CTNF 18/556,614 CTNF 84245 DETAILED ACTION Claims 1-139 were/stand cancelled. Claims 140-159 are pending. 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. Priority This application is a 371 of PCT/US2022/026001 04/22/2022 which claims benefit of 63/178,453 04/22/2021 as reflected in the filing receipt July 23 2024. Information Disclosure Statement The information disclosure statements (IDS) submitted on May 6 2025 and June 3 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Drawings 06-22 AIA The drawings are objected to because 37 C.F.R. 1.84 states “Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the current case, the words in Fig. 1, 9C-9E, 10, 11, 19-22 and 24 are illegible . 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 – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Specifically , Figures 19, 23 includes numerous nucleotide sequences with more than 10 specifically enumerated nucleotides and thus must be associated with a SEQ ID No. Required response – Applicant must provide: Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers; AND/OR A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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. Claim Objections 07-29-01 AIA Claim 140 is objected to because of the following informalities: the word “group” is missing after diacyl and before “and a linker” in line 11 on page 4 . Appropriate correction is required. 07-29-01 AIA Claim 157 is objected to because of the following informalities: the acronym “DMG-PEG2000” is not defined in the claims. When an acronym is used in a claim set, it should be defined the first time it appears in the claims. For the purposes of examination, the term “DMG-PEG2000” is interpreted to mean 1,2-dimyristoyl-glycero-3-methoxypolyethylene glycol-2000 . Appropriate correction is required. 07-29-03 AIA Claim 159 is objected to because the lines are crowded too closely together, making reading difficult. Substitute claims with lines one and one-half or double spaced on good quality paper are required. See 37 CFR 1.52(b). Claim Rejections - 35 USC § 112 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 140 and 142-159 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. Claims 141 claims the gene or transcript editing composition (part A) is encapsulated within the lipid composition (part B). In order to be a proper dependent claim, the scope of claim 140 and the other dependent claims would include non- encapsulation. However, the instant specification does not describe how the combination of part A and part B can achieve the claimed HDR correction rate of at least 25% unless it is encapsulated. Figure 10 and 11 of the instant specification showed HDR by three different approaches, specifically the staged two-particle approach, three-particle approach and a third wherein a single formulation contained all three components. But in all these examples either the total of part (a) or the pieces are encapsulated. The instant specification teaches that in order to utilize the HDR repair process, there are three required components that must work in tandem with one another: Cas9 protein, sgRNA and a single-stranded DNA template (page 127). The specification teaches that due to the difficult challenge of delivering these multiple cargoes, discovery and engineering of delivery systems is an important goal. It is taught that the instant invention is an all nucleic acid CRISPR/Cas system encapsulated in dLNPs to enable cytoplasmic delivery. Therefore, while the instant specification is clearly in possession of encapsulation of part (A) to achieve the claimed HDR correction rate, the instant specification fails to describe how such a correction rate could be achieved without encapsulation as contemplated by the instant claims. Note: MPEP 2163. Vas-Cath Inc. v. Mahurkar , 19 USPQ2d 1111, (Fed. Cir. 1991), makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed. " (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.) Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The chemical structure itself is required. See Fiers v. Revel , 25 USPQ2d 1601, 1606 (Fed. Circ. 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016, (Fed. Cir. 1991). In Fiddes v. Baird , 30 USPQ2d 1481, 1483, (Bd. Pat. App. & Int. 1993), claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co. , 43 USPQ2d 1398, 1404, 1405 (Fed. Cir. 1997) held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood , 107 F.3d at 1572, 41 USPQ2d at 1966. Furthermore, to the extent that a functional description can meet the requirement for an adequate written description, it can do so only in accordance with PTO guidelines stating that the requirement can be met by disclosing “sufficiently detailed, relevant identifying characteristics,” including “functional characteristics when coupled with a known or disclosed correlation between function and structure.” Univ. of Rochester v. G.D. Searle , 68 USPQ2d 1424, 1432 (DC WNY 2003). Here, the instant specification fails to describe the structures required to achieve the claimed correction rate when the components of part A are not encapsulated in the lipid composition. Only the encapsulation, but not the full breadth of the claim(s) meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC § 112 is severable from its enablement provision. (See page 1115.) 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 140-159 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 140 as currently written is vague and indefinite. The claim in the recitation of the degradable diacyl group indicates it has the structure of formula D-VII which includes Y3. PNG media_image1.png 645 1389 media_image1.png Greyscale It isn’t clear if that “or a group” is supposed to be an alternative choice for Y3 or if it is supposed to be an alternative choice for degradable diacyl group. Claim 140 as currently written is vague and indefinite. The claim recites: PNG media_image2.png 212 1206 media_image2.png Greyscale however, there is no n in the formula. Therefore, it isn’t clear what n is referencing. Claims 140 and 152 as currently written is vague and indefinite. The claim recites dendrimers or dendrons of formula D-I. An example is: PNG media_image3.png 751 430 media_image3.png Greyscale while this compound includes the claimed core, diacyl group and terminating group as required in claim 140, the compound does not include the required linker group. In claim 140 it states: wherein the repeating unit comprises a degradable diacyl group and a linker. Which indicates both are required. The claim also states “wherein when the repeating unit comprises a linker group (see page 5 of the claims) which would seem to indicate it isn’t required. This creates confusion and uncertainty as to the scope of the claimed ionizable cationic lipid because it isn’t clear if the linker is required or not. Claim 144 as currently written is vague and indefinite. The claim recites “or deletion (indel) rate” in line 2 of claim 144. As evidenced by Cheng et al. (Nature Nanotechnology, 2020) indicates that indel stands for insertions and deletions (page 319, left column, last paragraph), thus the recitation deletion and indel are not of the same scope. This creates confusion as to the scope of the claim as it isn’t clear if the claim is limited to the deletion rate or the indel rate. Claims 154 as currently written is vague and indefinite. The claim recites Y 3 is C1-C12 alkylene. This Y 3 is referencing the diacyl group set forth in (c) in claim 140: PNG media_image4.png 178 560 media_image4.png Greyscale but claim 154 also recites: PNG media_image5.png 252 1283 media_image5.png Greyscale which limits the Y 3 to 1-3 alkylene. Therefore, the scope of the claimed Formula X is unclear because it isn’t clear what recitation is limiting. Claim 157 as currently written is vague and indefinite. The claim recites 4AC3-SC8 but does not indicate the structure associated with this compound. Page 44 teaches a 4A3 which corresponds to: PNG media_image6.png 134 566 media_image6.png Greyscale . Page 54 indicates that SC8 corresponds to: PNG media_image7.png 88 512 media_image7.png Greyscale . Page 74 teaches a structure 4A3-g2-SC8 which corresponds to: PNG media_image8.png 788 1015 media_image8.png Greyscale . Page 78 teaches a structure 4A3-SC8 which corresponds to: PNG media_image9.png 270 950 media_image9.png Greyscale . But nowhere in the specification is the structure 4 AC3 -SC8 taught. Thus the claim is indefinite as it does not include the structure of the compounds included in the claim. In the interest of compact prosecution, the structure is interpreted as 4A3-SC8 as set forth on page 78 of the instant specification. Claims 141-143, 145-151, 153, 155-156 and 158-159 are included in the rejection as they depend on a rejected base claim and they do not clarify the issues. 07-30-03-h AIA Claim Interpretation Paragraph 00190 of the instant specification makes it clear that the Cn, for example (C≤n) defines the exact number of carbons in the group. Thus, these limitations are interpreted as limiting the scope of the substituent. Claim Rejections - 35 USC § 103 07-20-fti The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action: (a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made. 07-23-fti The factual inquiries set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-fti This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a). 07-21-fti Claim s 140-157 and 159 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Siegwart et al. (USPGPUB No. 20170121279) in view of Mello et al. (USPGPUB No. 20190345479) . Applicant Claims The instant application claims a method of performing homology directed repair (HDR) on a target gene in a population of cells, the method comprising contacting the population of cells with a composition comprising a lipid composition assembled with a gene or transcript editing composition, thereby resulting in a HDR correction rate of the target gene of at least 25%;wherein:(A) the gene or transcript editing composition comprises:(1) a polynucleotide comprising a sequence encoding a polynucleotide-guided nuclease;(2) a guide polynucleotide configured to complex with at least a portion of a target gene or transcript, or a polynucleotide comprising a sequence that encodes the guide polynucleotide; and (3) a donor polynucleotide configured to repair a modified target gene or transcript; and (B) the lipid composition comprises:(i) an ionizable cationic lipid having the structural Formula (D-I) or Formula (X);(ii) a steroid or steroid derivative;(iii) a phospholipid; and(iv) a polymer-conjugated lipid. Determination of the Scope and Content of the Prior Art (MPEP §2141.01) Siegwart et al. is directed to lipocationic dendrimer and uses thereof. Claimed is a dendrimer of the formula (I): PNG media_image10.png 46 486 media_image10.png Greyscale which corresponds to instantly claimed D1. Formula II corresponds to instantly claimed D-II. Formula III corresponds to instantly claimed D-III. Formula IV corresponds to instantly claimed D-IV. Formula VII corresponds to instantly claimed D-VII. Formula VI is the same as instantly claimed D-VI. Formula VIII is the same as instantly claimed D-VIII (claim 1). Claimed is a composition comprising the dendrimer and a nucleic acid (claims 60-62). Nucleic acids which can be included include CRISPR/CAS including mRNA and sgRNA. The Cas9 protein is an RNA guided protein. Taught is the evaluation of the composition to deliver nucleic acids for CRISPR/Cas gene editing (example 9, 10 and paragraph 0378-0392; 0498). Taught is the inclusion of one or more helper lipids include a steroid, a steroid derivative, a PEG lipid or a phospholipid (paragraph 0220). Exemplified composition for delivery of sgRNA include the dendrimer, DOPE, cholesterol and PEG-lipid. Molar ratios of lipid (or dendrimer):cholesterol:PEG-lipid were 50:38:5:0.5 with a mole ratio of lipid to nucleic acid of 200:1 (example 9). PEG lipids taught include dimyristoyl-sn-glycerol wherein the number of PEG repeat groups include 1 to 250 (paragraph 0221-0226). Figures 20A and 20B show the percentage encapsulation of the sgRNA (paragraph 0286). Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02) While Siegwart et al. teaches administration of a mRNA and sgRNA with the same lipid composition as instantly claimed, Siegwart et al. does not expressly teach homology directed repair or a donor polynucleotide (3). However, this deficiency is cured by Mello et al. Mello et al. is directed to compositions and methods for improved gene editing. Precise genome editing, in which the targeted sequence is re-written in a user-defined fashion requires the introduction of a donor template that the cell machinery can use in gene editing mechanism such as homology-directed DNA repair (HRT) (paragraph 0004). Taught are compositions can methods for improved gene editing, e.g. via homology directed repair (paragraph 0005). Taught is reducing off-target integration of a nucleic acid donor sequence into a target sequence of a genome in a cell (paragraph 0082). Gene editing takes place in two steps: inducing a double stranded break or other genetic lesion using nucleases such as Cas9 and repairing by a repair mechanism (paragraph 0110). Homology directed repair is a mechanism to repair a double stranded DNA break. HDR relies on the process of homologous recombination whereby stretches of nucleic acid sequence homology are used to repair the double stranded DNA break (paragraph 0111). Taught are modified nucleic acid donor templates which improve the efficiency, efficacy and/or precision of gene editing in vitro, ex vivo or in vivo (paragraph 0113). Claimed is a method of introducing a nucleic acid donor sequence into a target sequence of a genome in a cell, the method comprising contact the cell with a nucleic acid donor sequence and contacting the cell with an agent that creates a double-stranded break such as an RNA-guided nuclease (claim 36). Exemplified is the use of mCherry (red) fluorescence to show non-homologous end-joining which restores frame in a subset of indels. While precisely templated repair results in GFP (green) fluorescence. Cells were nucleoinfected with Cas9 and sgRNA encoding plasmids along with donor. Across a range of donor concentrations, a consistent and significant increase in HDR efficiency with end-modified donors. The efficiency peaked at 51.8% GFP positive cells. The gain of GFP was accompanied by a corresponding loss of mCherry cells. (paragraph 0216). Figure 5B clearly shows mCherry cell percent of less than 10%. It taught that the addition of chemically diverse terminal adapters to a donor DNA template can serve to dramatically improve HDR efficiency (paragraph 0225). Example 7 shows that Cas9 mRNA, sgRNA and donor DNA are utilized (paragraph 0228). The donor nucleic acid comprises a region having portion of nucleic acid homology to the target sequence (paragraph 0027). The portions of nucleic acid homology are about 20 bases in length to about 1000 bases in length (paragraph 0036). It is taught that homology of the nucleic acid sequences mediate HDR (paragraph 0120). Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143) It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Siegwart et al. and Mello et al. and utilize the lipid composition of Siegwart et al. to deliver a Cas9 mRNA, sgRNA and donor DNA to cells. One skilled in the art would have been motivated to deliver this combination in order to allow for homology directed repair as taught by Mello et al. Since the composition of Siegwart et al. are taught for delivering nucleic acids for CRISPR/Cas gene editing, there is a reasonable expectation of success. Regarding claim 140, 142-143: Mello et al. suggests that manipulation of the concentration of the donor DNA can achieve editing over 51.8% Regarding claim 140, 145-149: Part (A): Siegwart et al. expressly teaches administration of a mRNA encoding a Cas protein reading on (1) and an sgRNA (reading on 2). Mello et al. teaches a Cas9 mRNA reading on (1), an sgRNA reading on (2) and a donor DNA reading on (3). Regarding claim 140 and 155: Part (B): Siegwart et al. teaches the composition comprises the dendrimer reading on (i); cholesterol reading on (ii); DOPE reading on (iii); and PEG-lipid reading on (iv). The molar ratio exemplified is 50:38:5:0.5 (dendrimer:cholesterol:phospholipid/DOPE:PEG-lipid) which is the same as claim 155. Regarding claim 141: Siegwart et al. teaches encapsulation (paragraph 0286; Fig 20A and 20B). Regarding claim 144: Mello et al. establishes in Figure 5B mCherry cell percent of less than 10% which corresponds to off-target or indel rate. Regarding claim 150, Mello et al. teaches the donor nucleic acid comprises a region having portion of nucleic acid homology to the target sequence (paragraph 0027). The portions of nucleic acid homology are about 20 bases in length to about 1000 bases in length (paragraph 0036). It is taught that homology of the nucleic acid sequences mediate HDR (paragraph 0120). It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Siegwart et al. and Mello et al. and utilize a donor which is homologous (aka complementary/identical) to the target gene as Mello et al. teaches homologous portions and that homology mediates HDR. Regarding claim 151, example 7 teaches Cas9 mRNA in 50 ng/µl; sgRNA in 20 ng/µl and donor DNA in 10 ng/µl. Mello et al. teaches that increasing the concentration of the donor increases the HDR efficiency. Therefore, one skilled in the art would manipulate the concentration of the Cas9 mRNA, sgRNA and donor DNA in order to achieve the desired level of gene editing. Since the complex is involved in the editing and the concentrations of the components can affect the HDR efficiency as taught by Mello et al. there is a reasonable expectation of success in manipulating the concentration in order to achieve the desired level of HDR editing. Furthermore, it is generally noted that differences in concentrations do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Given that applicant did not point out the criticality of concentrations of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine where in a disclosed set of ranges is the optimum concentration. NOTE: MPEP 2144.05. Regarding claims 152-154 Specific compounds claimed in Siegwart et al. include: PNG media_image11.png 255 1147 media_image11.png Greyscale (paragraph 0476) which reads on the last structure of claim 152 (page 9) with R’ of a C8 alkyl as well as 4AC3-SC8 in light of the indefiniteness rejection above. This structure also reads on formula X in claim 154 with 4 branches (i.e. at least 3) wherein G is 0, Z is 1, the core corresponds to the second to last structure, Y3 is C2 alkylene and the terminating group is a C8-alkylthiol. PNG media_image12.png 598 1107 media_image12.png Greyscale (paragraph 0474) which clearly contains the diacyl group and the linker as well as A1 and A2 of O, Y3 is a C2 alkanediyl, Y1 is C2 alkanediyl, Y4 is C8 alkanediyl and R10 is hydrogen. The difference between claim 153 and this structure is the core is not exactly the same. However, the same cores as instant claim 153 are claimed in 46. It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Siegwart et al and Mello et al. and utilize any of the specifically taught cores. It would have been obvious to one of ordinary skill in the art to try any of the specifically taught cores as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). Regarding claim 156-157, specific dendrimers taught include 4A3-SC8 and exemplified compositions comprise cholesterol, DOPE and PEG-lipid. Specific PEG-lipids taught include DMG-PEG with an overlapping molecular weight (i.e. PEG2000 corresponds to 45 repeat units). In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Note MPEP 2144.05. Regarding claim 159: the composition can be formulated for administration intranasally (paragraph 0234). It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Siegwart et al and Mello et al. and utilize any specifically taught form of administration. It would have been obvious to one of ordinary skill in the art to try of the routes of administration as a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2141 KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007) . 07-21-aia AIA Claim 158 is rejected under 35 U.S.C. 103 as being unpatentable over Siegwart et al. in view of Mello et al. as applied to claims 140-157 and 159 above and in further view of Geall et al. (USPGPUB No. 20140141070) . Applicant Claims The instant application claims a ratio between a number of nitrogen atoms to a number of phosphorous atoms (N:P ratio) of from about is from about 2:1 to about 10:1. Determination of the Scope and Content of the Prior Art (MPEP §2141.01) The teachings of Siegwart et al. and Mello et al. are set forth above. Ascertainment of the Difference Between Scope the Prior Art and the Claims (MPEP §2141.02) Siegwart et al. does not expressly teach an N:P ratio claimed. However, this deficiency is cured by Geall et al. Geall et al. is directed to liposomes having a useful N:P ratio for delivery of RNA molecules. RNA encapsulated within a liposome comprising a cationic lipid, wherein the liposome and the RNA have a N:P ratio of between 1:1 and 20:1. The “N:P ratio” refers to the molar ratio of nitrogen atoms in the cationic lipid to phosphates in the RNA (paragraph 0005). The N:P ratio can be modified by varying the proportions of cationic lipid and RNA during liposome formation (paragraph 0043). Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143) It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Siegwart et al., Mello et al. and Geall et al. and utilize a N:P ratio between 1:1 and 20:1. One skilled in the art would have been motivated to utilize this ratio as it is a known ratio for delivery of RNA as taught by Geall et al. Since Siegwart et al. teaches the use of cationic dendrimers and Geall et al. teaches that the N:P ratios can be varied during formation of the lipid composition, there is a reasonable expectation of success . 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. 08-36 AIA Claim s 140-157 and 159 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-26 of U.S. Patent No. 12357580 in view of Mello et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope . The instant application claims a method of performing homology directed repair (HDR) on a target gene in a population of cells, the method comprising contacting the population of cells with a composition comprising a lipid composition assembled with a gene or transcript editing composition, thereby resulting in a HDR correction rate of the target gene of at least 25%;wherein:(A) the gene or transcript editing composition comprises:(1) a polynucleotide comprising a sequence encoding a polynucleotide-guided nuclease;(2) a guide polynucleotide configured to complex with at least a portion of a target gene or transcript, or a polynucleotide comprising a sequence that encodes the guide polynucleotide; and (3) a donor polynucleotide configured to repair a modified target gene or transcript; and (B) the lipid composition comprises:(i) an ionizable cationic lipid having the structural Formula (D-I) or Formula (X);(ii) a steroid or steroid derivative;(iii) a phospholipid; and(iv) a polymer-conjugated lipid. Patent ’580 claims a method for delivering a messenger ribonucleic acid (mRNA) into a cell the method comprising contacting said cell with a lipid composition encapsulating said mRNA wherein the lipid composition comprises: a cationic ionizable lipid at a molar percentage from about 5 to about 30; a phospholipid at a molar percentage from about 10 to about 45; a steroid or steroid derivative at a molar percentage from about 15 to about 50; and a polymer-conjugated lipid at a molar percentage from about 1 to about 6, wherein the molar percentage is determined based on the total mols of lipids present in the lipid composition; thereby delivering said mRNA into said cell, wherein the cationic ionizable lipid is a compound having the structure of Formula (I) which is the same as instantly claimed. DOPE is claimed, PEG-conjugated lipid is claimed and cholesterol is claimed. Intranasal administration is claimed. While Patent’ 580 claims the same lipid composition and that it can be used to deliver an mRNA, Patent ‘580 does not claim a method of homology directed repair with an mRNA that encodes a Cas9, a sgRNA and a donor. However, this deficiency are cured by Mello et al. Mello et al. is directed to compositions and methods for improved gene editing. Precise genome editing, in which the targeted sequence is re-written in a user-defined fashion requires the introduction of a donor template that the cell machinery can use in gene editing mechanism such as homology-directed DNA repair (HRT) (paragraph 0004). Taught are compositions can methods for improved gene editing, e.g. via homology directed repair (paragraph 0005). Taught is reducing off-target integration of a nucleic acid donor sequence into a target sequence of a genome in a cell (paragraph 0082). Gene editing takes place in two steps: inducing a double stranded break or other genetic lesion using nucleases such as Cas9 and repairing by a repair mechanism (paragraph 0110). Homology directed repair is a mechanism to repair a double stranded DNA break. HDR relies on the process of homologous recombination whereby stretches of nucleic acid sequence homology are used to repair the double stranded DNA break (paragraph 0111). Taught are modified nucleic acid donor templates which improve the efficiency, efficacy and/or precision of gene editing in vitro, ex vivo or in vivo (paragraph 0113). Claimed is a method of introducing a nucleic acid donor sequence into a target sequence of a genome in a cell, the method comprising contact the cell with a nucleic acid donor sequence and contacting the cell with an agent that creates a double-stranded break such as an RNA-guided nuclease (claim 36). Exemplified is the use of mCherry (red) fluorescence to show non-homologous end-joining which restores frame in a subset of indels. While precisely templated repair results in GFP (green) fluorescence. Cells were nucleoinfected with Cas9 and sgRNA encoding plasmids along with donor. Across a range of donor concentrations, a consistent and significant increase in HDR efficiency with end-modified donors. The efficiency peaked at 51.8% GFP positive cells. The gain of GFP was accompanied by a corresponding loss of mCherry cells. (paragraph 0216). Figure 5B clearly shows mCherry cell percent of less than 10%. It taught that the addition of chemically diverse terminal adapters to a donor DNA template can serve to dramatically improve HDR efficiency (paragraph 0225). Example 7 shows that Cas9 mRNA, sgRNA and donor DNA are utilized (paragraph 0228). The donor nucleic acid comprises a region having portion of nucleic acid homology to the target sequence (paragraph 0027). The portions of nucleic acid homology are about 20 bases in length to about 1000 bases in length (paragraph 0036). It is taught that homology of the nucleic acid sequences mediate HDR (paragraph 0120). It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘580 and Mello et al. and utilize the lipid composition of Patent ‘580 to deliver a Cas9 mRNA, sgRNA and donor DNA to cells. One skilled in the art would have been motivated to deliver this combination in order to allow for homology directed repair as taught by Mello et al. Since the composition of Patent ‘408 are taught for delivering nucleic acids for CRISPR/Cas gene editing, there is a reasonable expectation of success. Regarding claim 140, 142-143: Mello et al. suggests that manipulation of the concentration of the donor DNA can achieve editing over 51.8% Regarding claim 140, 145-149: Part (A): Mello et al. teaches a Cas9 mRNA reading on (1), an sgRNA (reading on (2) and a donor DNA (reading on (3)). Regarding claim 140 and 155: Part (B): Patent ’580 claims the same components and suggests concentration. It would have been obvious to one of ordinary skill in the art at the time of the instant invention to manipulate the concentrations in order to determine the optimal concentration. Regarding claim 144: Mello et al. establishes in Figure 5B mCherry cell percent of less than 10% which corresponds to indel rate. Regarding claim 150, Mello et al. teaches the donor nucleic acid comprises a region having portion of nucleic acid homology to the target sequence (paragraph 0027). The portions of nucleic acid homology are about 20 bases in length to about 1000 bases in length (paragraph 0036). It is taught that homology of the nucleic acid sequences mediate HDR (paragraph 0120). It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘580 and Mello et al. and utilize a donor which is homologous (aka complementary/identical) to the target gene as Mello et al. teaches homologous portions and that homology mediates HDR. Regarding claim 151, example 7 teaches Cas9 mRNA in 50 ng/µl; sgRNA in 20 ng/µl and donor DNA in 10 ng/µl. Mello et al. teaches that increasing the concentration of the donor increases the HDR efficiency. Therefore, one skilled in the art would manipulate the concentration of the Cas9 mRNA, sgRNA and donor DNA in order to achieve the desired level of gene editing. Since the complex is involved in the editing and the concentrations of the components can affect the HDR efficiency as taught by Mello et al. there is a reasonable expectation of success in manipulating the concentration in order to achieve the desired level of HDR editing. Furthermore, it is generally noted that differences in concentrations do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Given that applicant did not point out the criticality of concentrations of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine where in a disclosed set of ranges is the optimum concentration. NOTE: MPEP 2144.05 . 08-36 AIA Claim s 140-157 and 159 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-33 of U.S. Patent No. 11766408 in view of Mello et al. (USPGPUB No. 20190345479). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope . The instant application claims are set forth above. Patent ‘408 claims a composition comprising a SORT lipid composition assembled with a therapeutic agent which SORT lipid composition comprises (1) an ionizable cationic lipid (2) a permanently cationic selective organ targeting (SORT) lipid wherein the ionizable cationic lipid is of formula I which is the same as instantly claimed (claim 1). The composition further comprises a phospholipid (claim 6). The composition further comprises a polymer-conjugated lipid which is a PEG-conjugated lipid (claim 10). The composition further comprises a steroid or steroid derivative. The therapeutic agent includes a CRISPR related nucleic acid, a sgRNA, etc. A mRNA that encodes a Cas protein is claimed. A sgRNA is claimed. A double or single stranded DNA is also claimed. While patent ‘408 claims a composition with the same ingredients, patent ‘409 does not expressly teach homology directed repair. However, this deficiency is cured by Mello et al. The teachings of Mello et al. are set forth above. It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘408 and Mello et al. and utilize the lipid composition of Patent ‘408 to deliver a Cas9 mRNA, sgRNA and donor DNA to cells. One skilled in the art would have been motivated to deliver this combination in order to allow for homology directed repair as taught by Mello et al. Since the composition of Patent ‘408 are taught for delivering nucleic acids for CRISPR/Cas gene editing, there is a reasonable expectation of success. Regarding claim 140, 142-143: Mello et al. suggests that manipulation of the concentration of the donor DNA can achieve editing over 51.8% Regarding claim 140, 145-149: Part (A): Mello et al. teaches a Cas9 mRNA reading on (1), an sgRNA (reading on (2) and a donor DNA (reading on (3)). Regarding claim 140 and 155: Part (B): Patent ‘408 claims the same components and suggests concentration. It would have been obvious to one of ordinary skill in the art at the time of the instant invention to manipulate the concentrations in order to determine the optimal concentration. Regarding claim 144: Mello et al. establishes in Figure 5B mCherry cell percent of less than 10% which corresponds to an off-target or indel rate. Regarding claim 150, Mello et al. teaches the donor nucleic acid comprises a region having portion of nucleic acid homology to the target sequence (paragraph 0027). The portions of nucleic acid homology are about 20 bases in length to about 1000 bases in length (paragraph 0036). It is taught that homology of the nucleic acid sequences mediate HDR (paragraph 0120). It would have been obvious to one of ordinary skill in the art at the time of the instant invention to combine the teachings of Patent ‘408 and Mello et al. and utilize a donor which is homologous (aka complementary/identical) to the target gene as Mello et al. teaches homologous portions and that homology mediates HDR. Regarding claim 151, example 7 teaches Cas9 mRNA in 50 ng/µl; sgRNA in 20 ng/µl and donor DNA in 10 ng/µl. Mello et al. teaches that increasing the concentration of the donor increases the HDR efficiency. Therefore, one skilled in the art would manipulate the concentration of the Cas9 mRNA, sgRNA and donor DNA in order to achieve the desired level of gene editing. Since the complex is involved in the editing and the concentrations of the components can affect the HDR efficiency as taught by Mello et al. there is a reasonable expectation of success in manipulating the concentration in order to achieve the desired level of HDR editing. Furthermore, it is generally noted that differences in concentrations do not support the patentabilit