specific nucleases that require a guide molecule capable of forming a complex with said site-specific nucleases for purposes of directing site-specific binding to a target sequence of a target polynucleotide. However, while the instant claim language encompasses any site-specific nuclease, not all site-specific nucleases require such a guide molecule. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes experimentation with CRISPR site-specific nucleases (paragraphs [0793]-[0799]; Figure 33). While the specification contemplates other site specific nucleases, such as zinc finger nucleases or TALE systems (paragraphs [0213]-[0234]), neither of which require a guide molecule (reviewed in Kim and Kini, 2017), no description is provided of the use of such site specific nucleases in the instantly claimed composition or method, both of which require a guide molecule, as set forth above. Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of CRISPR site-specific nuclease-mediated editing, as facilitated by a guide molecule. The results are not necessarily predictive of any site-specific nuclease, as many site-specific nucleases do not require a guide molecule (i.e. ZFN or TALE systems, as set forth above). Thus, it is impossible for one to extrapolate from the CRISPR examples described herein those site-specific nucleases that would necessarily meet the structural/functional characteristics of the rejected claims, as only CRISPR site-specific nucleases require guide molecules to target a site of interest (reviewed in Kim and Kini, 2017). The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of non-CRISPR site-specific nucleases that require a guide molecule, as is instantly claimed. Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1, 3, 6-7, 9, 12-13, 17-18, 41-44, 46-47, 50, 52-53, 57, 62, 68, 71-74, and 76-89. 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 Claims 76-78 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. With regard to new claim 76, which depends from amended instant claim 3 reciting a composition, claim 76 recites a method in its preamble. It is thus unclear and indefinite from which claim new claim 76 depends and whether claim 76 is drawn to a method or a composition, as there is insufficient antecedent basis for the recitation of a method. For purposes of examination, the Examiner considers that new claim 76 is drawn to a composition and recites “the composition of claim 3 , wherein the retrotransposon RNA…” (bolded and underlined emphasis added). New claim 77 directly depends from claim 76 and does not resolve the basis of the rejection set forth above, as new claim 77 also recites a method in its preamble. Thus, for purposes of examination, the Examiner considers that new claim 77 is drawn to a composition and recites “the composition of claim 76, wherein the binding element…” (bolded and underlined emphasis added). It would be remedial to amend the instant claims to establish proper subject matter and dependency of the recited claims. With regard to new claim 78, which depends from amended instant claim 7 reciting a composition, claim 78 recites a method in its preamble. It is thus unclear and indefinite from which claim new claim 78 depends and whether claim 78 is drawn to a method or a composition, as there is insufficient antecedent basis for the recitation of a method. For purposes of examination, the Examiner considers that new claim 78 is drawn to a composition and recites “the composition of claim 7, wherein the site-specific nuclease…” (bolded and underlined emphasis added). It would be remedial to amend the instant claims to establish proper subject matter and dependency of the recited claims. Claim Rejections - 35 USC § 112(d) 07-36 AIA 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. 07-36-01 AIA Claim 86 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 86 depends from claim 13, which recites “the non-LTR retrotransposon polypeptide is R2.” In comparison, claim 86 recites “the R2 [of claim 13] is selected from Bombyx mori , Clonorchis sinensis , or Zonotrichia albicollis , or wherein the non-LTR retrotransposon is L1 ” (bolded emphasis added). Thus, there are two interpretations of claim 86: one in which the R2 of claim 13 is further limited to certain species, and one in which the R2 of claim 13 is not part of the claim, as the non-LTR retrotransposon is instead limited to L1, which is a separate and distinct retrotransposon from R2. Accordingly, in one interpretation of claim 86, it cannot be considered that claim 86 includes all the limitations of claim 13, as claim 13 requires an R2 retrotransposon, while claim 86 may be interpreted to require only an L1 retrotransposon . 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. Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15-03-aia AIA Claim s 1, 3, 6, 7, 9, 13, 52, 68, 76, 86, and 89 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019) . With regard to claim 1, which recites “an engineered or non-naturally occurring composition comprising: a site-specific nuclease polypeptide, or a polynucleotide comprising a coding sequence thereof; a non-LTR retrotransposon polypeptide connected to or otherwise capable of forming a complex with the site-specific nuclease polypeptide or a polynucleotide comprising a coding sequence thereof; a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence of a target polynucleotide; and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA comprises or encodes a donor polynucleotide,” Izhar discloses a gene editing composition (abstract) comprising at least one fusion protein, itself comprising a retrotransposon-encoded protein portion linked to a CRISPR nuclease portion (i.e. Cas9 (paragraph [0086])), as well as an RNA template molecule comprising an insert template sequence (between 10 and 10,000 nucleotides in length (paragraph [0047])) and a guide portion (abstract; paragraphs [0014] and [0023]). Izhar explicitly discloses that the fusion protein of the gene editing composition taught therein comprises a CRISPR nuclease (i.e. SpCas9) protein portion (with wild-type nuclease, catalytically inactive nuclease, or nickase activity) linked to a retrotransposon-encoded protein portion derived from R2 (and which may encode the full native protein) (paragraphs [0009], [0010], [0043], and [0132]). Thus, Izhar discloses each and every limitation of instant claim 1. With regard to claim 3, which recites “the retrotransposon RNA [of the composition of claim 1] is capable of forming a complex with the non-LTR retrotransposon polypeptide,” as set forth above, Izhar discloses a gene editing composition (abstract) comprising an RNA template molecule comprising an insert template sequence and a guide portion (abstract; paragraphs [0014] and [0023]). The RNA template molecule of Izhar is further disclosed to comprise a portion required for binding a retrotransposon-encoded protein, such as an R2 protein binding site or an L1 protein binding site (paragraph [0021]). Thus, Izhar discloses each and every additional limitation of instant claim 3. With regard to claim 6, which recites “the donor polynucleotide [of the composition of claim 1] is configured for insertion at, or adjacent to, the target nucleotide sequence,” Izhar further discloses that the RNA template taught therein encodes a sequence for reverse transcription and insertion of the reverse transcribed sequence into the genomic target site (paragraph [0014]). Thus, Izhar discloses each and every additional limitation of instant claim 6. With regard to claim 7, which recites “the site-specific nuclease polypeptide [of the composition of claim 1[ is a nickase, or wherein the site-specific nuclease polypeptide lacks endonuclease activity,” as set forth above, Izhar explicitly discloses that the fusion protein of the gene editing composition taught therein comprises a CRISPR nuclease (i.e. SpCas9) protein portion (with wild-type nuclease, catalytically inactive nuclease, or nickase activity) linked to a retrotransposon-encoded protein portion derived from R2 (and which may encode the full native protein) (paragraphs [0009], [0010], [0043], and [0132]). Thus, Izhar discloses each and every additional limitation of instant claim 7. With regard to claim 9, which recites “the non-LTR retrotransposon polypeptide [of the composition of claim 1] is a dimer, wherein the dimer subunits are connected or form a tandem fusion,” Izhar further discloses that the gene editing composition taught therein may further comprise an additional retrotransposon-encoded protein capable of forming a dimer with the retrotransposon-encoded protein of the first fusion protein, and wherein the additional retrotransposon-encoded protein is fused to the retrotransposon-encoded protein portion of the first fusion protein (paragraph [0120]). Thus, Izhar discloses each and every additional limitation of instant claim 9. With regard to claim 13, which recites “the non-LTR retrotransposon polypeptide [of the composition of claim 1] is R2,” as set forth above, Izhar explicitly discloses that the fusion protein of the gene editing composition taught therein comprises a CRISPR nuclease (i.e. SpCas9) protein portion (with wild-type nuclease, catalytically inactive nuclease, or nickase activity) linked to a retrotransposon-encoded protein portion derived from R2 (and which may encode the full native R2 protein) (paragraphs [0009], [0010], [0043], and [0132]). Thus, Izhar discloses each and every additional limitation of instant claim 13. With regard to claim 52, which recites “the donor polynucleotide [of the composition of claim 1] comprises a homology sequence of the target sequence,” as set forth above, Izhar discloses a gene editing composition (abstract) comprising an RNA template molecule comprising an insert template sequence and a guide portion (abstract; paragraphs [0014] and [0023]). The RNA template molecule of Izhar is further disclosed to comprise one or two homology arms that share homology with a target locus of a eukaryotic cell (paragraph [0014]). Thus, Izhar discloses each and every additional limitation of instant claim 52. With regard to claim 68, which recites “a method of inserting a donor polynucleotide sequence into a target comprising: introducing the engineered or non-naturally occurring composition of claim 1 to a cell or population of cells, wherein the complex of the site-specific nuclease polypeptide and the guide directs the non-LTR retrotransposon polypeptide to the target sequence, and wherein the non-LTR retrotransposon polypeptide inserts the donor polynucleotide encoded by the retrotransposon RNA at, or adjacent to, the target sequence,” as set forth above, Izhar anticipates the non-naturally occurring composition of claim 1. Izhar further disclose that the composition taught therein may be used in a method of altering a target nucleic acid sequence in a cell, said method comprising introducing the fusion protein taught therein (and set forth above), an RNA template as taught therein, and an RNA guide molecule to guide the CRISPR nuclease of the fusion protein to the targeted genomic locus (paragraphs [0021]-[0024]). Upon introduction of said composition, the RNA guide molecule guides the CRISPR nuclease of the fusion protein to the targeted genomic locus, after which the RNA insert template is reverse transcribed and inserted into the targeted genomic locus (paragraphs [0021]-[0024]). Thus, Izhar discloses each and every limitation of instant claim 68. With regard to claim 76, which recites “the retrotransposon RNA [of the composition of claim 3 (see section Claim Rejections - 35 USC § 112(b) )] comprises a binding element capable of binding to the non-LTR retrotransposon polypeptide,” as set forth above, Izhar discloses a gene editing composition (abstract) comprising an RNA template molecule comprising an insert template sequence and a guide portion (abstract; paragraphs [0014] and [0023]). The RNA template molecule of Izhar is further disclosed to comprise a portion required for binding a retrotransposon-encoded protein, such as an R2 protein binding site or an L1 protein binding site (paragraph [0021]). Thus, Izhar discloses each and every additional limitation of instant claim 76. With regard to claim 86, which recites “the R2 [of the composition of claim 13] is selected from Bombyx mori …or wherein the non-LTR retrotransposon polypeptide is L1,” as set forth above, Izhar explicitly discloses that the fusion protein of the gene editing composition taught therein comprises a CRISPR nuclease (i.e. SpCas9) protein portion (with wild-type nuclease, catalytically inactive nuclease, or nickase activity) linked to a retrotransposon-encoded protein (paragraphs [0009], [0010], [0043], and [0132]). Izhar further discloses that the retrotransposon taught therein may be an L1 retrotransposon (paragraphs [0010] and [0018]). Thus, Izhar discloses each and every additional limitation of instant claim 86. With regard to claim 89, which recites “the donor polynucleotide [of the method of claim 68]: introduces one or more mutations into the target polynucleotide, preferably, wherein the one or more mutations includes substitutions, deletions, and/or insertions, inserts a functional gene or gene fragment at the target polynucleotide sequence, corrects or introduces a premature stop codon in the target polynucleotide; disrupts or restores a splice site in the target polynucleotide, causes a shift in the open reading frame of the target polynucleotide; or a combination thereof,” as set forth above regarding instant claim 68, Izhar anticipates the non-naturally occurring composition of claim 1. Izhar further disclose that the composition taught therein may be used in a method of altering a target nucleic acid sequence in a cell, said method comprising introducing the fusion protein taught therein (and set forth above), an RNA template as taught therein, and an RNA guide molecule to guide the CRISPR nuclease of the fusion protein to the targeted genomic locus (paragraphs [0021]-[0024]). Upon introduction of said composition, the RNA guide molecule guides the CRISPR nuclease of the fusion protein to the targeted genomic locus, after which the RNA insert template is reverse transcribed and inserted into the targeted genomic locus (paragraphs [0021]-[0024]). Thus, Izhar discloses each and every limitation of instant claim 89 . 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. 07-20-02-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. 07-22-aia AIA Claim s 12, 18, 42, 44, 47, 50, 62, 71-73, 76, 77, and 83-87 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019) as applied to claim s 1, 3, 13, 52, and 68 above, and further in view of US 2020/0109398 A1 (hereinafter Rubens; filed 12/6/2019) . The disclosure of Izhar is described above and applied as before (see section Claim Rejections - 35 USC § 102 ). However, this disclosure does not teach the additional limitations of instant claims 12, 18, 42, 44, 47, 50, 62, 71-73, 76, 77, and 83-87. With regard to claim 12, which recites “the composition of claim 1, wherein the at least one of: nuclease domain(s), and/or a homing domain of the non-LTR retrotransposon polypeptide is/are inactivated,” as set forth above, Izhar anticipates the composition of instant claim 1. However, Izhar does not disclose that at least one of the claimed non-LTR retrotransposon domains is/are inactivated, as instantly claimed. This deficiency is cured by Rubens. Rubens also discloses methods and compositions for modulating a target genome (abstract), said compositions including the Gene Writer™ protein, which comprises a polypeptide (or a nucleic acid encoding the same) comprising a reverse transcriptase domain, an endonuclease domain (which may comprise a Cas9 nickase (paragraph [0105])), and a DNA binding domain (which targets different sites of the genome (paragraph [0090]; figure 3) (paragraph [0117]; figure 2). Additionally, Rubens discloses that the Gene Writer™ gene editing system comprises a template RNA (or DNA encoding the same), itself comprising a sequence that binds the polypeptide, a heterologous object sequence that encodes a therapeutic polypeptide (or a fragment or variant thereof) referred to as the payload domain for insertion into the target genome (paragraph [0178]), and a guide RNA compatible with Cas9 (paragraphs [0007], [0117], [0173], and [0274]; claim 21; figure 11). Thus, Rubens discloses a genome editing system comprising a polypeptide as set forth above, as well as at least one guide RNA compatible with site-specific nuclease Cas9 and a template RNA considered to read on the instantly claimed retrotransposon RNA comprising a donor polynucleotide. Furthermore, in Example 1, Rubens discloses that when delivering a Gene Writer™ system to a mammalian cell for site-specific insertion of exogenous DNA into a mammalian cell genome, the polypeptide component of the system (set forth above) is the R2Bm protein from Bombyx mori (paragraphs [0214]-[0215]). Rubens further discloses that the R2 provided therein may comprise a mutation in the endonuclease domain, thereby rendering the endonuclease domain inactive (Example 30). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 12. With regard to claim 18, which recites “the polynucleotide encoding the retrotransposon RNA [of the composition of claim 1] comprises a sequence encoding a poly(-A) tail,” as set forth above, Rubens discloses that the Gene Writer™ gene editing system comprises a template RNA (or DNA encoding the same), itself comprising a sequence that binds the polypeptide, a heterologous object sequence that encodes a therapeutic polypeptide (or a fragment or variant thereof) referred to as the payload domain for insertion into the target genome (paragraph [0178]), and a guide RNA compatible with Cas9 (paragraphs [0007], [0117], [0173], and [0274]; claim 21; figure 11). Rubens further discloses that the heterologous object sequence taught therein comprises a polyadenylation signal (paragraphs [0068]-[0074] and [0283]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 18. With regard to claim 42, which recites “the polynucleotide encoding…the retrotransposon RNA [of the composition of claim 1] is operably linked to [or] comprises a pol2 promoter, a pol3 promoter, or a T7 promoter,” as set forth above, Rubens discloses the instantly claimed retrotransposon RNA (paragraph [0178]). Furthermore, Rubens discloses that the heterologous object sequence of the retrotransposon RNA taught therein comprises an RNA Polymerase II or RNA polymerase III promoter driving expression of the same (paragraphs [0171] and [0172]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 42. With regard to claim 44, which recites “the composition of claim 1, further compris[es] an RNase…H,” as set forth above, Rubens discloses that the R2 element enzyme taught therein as part of the Gene Writer™ polypeptide may be derived from Bombyx mori (paragraphs [0214]-[0215]). However, Rubens also discloses that the non-LTR retrotransposon of the Gene Writer™ polypeptide taught therein may be derived from the R1 family, specifically from Blattella germanica , which comprises the mobile element ORF2, which contains an endonuclease, reverse transcriptase, and RNase H (Table 1: page 20). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 44. With regard to claims 47 and 50, which respectively recite that “the polynucleotide comprising the coding sequence of the site-specific nuclease polypeptide” or “of the non-LTR retrotransposon polypeptide” “is an mRNA,” Ruben discloses that the Genome Writer™ system taught therein may provided as a nucleic acid encoding the polypeptide of said system, wherein the term nucleic acid refers to nucleic acid species including mRNA molecules (paragraphs [0006], [0007], and [0083]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claims 47 and 50. With regard to claim 62, which recites “the donor polynucleotidesequence [sic] portion of the retrotransposon RNA [of the composition of claim 1] is an RNA comprising a poly(A) tail,” as set forth above, Rubens discloses that the Gene Writer™ gene editing system comprises a template RNA (or DNA encoding the same), itself comprising a sequence that binds the polypeptide, a heterologous object sequence that encodes a therapeutic polypeptide (or a fragment or variant thereof) referred to as the payload domain for insertion into the target genome (paragraph [0178]), and a guide RNA compatible with Cas9 (paragraphs [0007], [0117], [0173], and [0274]; claim 21; figure 11). Rubens further discloses that the heterologous object sequence taught therein comprises a polyadenylation signal (paragraphs [0068]-[0074] and [0283]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 62. With regard to claim 71, which recites “the donor polyncleotide [of the method of claim 68] is between 100 bases and 30 kb in length,” as set forth above, the template RNA of Rubens is disclosed to comprise a heterologous object sequence that encodes a therapeutic polypeptide (paragraph [0178]; Figure 11). The heterologous sequence of the template RNA is further disclosed to be between 50-30,000 base pairs (paragraph [0067], which falls within the instantly claimed range. Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 71. With regard to claim 72, which recites “the polypeptide and/or nucleic acid component(s) [of the method of claim 68] are provided via one or more polynucleotide(s) encoding the polypeptides and/or nucleic acid component(s), and wherein the one or more polynucleotide(s) are operably configured to express the polypeptides and/or nucleic acid component(s),” Rubens further discloses that the Gene Writer™ system taught therein may be delivered via viral vectors (paragraph [0285]). These vectors are disclosed to comprise nucleic acid constructs encoding the Gene Writer™ system, wherein said constructs are expressed under the control of appropriate promoters (paragraphs [0182] and [0183]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 72. With regard to claim 73, which recites “…the composition of claim 1 is delivered via liposomes, nanoparticles, exosomes, microvesicles, microinjection, a gene-gun, or one or more viral vectors,” Rubens further discloses that the Gene Writer™ system taught therein may be delivered via liposomes (paragraph [0206]) or via viral vectors (paragraph [0285]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 73. With regard to claim 76, which recites “the retrotransposon RNA [of the composition of claim 3 (see section Claim Rejections - 35 USC § 112(b) )] comprises a binding element capable of binding to the non-LTR retrotransposon polypeptide,” as set forth above, Rubens discloses the Gene Writer™ system, wherein said system further comprises a template RNA, said template RNA (or DNA encoding the same) comprising a sequence that binds the polypeptide , a heterologous object sequence that encodes a therapeutic polypeptide (or a fragment or variant thereof) referred to as the payload domain for insertion into the target genome (paragraph [0178]), and a guide RNA compatible with Cas9 (paragraphs [0007], [0117], [0173], and [0274]; claim 21; figure 11). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 76. With regard to claim 77, which recites “the binding element [of the composition of claim 76 (see section Claim Rejections - 35 USC § 112(b) )] comprises a hairpin structure,” as set forth above, the Gene Writer™ system of Rubens is taught to comprise a template RNA comprising a sequence that binds the polypeptide, such as a hairpin to interact with the protein as depicted in Figure 11. Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 77. With regard to claims 83 and 84, which recites “the non-LTR retrotransposon [of the composition of claim 9 or of claim 83] comprises a first retrotransposon polypeptide and a second retrotransposon polypeptide, wherein the second retrotransposon polypeptide comprises nuclease or nickase activity,” Rubens further discloses that some non-LTR retrotransposons utilize two subunits (paragraph [0145]). Accordingly, Rubens provides Gene Writer™ polypeptides comprising two wild-type retrotransposons (i.e. comprising endogenous nuclease activity), wherein they are joined with a linker to form a covalently “dimerized” protein (paragraphs [0104] and [0145]; Figure 17B). Thus, it is considered that Rubens discloses each and every additional limitation of instant claims 83 and 84. With regard to claim 85, which recites “the site-specific nuclease [of the composition of claim 84] is connected to the second retrotransposon polypeptide,” as set forth above, Rubens discloses that some non-LTR retrotransposons utilize two subunits (paragraph [0145]). Accordingly, Rubens provides Gene Writer™ polypeptides comprising two wild-type retrotransposons (i.e. comprising endogenous nuclease activity), wherein they are joined with a linker to form a covalently “dimerized” protein (paragraphs [0104] and [0145]; Figure 17B). While Rubens does not specifically disclose that the site-specific nuclease is connected to the second retrotransposon polypeptide, per MPEP § 2141(III), when there are a finite number of identified, predictable solutions, each with a reasonable expectation of success, it is “obvious to try” the finite number of identified, predictable solutions to arrive at the instantly claimed invention. In the instant case, while Rubens does not specifically disclose that the site-specific nuclease is connected to the second retrotransposon polypeptide, there are only two retrotransposon polypeptides in the system taught therein. One of ordinary skill in the art would not expect there to be a difference in function between connection of said site-specific nuclease to either the first or second retrotransposon polypeptide. Accordingly, one of ordinary skill in the art would reasonably be motivated to connect the site-specific nuclease to both the first and second retrotransposon polypeptide, separately, to determine which functions optimally. Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 85. With regard to claim 86, which recites “the R2 [of the composition of claim 13] is selected from Bombyx mori …or wherein the non-LTR retrotransposon is L1,” as set forth above, Rubens discloses that the R2 element enzyme taught therein as part of the Gene Writer™ polypeptide may be derived from Bombyx mori (paragraphs [0214]-[0215]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 86. With regard to claim 87, which recites “the homology sequence [of the composition of claim 52] comprises a length of 1 to 30 nucleotides, 4 to 10 nucleotides, or 10 to 25 nucleotides,” as set forth above, the template RNA of Rubens is disclosed to comprise a sequence that binds the polypeptide, a heterologous object sequence that encodes a therapeutic polypeptide (or a fragment or variant thereof) referred to as the payload domain for insertion into the target genome (paragraph [0178]), and a guide RNA compatible with Cas9 (paragraphs [0007], [0117], [0173], and [0274]; claim 21; figure 11). Furthermore, the template RNA is disclosed to comprise homology to the target DNA, wherein the template RNA comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 bases of exact homology to the target DNA at the 3’ end of the RNA and/or at the 5’ end of the RNA (paragraph [0159]). Thus, it is considered that Rubens discloses each and every additional limitation of instant claim 87. Given that Izhar discloses the composition of instant claim 1, as set forth above, and that Rubens discloses the similar Gene Writer™ system, wherein said system is modified as set forth above, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to modify the system taught in Izhar as taught in Rubens to predictably generate an effective gene-editing composition with optimized functionality, wherein said composition is capable of displaying both CRISPR nuclease target recognition specificity and target-primed reverse transcription (as disclosed in both Izhar (paragraph [0012]) and Rubens (paragraph [0118])), thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone (Izhar: paragraph [0012]). One would have been motivated to make such modifications in order to receive the expected benefit of generating an effective gene-editing composition with optimized functionality that displays reduced off-target effects relative to a CRISPR nuclease alone . 07-22-aia AIA Claim s 17 and 78 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019) as applied to claim s 1 and 7 above, and further in view of US 2020/0109398 A1 (hereinafter Rubens; filed 12/6/2019), Mita et al., 2018 (hereinafter Mita), and Ma et al., 2016 (hereinafter Ma) . The disclosure of Izhar is described above and applied as before (see section Claim Rejections - 35 USC § 102 ). However, this disclosure does not teach the nuclear localization signals of instant claims 17 and 78. With regard to claim 17, which recites “the non-LTR retrotransposon polypeptide [of the composition of claim 1] comprises a nuclear localization signal,” while Rubens discloses that the Gene Writer™ polypeptide taught therein (comprising a reverse transcriptase domain (which may be derived from R2 retrotransposons (paragraphs [0114], [0116], and [0117]; Figure 1)), an endonuclease domain (which may comprise a Cas9 nickase (paragraph [0105)) and a DNA binding domain (which targets different sites of the genome (paragraph [0090]; Figure 3))) further comprises a nuclear localization signal (paragraphs [0126] and [0127]), Rubens does not specifically disclose that the non-LTR retrotransposon polypeptide comprises said nuclear localization signal. This deficiency is cured by Mita, which discloses that nuclear localization of non-LTR retrotransposons such as the L1 retrotransposon is essential for said retrotransposon to gain access to its targeted genomic DNA (page 16, paragraph 6). Therefore, one of ordinary skill in the art would have been motivated by the disclosure of Rubens to attach a nuclear localization signal to the genome editing compositions disclosed therein (and in Izhar) to the non-LTR retrotransposons of the same (as is also in Izhar) in order to ensure that the non-LTR retrotransposon is able to gain access to its targeted genomic DNA, which is essential to its function (as disclosed in Mita). Thus, it is considered that Rubens and Mita collectively disclose and/or motivate each and every additional limitation of instant claim 17. With regard to claim 78, which recites “the site-specific nuclease polypeptide [of the method of claim 7] further comprises a nuclear localization signal,” as set forth above, while Rubens discloses that the Gene Writer™ polypeptide taught therein comprises a nuclear localization signal (paragraphs [0126] and [0127]), Rubens does not specifically disclose that the site-specific nuclease polypeptide comprises said nuclear localization signal. This deficiency is cured by Ma, which discloses that nuclear Cas9-guide RNA complex levels limit the targeting efficiency of CRISPR editing (abstract). This was determined by studying CRISPR nuclear dynamics, wherein dCas9 was fused to two nuclear localization signals (Figure 1). While Ma discloses that nuclear guide RNA concentration is a limiting factor for efficient DNA targeting (page 530, column 2, paragraph 3), Ma also discloses that Cas9 is indispensable for guide RNA stability (page 530, column 1, paragraph 2-page 530, column 2, paragraph 2). Therefore, one of ordinary skill in the art would have been motivated by the disclosure of Rubens to attach a nuclear localization signal to the genome editing compositions disclosed therein (and in Izhar) to the site-specific nucleases of the same (as is also in Izhar) in order to ensure that Cas9 is effectively and efficiently localized to the nucleus for purposes of stabilizing the requisite guide RNAs, the nuclear concentration of which is a limiting factor for efficient DNA targeting (as disclosed in Ma). Thus, it is considered that Rubens and Ma collectively disclose and/or motivate each and every additional limitation of instant claim 78. Given that Izhar discloses the composition of claim 1, as set forth above, that Rubens discloses that the Gene Writer™ polypeptide disclosed therein comprises a nuclear localization signal, and that Mita and Ma respectively disclose that nuclear localization of non-LTR retrotransposons is required for proper functioning thereof and that CRISPR editing efficiency is limited by nuclear levels of guide RNAs, which are stabilized by Cas9, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to attach a nuclear localization signal (as disclosed in Rubens) to either the non-LTR retrotransposon or site-specific nuclease polypeptide portion taught therein to predictably facilitate non-LTR retrotransposon function (as disclosed in Mita) or to stabilize nuclear guide RNAs to optimize CRISPR editing efficiency (as disclosed in Ma). One would have been motivated to make such a modification in order to receive the expected benefit of more effectively and efficiently targeting genomic DNA with the genome editing machinery of said system . 07-22-aia AIA Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019) as applied to claim 1 above, and further in view of Kapitonov et al., 2016 (hereinafter Kapitonov; of record) . The disclosure of Izhar is described above and applied as before (see section Claim Rejections - 35 USC § 102 ). However, this disclosure does not teach the IscB or TnpB site-specific nuclease polypeptide of instant claim 41. With regard to amended claim 41, which recites "the site specific nuclease polypeptide [of the composition of claim 1] is an lscB or a TnpB," as set forth above, Izhar discloses the composition of claim 1. However, Izhar does not disclose that the site-specific nuclease taught therein is an IscB or a TnpB. Kapitonov discloses that numerous distant, standalone homologs of Cas9 (specifically non-autonomous transposons) have been identified outside of CRISPR-Cas systems, said homologs possessing sequence features that are shared with Cas9, including the RuvC-like and the HNH nuclease domains (abstract; page 797, column 1, paragraph 2-page 797, column 2, paragraph 1). Such Cas9 homologs are disclosed to be lscB, which is the closest known homolog of Cas9 that is not linked to CRISR-Cas systems (figure 1; page 799, column 1, paragraph 2-page 799, column 2, paragraph 1; page 804, column 2, paragraph 2), as well as TnpB, which is thought to be the ancestral form to both lscB and Cas9 (page 806, column 1, paragraph 3). Thus, Kapitonov et al., 2016 discloses that lscB and TnpB are both Cas9 homologs comprising the RuvC-like and HNH nuclease domains found in Cas9. Given that Izhar discloses the composition of claim 1 (as set forth above) comprising a site-specific nuclease (such as Cas9 or a functional variant thereof) to guide targeted insertion of a retrotransposon RNA donor nucleic acid sequence, and that Kapitonov discloses that lscB and TnpB are both Cas9 homologs comprising the RuvC-like and HNH nuclease domains found in Cas9, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to utilize the Cas9 homolog lscB or TnpB (as disclosed in Kapitonov) as the site-specific nuclease in the composition disclosed in Izhar to predictably facilitate targeted insertion of a retrotransposon RNA donor nucleic acid sequence at a genomic locus specified by the site-specific nuclease lscB or TnpB. One would have been motivated to make such a modification in order to receive the expected benefit of inserting a donor nucleic acid sequence at a genomic locus specified by the site-specific nuclease lscB or TnpB . 07-22-aia AIA Claim s 43 and 46 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019) as applied to claim s 1 and 7 above, and further in view of Viollet et al., 2014 (hereinafter Viollet) . The disclosure of Izhar is described above and applied as before (see section Claim Rejections - 35 USC § 102 ). However, this disclosure does not teach the complementarity of the 3’ end of the retrotransposon RNA to the exposed target nucleotide sequence of instant claim 43, nor does it teach the overhang hybridization of instant claim 46. With regard to amended claim 43, which recites “the 3’ end of the retrotransposon RNA [of the composition of claim 7] is complementary to the target nucleotide sequence, specifically to a portion of a the [sic] nicked target nucleotide sequence that is exposed upon nicking by the site-specific nuclease polypeptide,” as set forth above, Izhar discloses the composition of claim 7, which comprises a nickase site-specific nuclease polypeptide fused to a non-LTR retrotransposon, a guide molecule, and a polynucleotide encoding a retrotransposon RNA (see above). Izhar explicitly discloses that the fusion proteins taught therein display target-primed reverse transcription (TPRT) activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone (paragraphs [0009]-[0013]; Example 1). However, Izhar does not teach the structural limitations of instant claim 43. This deficiency is cured by Viollet. Viollet discloses mechanisms of L1 retrotransposition (abstract), specifically the snap-velcro model of L1 reverse transcription priming (Figure 2). As depicted in Figure 2 of Viollet, the mechanism of TPRT varies between R2 and L1 retrotransposons in that R2 does not require sequence complementarity to initiate reverse transcription priming; whereas, L1 retrotransposons do require sequence complementarity to the nicked target sequence to initiate reverse transcription priming (see section “The Snap-Velcro Model of L1 Reverse Transcription Initiation”), as is instantly claimed. Thus, it is considered that Viollet discloses each and every additional limitation of instant claim 43. With regard to claim 46, which recites “the retrotransposon RNA [of the composition of claim 1] comprises a region capable of hybridizing with an overhang of the target polynucleotide,” as set forth above, while Izhar discloses the composition of instant claim 1, Izhar does not teach the structural limitations of instant claim 46. This deficiency is cured by Viollet. As set forth above, Viollet discloses mechanisms of L1 retrotransposition (abstract), specifically the snap-velcro model of L1 reverse transcription priming (Figure 2). As depicted in Figure 2 of Viollet, the mechanism of TPRT varies between R2 and L1 retrotransposons in that R2 does not require sequence complementarity to initiate reverse transcription priming; whereas, L1 retrotransposons do require sequence complementarity and hybridization to the nicked target sequence to initiate reverse transcription priming (see section “The Snap-Velcro Model of L1 Reverse Transcription Initiation”), as is instantly claimed. Thus, it is considered that Viollet discloses each and every additional limitation of instant claim 46. Given that Izhar discloses the composition of instant claims 1 and 7, said composition comprising a nickase site-specific nuclease polypeptide fused to a non-LTR retrotransposon, a guide molecule, and a polynucleotide encoding a retrotransposon RNA, and that Viollet discloses that L1 retrotransposons require sequence complementarity to the nicked target sequence in order to initiate reverse transcription priming for insertion, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the retrotransposon RNA of Izhar such that it comprises sequence complementarity to the nicked target sequence in the appropriate orientation to predictably initiate targeted insertion via reverse transcription priming. One would have been motivated to make such a modification in order to receive the expected benefit of initiating targeted insertion via reverse transcription priming, which provides a dual safety mechanism that greatly reduces off-target effects when combined with CRISPR target recognition . 07-22-aia AIA Claim s 53, 57, 74, 79-82, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019) as applied to claim s 1, 52, 53, 57, and 68 above, and further in view of Jiang and Doudna, 2017 (hereinafter Doudna; of record), as evidenced by Jiang et al., 2016 (hereinafter Jiang) . The disclosure of Izhar is described above and applied as before (see section Claim Rejections - 35 USC § 102 ). However, this disclosure does not teach the additional sequence limitations of instant claims 53, 57, 74, 79-82, and 88. With regard to claim 53, which recites “the homology sequence [of the composition of claim 52] is of a region on a strand of the target sequence that contains a PAM of the site-specific nuclease polypeptide,” as set forth above, Izhar discloses the composition of instant claim 52. Izhar further discloses that type II CRISPR systems utilize a mature crRNA:tracrRNA complex to direct a CRISPR nuclease (i.e. Cas9) to the target DNA via Watson-Crick base-pairing between the crRNA spacer and the target DNA protospacer sequence next to the PAM, which is an additional requirement for target recognition. Thus, Izhar asserts that a skilled artisan will appreciate that the guide RNA sequence is designed to associate with a target genomic DNA sequence of interest next to a PAM corresponding to the type of CRISPR nuclease utilized (paragraph [0098]). This is consistent with the teachings of Doudna. Doudna discloses that site-specific nuclease CRISPR-Cas target recognition strictly requires the presence of an associated short protospacer adjacent motif (PAM) flanking the target site (abstract; Figures 1a and 2). Therefore, one of ordinary skill in the art would certainly be aware that in order for a CRISPR system to function, the target sequence must contain a PAM of the CRISPR nuclease, as instantly claimed. Thus, Izhar and Doudna disclose each and every limitation of instant claim 53. With regard to claim 57, which recites “the homology sequence [of the composition of claim 52] is [of] a region on a strand that binds to the guide,” as set forth above, Izhar discloses the composition of instant claim 52. Furthermore, as set forth above, Doudna discloses principles by which CRISPR systems function. Doudna further discloses that Cas9 is directed to a specified sequence in the genome via a user-defined guide RNA, which contains a spacer sequence that is complementary to and hybridizes with the user-defined target sequence, thereby directing mutagenic NHEJ or knock-in via HDR when in the presence of a donor template containing a sequence of interest flanked by homology arms (Figures 1a and 2, page 508, paragraph 3). Thus, Doudna discloses that functional homology sequences for initiating HDR must be of a region on a strand that binds to the guide, as instantly claimed. It is thus considered that Doudna discloses each and every additional limitation of instant claim 57. With regard to claim 74, which recites “the donor polynucleotide [of the method of claim 68] is inserted at a region on the target sequence that is 3’ of a PAM-containing strand, or at a region on the target sequence that is 3’ of a sequence complementary to the guide molecule,” as set forth above, Izhar discloses the method of instant claim 68. While Izhar does not disclose that the donor polynucleotide is inserted at a region that is 3’ of a PAM-containing strand, as instantly claimed, this deficiency is cured by Doudna. Doudna discloses that Cas9 is directed to a specified DNA sequence in the genome via a user-defined guide RNA, which contains a spacer sequence that is complementary to and hybridizes with the user-defined targeted sequence, thereby directing mutagenic NHEJ or knock-in via HDR when in the presence of a donor template containing a sequence of interest flanked by homology arms (Figures 1 a and 2; page 508, paragraph 3). As depicted in Figure 2 of Doudna, CRISPR-Cas9-mediated knock-in via HDR results in a donor sequence being inserted 3' of a target sequence complementary to the guide molecule, as in instant claim 74. Thus, it is considered that Doudna discloses each and every additional limitation of instant claim 74. With regard to claim 79, which recites “the region [of the composition of claim 57] comprises at least a portion of a guide-binding sequence,” as set forth above, Doudna discloses principles by which CRISPR systems function. Doudna further discloses that Cas9 is directed to a specified sequence in the genome via a user-defined guide RNA, which contains a spacer sequence that is complementary to and hybridizes with the user-defined target sequence, thereby directing mutagenic NHEJ or knock-in via HDR when in the presence of a donor template containing a sequence of interest flanked by homology arms (Figures 1a and 2, page 508, paragraph 3). Thus, Doudna discloses that functional homology sequences for initiating HDR must be of a region on a strand that binds to the guide and must comprise at least a portion of a guide-binding sequence, as instantly claimed. It is thus considered that Doudna discloses each and every additional limitation of instant claim 79. With regard to claim 80, which recites “the region [of the composition of claim 79] comprises a sequence on the 3’ side of the guide binding sequence,” as set forth above, Doudna discloses principles by which CRISPR systems function. Doudna further discloses that Cas9 is directed to a specified sequence in the genome via a user-defined guide RNA, which contains a spacer sequence that is complementary to and hybridizes with the user-defined target sequence, thereby directing mutagenic NHEJ or knock-in via HDR when in the presence of a donor template containing a sequence of interest flanked by homology arms (Figures 1a and 2, page 508, paragraph 3). As shown in Figure 2 of Doudna, the homology sequence of a region on a strand that binds to the guide of the donor DNA comprises sequences flanking the insert of interest (i.e. both 5’ and 3’ of the guide binding sequence), which is inserted following cleavage at a user-specified gRNA sequence adjacent to a PAM site. Thus, it is considered that Doudna discloses each and every additional limitation of instant claim 80. With regard to claim 81, which recites “the guide molecule [of the composition of claim 79] forms a[n] RNA-DNA duplex with the target sequence, and wherein the region of the strand comprises a sequence located 5 to 15 nucleotides from the 3’ end of the RNA-DNA duplex,” as set forth above, Doudna discloses principles by which CRISPR systems function. Doudna further discloses that once Cas9 has found a target site with the appropriate PAM sequence, it triggers local DNA melting at the PAM-adjacent nucleation site, followed by RNA strand invasion to form an RNA-DNA hybrid and a displaced DNA strand termed the R-loop from PAM-proximal to PAM-distal ends (page 516, paragraph 2). As shown in Figure 4b of Doudna, this RNA-DNA hybrid is formed between the user-defined spacer of the guide sequence and the target sequence, which is consistent with the teachings of Jiang (see Figure 1B). The instant claim recites that the region of the strand comprises a sequence located 5 to 15 nucleotides from the 3’ end of the RNA-DNA duplex. The Examiner notes that the region of the strand is defined in claim 57. Claim 57 defines the region of the strand as a sequence of the target strand, the sequence of which is comprised within the homology sequence of the composition of claim 52. Thus, the region of the strand of claim 81 is interpreted to recite that the region of the targeted strand from which the homology sequence is derived must comprise a sequence located 5 to 15 nucleotides from the 3’ end of the RNA-DNA duplex. As disclosed in Doudna, CRISPR systems are designed to knock-in a sequence of interest into a targeted site of the genome and that the genome comprises nucleotides both upstream and downstream of the RNA-DNA duplex (i.e. the R-loop) (Figure 2). Thus, it is considered that there is a sequence located 5 to 15 nucleotides from the 3’ end of the RNA-DNA duplex, as instantly claimed. It is therefore considered that Doudna, as evidenced by Jiang, discloses each and every additional limitation of instant claim 81. With regard to claim 82, which recites “the region [of the composition of claim 81] comprises a sequence of 10 nucleotide[s] from the 3’ side of the RNA-DNA duplex,” as set forth above, the Examiner notes that the region of the strand is defined in claim 57. Claim 57 defines the region of the strand as a sequence of the target strand, the sequence of which is comprised within the homology sequence of the composition of claim 52. Thus, the region of the strand of claim 82 is interpreted to recite that the region of the targeted strand from which the homology sequence is derived must comprise a sequence of 10 nucleotides from the 3’ end of the RNA-DNA duplex. As set forth above, Doudna discloses that CRISPR systems are designed to knock-in a sequence of interest into a targeted site of the genome and that the genome comprises nucleotides both upstream and downstream of the RNA-DNA duplex (i.e. the R-loop) (Figure 2). Thus, it is considered that the region of the strand of claim 82 comprises a sequence of 10 nucleotides from the 3’ side of the RNA-DNA duplex. It is therefore considered that Doudna, as evidenced by Jiang, discloses each and every additional limitation of instant claim 82. With regard to claim 88, which recites “the region [of the composition of claim 53] comprises the PAM sequence or wherein the region is at the 3’ side of a cleavage site of the site-specific nuclease polypeptide,” the Examiner notes that the instant claim may be interpreted such that the only requisite limitation is that the region comprises the PAM sequence. As set forth above, Izhar further discloses that type II CRISPR systems utilize a mature crRNA:tracrRNA complex to direct a CRISPR nuclease (i.e. Cas9) to the target DNA via Watson-Crick base-pairing between the crRNA spacer and the target DNA protospacer sequence next to the PAM, which is an additional requirement for target recognition. Thus, Izhar asserts that a skilled artisan will appreciate that the guide RNA sequence is designed to associate with a target genomic DNA sequence of interest next to a PAM corresponding to the type of CRISPR nuclease utilized (paragraph [0098]). This is consistent with the teachings of Doudna. Doudna discloses that site-specific nuclease CRISPR-Cas target recognition strictly requires the presence of an associated short protospacer adjacent motif (PAM) flanking the target site (abstract; Figures 1a and 2). Therefore, one of ordinary skill in the art would certainly be aware that in order for a CRISPR system to function, the target sequence must contain a PAM of the CRISPR nuclease, as instantly claimed. Thus, Izhar and Doudna collectively disclose each and every additional limitation of instant claim 88. Given that Izhar discloses the methods and compositions of instant claims 1, 52, 53, 57, and 68 (as set forth above), and that Doudna discloses principle by which CRISPR systems function, including target sequence requirements for successful knock-in and R-loop formation as part of targeted DNA cleavage, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to design the system of Izhar, which comprises CRISPR nucleases and variants thereof, in accordance with the principles disclosed in Doudna (as evidenced by Jiang) to predictably generate a gene editing composition capable of effectively mediating targeted cleavage and knock-in at a genomic target site. One would have been motivated to make such a modification in order to receive the expected benefit of generating a gene editing composition capable of effectively mediating targeted cleavage and knock-in at a genomic target site. Double Patenting 08-33 AIA 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. Claims 1, 6, 68, and 72 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 39, 47, and 49 of copending Application No. 18/249,865 (corresponds to US 2023/0383272 A1; of record; claims amended 05/18/2026) in view of US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019). Claim 39 of copending application '865 recites an engineered, non-naturally occurring composition comprising a Cas protein, a non-LTR retrotransposon associated with the Cas protein, a single guide molecule capable of forming a complex with the Cas protein and directing site-specific binding to a target sequence, and a donor construct for insertion into the targeted sequence. Claims 47 and 49 further recite one or more polynucleotides encoding one or more components of said composition, as well as a method of using said composition to direct the non-LTR retrotransposon protein to the target sequence, thereby facilitating insertion of the donor polynucleotide sequence at the target sequence, optionally introducing one or more base edits. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide, a non-LTR retrotransposon polypeptide connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). The instant application also recites at claim 68 a method of using said engineered or non-naturally occurring composition to insert a donor polynucleotide sequence into a target polynucleotide via the guide directing the non-LTR retrotransposon polypeptide to the target sequence, after which the non-LTR retrotransposon polypeptide inserts the donor polynucleotide at or adjacent to the target sequence, thereby introducing substitution, deletion, and/or insertion mutations. These composition components are provided via one or more polynucleotides encoding said components per instant claim 72. While instant claim 1 recites that the donor polynucleotide is a component of the retrotransposon RNA taught therein, copending application '865 is silent as to the donor polynucleotide being a component of the non-LTR retrotransposon RNA. However, this deficiency is cured by Izhar, which discloses a gene editing composition (abstract) comprising at least one fusion protein, itself comprising a retrotransposon-encoded protein portion linked to a CRISPR nuclease portion (i.e. Cas9 (paragraph [0086])), as well as an RNA template molecule comprising an insert template sequence (between 10 and 10,000 nucleotides in length (paragraph [0047])) and a guide portion (abstract; paragraphs [0014] and [0023]). Per Izhar, the fusion proteins taught therein display target-primed reverse transcription (TPRT) activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone (paragraphs [0009]-[0013]; Example 1). Thus, in view of Izhar, the engineered, non-naturally occurring composition of copending claim 39 reads on the composition of instant claim 1 and 6, the components of which are recited to be encoded by polynucleotide(s) at instant claim 72 and copending claim 47. Additionally, copending claim 49 reads on the method of instant claim 68, as set forth above. Given that copending application '865 recites an engineered or non-naturally occurring composition that reads on the instantly claimed engineered or non-naturally occurring composition with the exception of the claimed donor polynucleotide being a component of the non-LTR retrotransposon RNA, and that Izhar discloses a gene editing composition comprising at least one fusion protein, itself comprising an RNA template molecule comprising an insert template sequence, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to engineer the composition of copending application '865 such that the donor polynucleotide is a component of non-LTR retrotransposon RNA (as disclosed in Izhar) to predictably insert a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site specific nuclease of the instantly claimed composition such that said composition displays TPRT activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone. One would have been motivated to make such a modification in order to receive the expected benefit of inserting a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site-specific nuclease of the instantly claimed composition in a manner that reduces off-target effects relative to a CRISPR nuclease alone. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 41, 68, 72, 73, and 89 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37, 39, 40, 42, and 45- 48 of copending Application No. 18/271,684 (corresponds to US 2024/0084332 A1; of record) in view of US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019). Claim 37 of copending application '684 recites an engineered, non-naturally occurring composition comprising a TnpB polypeptide, a non-LTR retrotransposon protein associated with said TnpB polypeptide, and an wRNA component (comprising a donor template comprising a homology region (per copending claim 42) located between two binding elements capable of forming a complex with the non-LTR retrotransposon protein) capable of forming a complex with the TnpB protein and directing site-specific binding of the complex to a target sequence of a target polynucleotide. The TnpB polypeptide taught therein may be engineered to have nickase activity per copending claim 39. Additionally, the ωRNA component molecule directs the fusion protein to a target sequence 3' of the targeted insertion site per copending claim 40. Claims 45- 48 further recite one or more polynucleotides encoding one or more components of said composition (as well as one or more vectors comprising the same), as well as a method of using said composition to direct the non-LTR retrotransposon protein to the target sequence, thereby facilitating insertion of the donor polynucleotide sequence at the target sequence and introducing one or more base edits. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (such as TpnB, as recited at instant claim 41), a non-LTR retrotransposon polypeptide connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of farming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). The site-specific nuclease polypeptide of the instant application is further recited to lack nuclease activity or be a nickase at instant claim 7. The instant application also recites at claims 68 and 89 a method of using said engineered or non-naturally occurring composition to insert a donor polynucleotide sequence into a target polynucleotide via the guide directing the non-LTR retrotransposon polypeptide to the target sequence, after which the non-LTR retrotransposon polypeptide inserts the donor polynucleotide at or adjacent to the target sequence, thereby introducing substitution, deletion, and/or insertion mutations. These composition components are provided via one or more polynucleotides encoding said components per instant claim 72. The polynucleotides encoding said components may be delivered via viral vectors comprising the same per instant claim 73. While instant claim 1 recites that the donor polynucleotide is a component of the retrotransposon RNA taught therein, copending application '684 is silent as to the donor polynucleotide being a component of the non-LTR retrotransposon RNA. However, this deficiency is cured by Izhar, which discloses a gene editing composition (abstract) comprising at least one fusion protein, itself comprising a retrotransposon-encoded protein portion linked to a CRISPR nuclease portion (i.e. Cas9 (paragraph [0086])), as well as an RNA template molecule comprising an insert template sequence (between 10 and 10,000 nucleotides in length (paragraph [0047])) and a guide portion (abstract; paragraphs [0014] and [0023]). Per Izhar, the fusion proteins taught therein display target-primed reverse transcription (TPRT) activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone (paragraphs [0009]-[0013]; Example 1). Thus, in view of Izhar, the engineered, non-naturally occurring composition of claim 37 of copending application '684 reads on the composition of instant claims 1, 3, 6, 7, and 41, the components of which are recited to be encoded by polynucleotide(s) at instant claim 72 and copending claim 45 (which may be delivered via a vector per instant claim 73 and copending claim 46). Additionally, copending claims 47 and 48 read on the method of instant claims 68 and 89, as set forth above. Given that copending application '684 recites an engineered or non-naturally occurring composition that reads on the instantly claimed engineered or non-naturally occurring composition with the exception of the claimed donor polynucleotide being a component of the non-LTR retrotransposon RNA, and that Izhar discloses a gene editing composition comprising at least one fusion protein, itself comprising an RNA template molecule comprising an insert template sequence, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to engineer the composition of copending application '865 such that the donor polynucleotide is a component of non-LTR retrotransposon RNA (as disclosed in Izhar) to predictably insert a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site specific nuclease of the instantly claimed composition such that said composition displays TPRT activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone. One would have been motivated to make such a modification in order to receive the expected benefit of inserting a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site-specific nuclease of the instantly claimed composition in a manner that reduces off-target effects relative to a CRISPR nuclease alone. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 9, 13, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7, 11, and 19 of copending Application No. 18/276,471 (corresponds to US 2024/0132916 A1; of record; claims amended 04/17/2026) in view of US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019). Claim 1 of copending application '471 recites an engineered composition comprising a site-specific nuclease (such as an lscB or a TnpB per copending claim 2), a non-LTR retrotransposon polypeptide fused to said site-specific nuclease, and a donor construct comprising a donor polynucleotide sequence for insertion into the target polynucleotide and comprising one or more elements capable of forming a complex with the non-LTR retrotransposon polypeptide. Copending claim 7 further recites that the non-LTR retrotransposon polypeptide is a dimer, wherein the dimer subunits are connected or form a tandem fusion. Copending claim 11 further recites that the non-LTR retrotransposon is R2. Finally, co pending claim 19 recites that the donor taught therein comprises first and second homology regions in addition to the donor template for insertion into the target polynucleotide. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (such as TpnB, as recited at instant claim 41), a non-LTR retrotransposon polypeptide (such as R2 as recited at instant claim 13) connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). The site-specific nuclease polypeptide of the instant application is further recited to lack nuclease activity or be a nickase at instant claim 7. Instant claim 9 further recites that the non-LTR retrotransposon polypeptide taught therein is a dimer, wherein the dimer subunits are connected or form a tandem fusion. While instant claim 1 recites that the donor polynucleotide is a component of the retrotransposon RNA taught therein, copending application '471 is silent as to the donor polynucleotide being a component of the non-LTR retrotransposon RNA. However, this deficiency is cured by Izhar, which discloses a gene editing composition (abstract) comprising at least one fusion protein, itself comprising a retrotransposon-encoded protein portion linked to a CRISPR nuclease portion (i.e. Cas9 (paragraph [0086])), as well as an RNA template molecule comprising an insert template sequence (between 10 and 10,000 nucleotides in length (paragraph [0047])) and a guide portion (abstract; paragraphs [0014] and [0023]). Per Izhar, the fusion proteins taught therein display target-primed reverse transcription (TPRT) activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone (paragraphs [0009]-[0013]; Example 1). Thus, in view of Izhar, the engineered, non-naturally occurring composition of claims 1, 2, 7, 11, and 19 of copending application '471 reads on the composition of instant claims 1, 3, 6, 7, 9, 13 and 41. Given that copending application '471 recites an engineered or non-naturally occurring composition that reads on the instantly claimed engineered or non-naturally occurring composition with the exception of the claimed donor polynucleotide being a component of the non-LTR retrotransposon RNA, and that Izhar discloses a gene editing composition comprising at least one fusion protein, itself comprising an RNA template molecule comprising an insert template sequence, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to engineer the composition of copending application '865 such that the donor polynucleotide is a component of non-LTR retrotransposon RNA (as disclosed in Izhar) to predictably insert a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site specific nuclease of the instantly claimed composition such that said composition displays TPRT activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone. One would have been motivated to make such a modification in order to receive the expected benefit of inserting a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site-specific nuclease of the instantly claimed composition in a manner that reduces off-target effects relative to a CRISPR nuclease alone. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 13, 17, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 11 of copending Application No. 18/047,685 (corresponds to US 2023/0272434 A1; claims amended 01/14/2026) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Copending claim 1 recites a genome editing system, said genome editing system comprising an R2 element enzyme comprising a nuclear localization signal and fused to a Cas9 or Cas12 protein having nickase activity, at least one guide RNA, and a payload RNA, wherein the payload RNA comprises a protein binding element and an insertion template comprising a nucleic acid sequence for insertion into a genome, as well as a Cas9 or Cas12 guide RNA comprising a 5’ and/or 3’ homology sequence. Per copending claim 11, the targeted genomic locus is a genomic locus other than a 28S rRNA locus. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide, a non-LTR retrotransposon polypeptide (such as R2 as recited at instant claim 13) connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6) that further comprises a homology sequence of the target sequence (as recited at instant claim 52). The site-specific nuclease polypeptide of the instant application is further recited to lack nuclease activity or be a nickase at instant claim 7. Instant claim 17 further recites that the non-LTR retrotransposon polypeptide comprises a nuclear localization signal. Thus, the copending and instantly claimed compositions are not patentably distinct from each other, as copending application ‘685 recites each and every limitation of instant claims 1, 3, 6, 7, 13, 17, and 52. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 41, 52, and 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 54, 55, 57, 60, 68, and 70 of copending Application No. 18/032,868 (corresponds to US 2023/0392131 A1; claims amended 01/06/2026) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Copending claim 54 recites an engineered, non-naturally occurring composition (as well as a polynucleotide encoding the same per claim 55) comprising a catalytically inactive IscB protein complexed with a reverse transcriptase and guided to a target sequence via a CRISPR-associated guide molecule further comprising a donor sequence for insertion into the target polynucleotide. Copending claim 57 recites a method of modifying target polynucleotides, said method comprising delivering the composition of claim 54 (or polynucleotides encoding the same) to a cell such that the complex directs the reverse transcriptase to the target sequence to facilitate insertion of the donor sequence from the CRISPR-associated guide molecule. Copending claim 60 also recites an engineered, non-naturally occurring composition (as well as a polynucleotide encoding the same per claim 68), said composition comprising a nickase IscB protein, a non-LTR retrotransposon protein associated or complexed with the IscB protein, a CRISPR-associated sgRNA, and a donor construct comprising a donor polynucleotide for insertion to the target polynucleotide located between two binding elements capable of forming a complex with the non-LTR retrotransposon protein and further comprising a homology region. Finally, copending claim 70 recites a method of modifying target polynucleotides, said method comprising delivering the composition of claim 60 (or polynucleotides encoding the same) to a cell such that the complex directs the non-LTR retrotransposon protein to the target sequence and the non-LTR retrotransposon protein facilitates insertion of the donor polynucleotide sequence from the donor construct into the target polynucleotide. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (such as IscB, as recited at instant claim 41; may be a nickase per instant claim 7), a non-LTR retrotransposon polypeptide connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). The site-specific nuclease polypeptide of the instant application is further recited to lack nuclease activity or be a nickase at instant claim 7. Instant claim 52 further recites that the donor polynucleotide comprises a homology sequence of the target sequence. Finally, instant claim 68 recites a method of inserting a donor polynucleotide sequence into a target, said method comprising introducing the composition of instant claim 1 to a cell, wherein the complex of the site-specific nuclease polypeptide and the guide directs the non-LTR retrotransposon polypeptide to the target sequence, and wherein the non-LTR retrotransposon polypeptide inserts the donor polynucleotide encoded by the retrotransposon RNA at or adjacent to the target sequence. Thus, the copending and instantly claimed compositions are not patentably distinct from each other, as copending application ‘868 recites each and every limitation of instant claims 1, 3, 6, 7, 41, 52, and 68. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 13, 17, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 14, 16, 33, and 35 of copending Application No. 18/301,732 (corresponds to US 2024/0035008 A1; claims amended 02/19/2026) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Copending claim 1 recites a genome editing system comprising an R2 element enzyme and a payload RNA, wherein the payload RNA comprises an insertion template for insertion into the genome and one or more of a 5’ homology region, a 3’ homology region, and a protein binding element. Per copending claims 5 and 14, the R2 element enzyme claimed therein is modified to be a fusion protein, said fusion protein comprising a Cas12 protein that is fully active or functioning as a nickase (copending claim 16). The system claimed therein further comprises a Cas9 or Cas12 guide RNA (copending claim 33). Finally, the R2 element recited therein may further comprise a nuclear localization signal per copending claim 35. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide may be a nickase per instant claim 7), a non-LTR retrotransposon polypeptide (R2 per instant claim 13) connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site- specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). The R2 retrotransposon of the instant application further comprises a nuclear localization signal per instant claim 17. Instant claim 52 further recites that the donor polynucleotide comprises a homology sequence of the target sequence. Thus, the copending and instantly claimed compositions are not patentably distinct from each other, as copending application ‘732 recites each and every limitation of instant claims 1, 3, 6, 7, 13, 17, and 52. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 41, and 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27, 29, and 37 of copending Application No. 18/717,020 (corresponds to US 2025/0034622 A1) in view of US 2022/0298495 A1 (hereinafter Izhar; effectively filed 06/12/2019). Copending claim 27 recites an engineered, non-naturally occurring composition comprising a TnpB Cas polypeptide that is catalytically inactive (or has been engineered to have nickase activity per copending claim 29) fused to a non-LTR retrotransposon polypeptide associated with or otherwise capable of forming a complex with said TnpB polypeptide, and a nucleic acid component capable of forming a complex with the Cas polypeptide and directing site-specific binding of the complex, said nucleic acid component further comprising a donor construct encoding a donor sequence for insertion into the target polynucleotide and located between two binding elements capable of forming a complex with the non-LTR retrotransposon polypeptide. Finally, copending claim 37 recites a method of modifying target polynucleotides, said method comprising delivering the composition of copending claim 29 (set forth above) to a cell such that the complex directs the non-LTR retrotransposon protein to the target sequence to facilitate insertion of the donor polynucleotide sequence from the donor construct into the target polynucleotide. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (such as TpnB, as recited at instant claim 41; may be a nickase per instant claim 7), a non-LTR retrotransposon polypeptide connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). The site-specific nuclease polypeptide of the instant application is further recited to lack nuclease activity or be a nickase at instant claim 7. Finally, instant claim 68 recites a method of inserting a donor polynucleotide sequence into a target, said method comprising introducing the composition of instant claim 1 to a cell, wherein the complex of the site-specific nuclease polypeptide and the guide directs the non-LTR retrotransposon polypeptide to the target sequence, and wherein the non-LTR retrotransposon polypeptide inserts the donor polynucleotide encoded by the retrotransposon RNA at or adjacent to the target sequence. While instant claim 1 recites that the instantly claimed composition comprises a guide molecule, copending application ‘020 is silent as to the donor polynucleotide being a component of the non-LTR retrotransposon RNA. However, this deficiency is cured by Izhar, which discloses a gene editing composition (abstract) comprising at least one fusion protein, itself comprising a retrotransposon-encoded protein portion linked to a CRISPR nuclease portion (i.e. Cas9 (paragraph [0086])), as well as an RNA template molecule comprising an insert template sequence (between 10 and 10,000 nucleotides in length (paragraph [0047])) and a guide portion (abstract; paragraphs [0014] and [0023]). Per Izhar, the fusion proteins taught therein display target-primed reverse transcription (TPRT) activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone (paragraphs [0009]-[0013]; Example 1). Thus, in view of Izhar, the engineered, non-naturally occurring composition and method of using the same of claims 27, 29, and 37 of copending application ‘020 reads on the composition and method of using the same of instant claims 1, 3, 6, 7, 41, and 68. Given that copending application ‘020 recites an engineered or non-naturally occurring composition that reads on the instantly claimed engineered or non-naturally occurring composition with the exception of the claimed guide RNA sequence, and that Izhar discloses a gene editing composition comprising at least one fusion protein, itself comprising a guide molecule, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to engineer the composition of copending application ‘020 such that the guide RNA is included as a component of the gene editing composition (as disclosed in Izhar) to predictably insert a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site specific nuclease of the instantly claimed composition such that said composition displays TPRT activity in addition to the target recognition specificity of CRISPR nucleases, thereby providing a dual safety mechanism that greatly reduces off-target effects relative to a CRISPR nuclease alone. One would have been motivated to make such a modification in order to receive the expected benefit of inserting a user-specified donor polynucleotide sequence at a targeted genomic locus specified by the site-specific nuclease of the instantly claimed composition in a manner that reduces off-target effects relative to a CRISPR nuclease alone. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, and 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12, 17, and 35 of copending Application No. 19/016,260 (corresponds to US 2025/0223577 A1; claims amended 03/31/2025) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Copending claim 1 recites a non-naturally occurring, engineered composition comprising a hybrid CRISPR-Cas polypeptide and a guide RNA molecule comprising a reprogrammable spacer sequence and being capable of forming a complex with the hybrid CRISPR-Cas polypeptide and directing the polypeptide to a target polynucleotide. Copending claims 12 and 17 further recite that the hybrid CRISPR-Cas protein further comprises a functional domain such as a non-LTR retrotransposon protein and further comprising a donor template encoding a donor polynucleotide sequence for insertion into the target polynucleotide and located between two binding elements capable of forming a complex with the non-LTR retrotransposon protein. Finally, copending claim 35 recites a method of using the composition of copending claim 17 to a cell such that the complex directs the non-LTR retrotransposon protein to the target sequence and the non-LTR retrotransposon protein facilitates insertion of the donor polynucleotide sequence from the donor construct into the target polynucleotide. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide, a non-LTR retrotransposon polypeptide connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). Finally, instant claim 68 recites a method of inserting a donor polynucleotide sequence into a target, said method comprising introducing the composition of instant claim 1 to a cell, wherein the complex of the site-specific nuclease polypeptide and the guide directs the non-LTR retrotransposon polypeptide to the target sequence, and wherein the non-LTR retrotransposon polypeptide inserts the donor polynucleotide encoded by the retrotransposon RNA at or adjacent to the target sequence. Thus, the copending and instantly claimed compositions are not patentably distinct from each other, as copending application ‘260 recites each and every limitation of instant claims 1, 3, 6, and 68. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 6, and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22 and 25 of copending Application No. 18/712,779 (corresponds to US 2026/0117211 A1; claims amended 03/31/2025) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Copending claim 22 recites and engineered, non-naturally occurring composition (encoded by one or more polynucleotides per copending claim 25) comprising an IscB polypeptide, a non-LTR retrotransposon protein associated with or otherwise capable of forming a complex with the IscB polypeptide, and a ωRNA molecule capable of forming a complex with the IscB polypeptide and directing site-specific binding of the complex to a target sequence of a target polynucleotide, wherein the ωRNA molecule further comprises a donor template encoding a donor sequence for insertion into the target polynucleotide. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (such as IscB per instant claim 41), a non-LTR retrotransposon polypeptide connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). Thus, the copending and instantly claimed compositions are not patentably distinct from each other, as copending application ‘779 recites each and every limitation of instant claims 1, 6, and 41. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 1, 3, 6, 7, 13, 52, and 68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 13, 20, 24, and 44 of copending Application No. 19/333,523 (corresponds to US 2026/0008827 A1; claims amended 12/02/2025) (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. Copending claim 1 recites an engineered or non-naturally occurring composition for targeted transposition of a donor polynucleotide into a target polynucleotide, said composition comprising a programmable DNA-binding protein configured to bind a target sequence with a target polynucleotide (i.e. a Cas nickase per copending claim 2), a non-LTR retrotransposon (R2 per copending claims 13 and 20) fused to or otherwise capable of associating with the programmable DNA-binding protein, and a donor construct comprising a donor polynucleotide for insertion into the target polynucleotide and an engineered binding element capable of forming a complex with the non-LTR retrotransposon polypeptide. Per copending claim 2, when the programmable DNA-binding protein is a CRISPR-Cas system comprising a Cas protein, the composition further comprises one or more guide molecules capable of forming a complex with the Cas protein and directing sequence-specific binding of the complex to the target sequence within the target polynucleotide. Furthermore, per copending claim 24, the donor construct comprises a donor polynucleotide further comprising a first homology region, a donor template for insertion into the target polynucleotide, and a second homology region. Finally, copending claim 44 recites a method of using the composition of claim 1, said method comprising introducing the composition of copending claim 1 into a cell, wherein the programmable DNA-binding protein directs the non-LTR retrotransposon polypeptide to the target sequence within the target polynucleotide, and the non-LTR retrotransposon polypeptide inserts the donor polynucleotide into the target polynucleotide at or adjacent to the target sequence. In comparison, instant claim 1 recites an engineered or non-naturally occurring composition comprising a site-specific nuclease polypeptide (which may be a nickase per instant claim 7), a non-LTR retrotransposon polypeptide (such as R2 per instant claim 13) connected to the site-specific nuclease polypeptide, a guide molecule capable of forming a complex with the site-specific nuclease polypeptide and directing site-specific binding to a target sequence, and a polynucleotide encoding a retrotransposon RNA, wherein the retrotransposon RNA is capable of forming a complex with the non-LTR retrotransposon polypeptide (as recited at instant claim 3) and comprises or encodes a donor polynucleotide for insertion at a target sequence (as recited at instant claim 6). Furthermore, instant claim 52 recites that the donor polynucleotide comprises a homology sequence of the target sequence. Finally, instant claim 68 recites a method of inserting a donor polynucleotide sequence into a target, said method comprising introducing the composition of instant claim 1 to a cell, wherein the complex of the site-specific nuclease polypeptide and the guide directs the non-LTR retrotransposon polypeptide to the target sequence, and wherein the non-LTR retrotransposon polypeptide inserts the donor polynucleotide encoded by the retrotransposon RNA at or adjacent to the target sequence. Thus, the copending and instantly claimed compositions are not patentably distinct from each other, as copending application ‘523 recites each and every limitation of instant claims 1, 3, 6, 7, 13, 52, and 68. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Conclusion No claims are allowed. Claims 1, 12, 18, 42-44, 57, 62, 78, 81, 82, 84, and 89 are objected to. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-Th 8-5, F 8-12. 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, Jennifer Dunston can be reached at 571-272-2916. 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. /SARAH E ALLEN/ Examiner, Art Unit 1637 /J. E. ANGELL/Primary Examiner, Art Unit 1637 Application/Control Number: 17/778,192 Page 2 Art Unit: 1637 Application/Control Number: 17/778,192 Page 3 Art Unit: 1637 Application/Control Number: 17/778,192 Page 4 Art Unit: 1637 Application/Control Number: 17/778,192 Page 5 Art Unit: 1637 Application/Control Number: 17/778,192 Page 6 Art Unit: 1637 Application/Control Number: 17/778,192 Page 7 Art Unit: 1637 Application/Control Number: 17/778,192 Page 8 Art Unit: 1637 Application/Control Number: 17/778,192 Page 9 Art Unit: 1637 Application/Control Number: 17/778,192 Page 10 Art Unit: 1637 Application/Control Number: 17/778,192 Page 11 Art Unit: 1637 Application/Control Number: 17/778,192 Page 12 Art Unit: 1637 Application/Control Number: 17/778,192 Page 13 Art Unit: 1637 Application/Control Number: 17/778,192 Page 14 Art Unit: 1637 Application/Control Number: 17/778,192 Page 15 Art Unit: 1637 Application/Control Number: 17/778,192 Page 16 Art Unit: 1637 Application/Control Number: 17/778,192 Page 17 Art Unit: 1637 Application/Control Number: 17/778,192 Page 18 Art Unit: 1637 Application/Control Number: 17/778,192 Page 19 Art Unit: 1637 Application/Control Number: 17/778,192 Page 20 Art Unit: 1637 Application/Control Number: 17/778,192 Page 21 Art Unit: 1637 Application/Control Number: 17/778,192 Page 22 Art Unit: 1637 Application/Control Number: 17/778,192 Page 23 Art Unit: 1637 Application/Control Number: 17/778,192 Page 24 Art Unit: 1637 Application/Control Number: 17/778,192 Page 25 Art Unit: 1637 Application/Control Number: 17/778,192 Page 26 Art Unit: 1637 Application/Control Number: 17/778,192 Page 27 Art Unit: 1637 Application/Control Number: 17/778,192 Page 28 Art Unit: 1637 Application/Control Number: 17/778,192 Page 29 Art Unit: 1637 Application/Control Number: 17/778,192 Page 30 Art Unit: 1637 Application/Control Number: 17/778,192 Page 31 Art Unit: 1637 Application/Control Number: 17/778,192 Page 32 Art Unit: 1637 Application/Control Number: 17/778,192 Page 33 Art Unit: 1637 Application/Control Number: 17/778,192 Page 34 Art Unit: 1637 Application/Control Number: 17/778,192 Page 35 Art Unit: 1637 Application/Control Number: 17/778,192 Page 36 Art Unit: 1637 Application/Control Number: 17/778,192 Page 37 Art Unit: 1637 Application/Control Number: 17/778,192 Page 38 Art Unit: 1637 Application/Control Number: 17/778,192 Page 39 Art Unit: 1637 Application/Control Number: 17/778,192 Page 40 Art Unit: 1637 Application/Control Number: 17/778,192 Page 41 Art Unit: 1637 Application/Control Number: 17/778,192 Page 42 Art Unit: 1637 Application/Control Number: 17/778,192 Page 43 Art Unit: 1637 Application/Control Number: 17/778,192 Page 44 Art Unit: 1637 Application/Control Number: 17/778,192 Page 45 Art Unit: 1637 Application/Control Number: 17/778,192 Page 46 Art Unit: 1637 Application/Control Number: 17/778,192 Page 47 Art Unit: 1637 Application/Control Number: 17/778,192 Page 48 Art Unit: 1637 Application/Control Number: 17/778,192 Page 49 Art Unit: 1637 Application/Control Number: 17/778,192 Page 50 Art Unit: 1637 Application/Control Number: 17/778,192 Page 51 Art Unit: 1637 Application/Control Number: 17/778,192 Page 52 Art Unit: 1637 Application/Control Number: 17/778,192 Page 53 Art Unit: 1637 Application/Control Number: 17/778,192 Page 54 Art Unit: 1637 Application/Control Number: 17/778,192 Page 55 Art Unit: 1637 Application/Control Number: 17/778,192 Page 56 Art Unit: 1637 Application/Control Number: 17/778,192 Page 57 Art Unit: 1637 Application/Control Number: 17/778,192 Page 58 Art Unit: 1637 Application/Control Number: 17/778,192 Page 59 Art Unit: 1637 Application/Control Number: 17/778,192 Page 60 Art Unit: 1637 Application/Control Number: 17/778,192 Page 61 Art Unit: 1637 Application/Control Number: 17/778,192 Page 62 Art Unit: 1637 Application/Control Number: 17/778,192 Page 63 Art Unit: 1637
Prosecution Insights