Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. DETAILED ACTION Clams 1-15 are pending in the present application. Claims 1-15 have been examined on the merits as detailed below: Information Disclosure Statement Applicant’s information disclosure statement (IDS) filed January 2, 2024 is acknowledged. The submission is in compliance with the provisions of 37 CFR §1.97. Accordingly, the Examiner has considered the information disclosure statement, and a signed copy is enclosed herewith. Drawings The Drawings filed on March 2, 2023 are acknowledged and have been accepted by the Examiner . Claim Objections Claim s 7-11, 13 and 15 are objected to because of the following informalities : Claim s 7-11, 13 and 15 do not comply with MPEP 608.01(m) which requires that each claim end with a period . Correction is required. Claim 1 4 is objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from another multiple dependent claim. See MPEP § 608.01(n). Claim 14 is dependent on multiple dependent claim 11, for example. Accordingly, claim 1 4 has not been further treated on the merits. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claim s 1, 3, 6, 7, 8, 10, 11-13 and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention. Claim 1 is rejected because the claim recites the phrase, “the rest of the amiR ” . The claim is rejected for a lack of antecedent basis because the claim never makes reference to the term, “ amiR ”. Appropriate correction is required. Claim 10 is rejected because it recites the term, “disease target”. The claim is rejected for a lack of antecedent basis because claim 7, from which claim 10 depends never makes reference to the term, “disease target”. Appropriate correction is required. Claim 6 is rejected because the preamble of the claim recites the phrase, “An artificial miRNA of claim 4”. The claim is rejected for a lack of antecedent basis because claim 4 , from which claim 6 depends makes reference to a “siRNA duplex” and not “artificial miRNA”. C orrection is required. Claim 11 is rejected because it recites the term, “the delivery”. The claim is rejected for a lack of antecedent basis because claim 1-6, from which claim 11 depends never makes reference to any delivery. Appropriate correction is required. Claims 3, 6 and 11-13 are indefinite because the article “a” is improperly recited instead of “the” in the claims. Applicant is reminded that t he definite article is used before singular and plural nouns when the noun is specific or particular. “ The ” signals that the noun is definite, that it refers to a particular member of a group . Claims 7, 8, 10 and 15 are indefinite because the claims fail to set forth the specific steps necessary to achieve treatment of neoplastic diseases associated with kras point mutations; or treating of cancer with kras mutation . A method claim is considered indefinite when it fails to clearly outline the necessary actions or steps required to achieve the claimed invention, rendering the scope of the protection unclear to a person of ordinary skill in the art . Correction is required. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. Claim Rejections - 35 USC § 103 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. 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. 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. Claims 1, 3, 7-1 3 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over ACUNZO et al. ( PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (PNAS), V ol. 114, N o. 21, 23 May 2017 (2017-05-23), pages E4203-E4212 , plus Supplemental Information ) in view of EP 4000638 A1 (UNIV TOKYO) date of filing 16.02.2020 and WO 2017/223135 A1 (MODERNATX INC) 28 December 2017 . The claims are drawn a n artificial miRNA duplex for targeting mutants of kras , whose guide strand sequence follows the following rules: the 7th nt matches with the mutant target sequence (mismatched against the WT sequence). The rest of the amiR has one additional mismatch with the corresponding target sequence in either position 10 or position 11. ACUNZO teach miRNAs targeting a mutant of KRAS for use in treating cancer. From said miRNAs, a-miR-KD6 7th nucleotide matches with the 7 th nucleotide of the mutant KRAS (KRAS G120) sequence and comprises three mismatches in positions 9, 10 and 11 relative to said sequence . See Figure S3a . A significant KRAS G120 inhibition was shown upon in vitro treatment with a-miR-KD6 while maintaining a stable wild-type KRAS expression . See Figure S3b . Regarding ACUNZO, t he present Specification is explicit in disclosing: Acunzo et al (PNAS 2017, 114:E4203-E4212) designed amiRs with seed regions matching a stretch of kras coding region that contains the kras point mutation, producing 6 amiRs for each point mutation. In addition, a central bulge was introduced in the amiR sequences to produce 3-nt mismatches with the kras mRNA target to diminish siRNA-like activity. Overall, the amiRs had a seed region that perfectly matched the kras mutant target, with 3 nt mismatches in total for the mutant. Meanwhile, the amiRs contained an additional mismatch to the seed region of kras wt , resulting in 4 nt mismatches total for the wt , thus producing selectivity for the kras mutant over kras wt. ACUNZO does not necessarily teach a miRNA duplex for targeting mutants of kras , whose guide strand sequence follows the following rules: the 7th nt matches with the mutant target sequence (mismatched against the WT sequence). The rest of the amiR has one additional mismatch with the corresponding target sequence in either position 10 or position 11 . However, ACUNZO teach miRNA duplexes comprising mismatch nucleotides for the inhibition of mutant KRAS alleles. The skilled person wanting to optimize silencing efficiency would contemplate changing and reducing the number of mismatches when aiming for efficient and selective inhibition of mutant KRAS alleles . Therefore, a miRNA duplex for targeting mutants of kras , whose guide strand sequence follows the following rules: the 7th nt matches with the mutant target sequence (mismatched against the WT sequence). The rest of the amiR has one additional mismatch with the corresponding target sequence in either position 10 or position 11 is a matter of design choice made during the course of routine optimization and experimentation. Further, Applicant is reminded that it is held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See In re Aller , 105 USPQ 233. Furthermore, UNIV TOKYO teach modified iRNA molecules targeting a mutant allele of a gene, where the mutant allele contains a single point mutation relative to a wild-type allele. Specifically, UNIV TOKYO teach chemically modified siRNAs targeting mutant KRAS, in which positions 10 or 11 of the guide strand match the position of the point mutation in a mutant allele, exhibiting higher specificity for silencing the mutant KRAS allele over the wild-type KRAS allele . See Abstract and Example 1. UNIV TOKYO also shows that a single additional mismatch is sufficient to improve selectivity for the mutant target . See Fig. 5 , for example. MODERNATX teach the use of nanoparticles is considered to be routine practice in the field for delivery of nucleic acids . For example, MODERNATX teach siRNA molecules comprising a lipid composition comprisin g DODMA, DOPE, cholesterol and PEG2000-DMG . See page 30. The rati o disclosed in present claim 13 is considered to be a variation of a standard lipid formulation made during the course of routine optimization and experimentation . Before the effective filing date of the claimed invention, miRNA duplexe s comprising mismatch nucleotides for the inhibition of mutant KRAS alleles was known in the art of ACUNZO . A person of ordinary skill in the art would have been motivated to modify the teachings of ACUNZO to include miRNA duplexe s comprising mismatch nucleotides for the inhibition of mutant KRAS alleles with reduced number of mismatches as taught and suggested by UNIV TOKYO . A person of ordinary skill in the art would have expected reasonable success to devise the artificial miRNA duplex for targeting mutants of kras as instantly claimed using the disclosures of ACUNZO as an exact blueprint for making and using miRNA duplexes comprising mismatch nucleotides for the inhibition of mutant KRAS alleles . Therefore, the subject matter of claims 1, 3, 7-13 and 15 are obvious over ACUNZO , in view of UNIV TOKYO and MODERNATX . ****** Claims 4, 6, 7-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over PAPKE et al. (A CS Pharmacol.Transl.Sci.2021,4,703 - 712 , plus Supplemental Information ) in view of EP 4000638 A1 (UNIV TOKYO) date of filing 16.02.2020 and WO 2017/223135 A1 (MODERNATX INC) 28 December 2017 . The claims are drawn to a n siRNA duplex for targeting of mutant of kras , whose target sequence is from the 2ⁿᵈ nt of codon 10 to the 2ⁿᵈ nt of codon 16, whose guide strand sequence contains 0-1 nt mismatch (mismatch at position 4 with C to A substitution) with the point mutated target sequence and 1-2 nt mismatch against kras wild-type ( WT ) (position 4 and the site of the point mutation). PAPKE teach siRNAs targeting a mutant of KRAS for use in treating cancer. From said siRNAs, EFTX-D1 target sequence is from the 2 nd nucleotide of codon 10 to the 2nd nucleotide of codon 16 and comprises two mismatches with mutant KRAS (KRAS G12D) sequence and three mismatches with wild-type KRAS sequence . See Figure s 1 c and S-1 . A significant KRAS G12D inhibition was shown upon in vitro treatment with said siRNA . See Figure s 1d and S-2 , for example . Regarding PAPKE, t he present Specification is explicit in disclosing: Papke et al. designed an siRNA that has 2 mismatches each against G12C, G12D, and G13D, and 3 mismatches against kras wt. As a result, the final sequence EFTX-D1 showed silencing activity against all 3 mutants while supposedly greatly reducing silencing activity against the kras WT. PAPKE does not necessarily teach a n siRNA duplex for targeting of mutant of kras , whose target sequence is from the 2ⁿᵈ nt of codon 10 to the 2ⁿᵈ nt of codon 16, whose guide strand sequence contains 0-1 nt mismatch (mismatch at position 4 with C to A substitution) with the point mutated target sequence and 1-2 nt mismatch against kras wild-type (WT) (position 4 and the site of the point mutation) . However, PAPKE teach s iRNA duplexes, comprising mismatch nucleotides for the inhibition of mutant KRAS alleles. The skilled person wanting to optimize silencing efficiency would contemplate changing and reducing the number of mismatches when aiming for efficient and selective inhibition of mutant KRAS alleles . Therefore, a n siRNA duplex for targeting of mutant of kras , whose target sequence is from the 2ⁿᵈ nt of codon 10 to the 2ⁿᵈ nt of codon 16, whose guide strand sequence contains 0-1 nt mismatch (mismatch at position 4 with C to A substitution) with the point mutated target sequence and 1-2 nt mismatch against kras wild-type (WT) (position 4 and the site of the point mutation) is a matter of design choice made during the course of routine optimization and experimentation. Further, Applicant is reminded that it is held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See In re Aller , 105 USPQ 233. UNIV TOKYO and MODERNATX are relied upon as discussed supra . The rati o disclosed in present claim 13 is considered to be a variation of a standard lipid formulation made during the course of routine optimization and experimentation . Before the effective filing date of the claimed invention, s iRNA duplexe s comprising mismatch nucleotides for the inhibition of mutant KRAS alleles was known in the art of PAPKE . A person of ordinary skill in the art would have been motivated to modify the teachings of PAPKE to include s iRNA duplexe s comprising mismatch nucleotides for the inhibition of mutant KRAS alleles with reduced number of mismatches as taught and suggested by UNIV TOKYO . A person of ordinary skill in the art would have expected reasonable success to devise the s iRNA duplex for targeting mutants of kras as instantly claimed using the disclosures of PAPKE as an exact blueprint for making and using s iRNA duplexes comprising mismatch nucleotides for the inhibition of mutant KRAS alleles . Therefore, the subject matter of claims 4, 6 -13 and 15 are obvious over PAPKE , in view of UNIV TOKYO and MODERNATX . Conclusion /Claims Free of the Prior Art Claims 2 and 5 are objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claims drawn to a n artificial miRNA with SEQ ID 8 and 9 for selective targeting of KRAS G12D ; and a n siRNA with SEQ ID 11 and 12 for selective targeting of KRAS G12D are free of the prior art. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F. If attempts to reach the Examiner by telephone are unsuccessful, the Examiner's supervisor, Ram Shukla can be reached on 571-272-0735. 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It also enables applicants to view the scanned images of their own application file folder(s) as well as general patent information available to the public. For all other customer support, please call the USPTO Call Center (UCC) at 800-786-9199. /TERRA C GIBBS/ Primary Examiner, Art Unit 1635