CTNF 18/176,126 CTNF 97170 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. Claims 1-12, 19-21, 24-25, 27, 46, and 50 are pending. Election/Restrictions Applicant’s election without traverse of Invention Group I, Claims 1-12 and 19, in the reply filed on 10 March 2026 is acknowledged. Applicant is correct that Claim 19 should be in Group I, not Group II. 08-06 AIA Claim s 20-21, 24-25, 27, 46, and 50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 March 2026 . Claims 1-12 and 19 are examined . Information Disclosure Statement The IDS(es) has been considered. The Spec. cites references. 06-49-06 AIA The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Drawings 06-22 AIA The drawings are objected to because : the application contains color drawings which are not accepted without a granted petition . Instructions for submitting the petition appear below . 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. Color Drawings 06-24-01 AIA Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification: The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2). Specification 07-29-04 The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 39. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. 07-30-03-h AIA Claim Interpretation The claims recite a polyamine-based polymer which the Spec. defines (¶70): "polyamine-based polymer" refers to a polymer comprising individual monomers which comprise two or more nitrogen containing groups or moieties . Claim 1 recites a dsRNA comprising first or “A” and second or “B” strands. The claim is broadly interpreted as either strand (first/A or second/B) is permitted to be the sense/passenger or antisense/guide strand. Claim 1 also recites that the dsRNA is in complex with the polyamine-based polymer. The Spec. doesn’t provide any definition for in complex with so the claim is broadly interpreted as meaning that the dsRNA is in any kind of association with the polyamine-based polymer. Claim 6 recites optionally. Any optional limitation or limitation depending from an optional limitation is interpreted as fully optional. Claims 9-12 recite a lipid component which isn’t defined in the Spec. In the interest of compact prosecution, a lipid component is broadly interpreted as any lipid. Claim Objections 07-29-01 AIA Claim 6 is objected to because of the following informalities: Claim 6 recites …comprises PEI, optionally wherein the PEI is linear or branched , and wherein the average molecular weight of the polymer is… but should replace the underlined comma with a semicolon. In the interest of compact prosecution, the claim is interpreted as requiring that (1) the polymer comprises any PEI and (2) the average molecular weight of the polymer is 2000-25000 Da… Appropriate correction is required. 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 1-12 and 19 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. This is a written description rejection. Claim 1 recites a composition comprising (1) a dsRNA having a first strand … 5’-A01-A02-A03-A04-A05-A06-A07-…A21-3’ … wherein the region A02-A07 of the dsRNA is GGGGGC … . That broad claim encompasses the large genus of dsRNAs comprising strands of at least 21-mer wherein at least one strand comprises the sequence GGGGGC at positions 2-7. Any kind of dsRNA that comprises strands of at least 21-mer and comprises the sequence GGGGGC at positions 2-7 on at least one strand would be encompassed by the claims as instantly presented. An original claim may lack written description support when a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See MPEP 2163. Applicant has not provided sufficient evidence that, at time of filing, they were in possession of compositions comprising any dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7 or that they were in possession of a representative number of such dsRNA compositions. The Spec. describes (¶5) compositions comprising any dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7. The claims encompass all members of that genus of compositions comprising any dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7. The Spec. and SEQ Listing disclose only 7 SEQ ID NOs and only one of those comprises the sequence GGGGGC at positions 2-7. Many more dsRNAs comprising sequences comprising GGGGGC at positions 2-7 exist. Therefore, the Spec. does not demonstrate that Applicants were in possession of a representative number of species within the genus of compositions comprising dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7 such that they may claim the entire genus. There exist numerous genes comprising the sequence GGGGGC or a sequence complementary to that sequence. dsRNAs targeting those genes and portions of the genes comprising the sequence GGGGGC have diverse structures that underlie their function. Applicant has demonstrated possession of only one such dsRNA, SEQ ID NO 5. The one sequence, SEQ ID NO 5, is not sufficient to provide written description support for any compositions comprising dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7. The one sequence does not necessarily share any core structure with any dsRNA comprising GGGGGC at positions 2-7. Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for being any dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7. The Spec. does not disclose any core structure, partial structure, physical or chemical property, or functional characteristic coupled with a known or disclosed structure/function relationship responsible for being any dsRNA comprising strands of at least 21-mer, wherein at least one strand comprises the sequence GGGGGC at positions 2-7 in such a way to demonstrate possession of the full invention as claimed at time of filing. The specification teaches only these species within the claimed genus, namely SEQ ID NO 5, but that is only a paltry number compared with the breadth of what is claimed. .Altogether, the number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genus. While none of these elements is specifically required to demonstrate possession, in combination their absence means that one skilled in the art at the time of filing would conclude that the inventors lacked possession of the full breadth of the invention claimed. Claims 1, 5, and 9 are rejected for failing to demonstrate possession of the claimed invention. Claims 2-12 and 19 are rejected because they depend from Claim(s) 1, 5, and/or 9 and do not remedy the issues. 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 6-8 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. 07-34-10 Regarding Claim 6 , the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 6 is rejected for those reasons. Claims 7-8 are rejected because they depend from Claim 6 and don’t remedy the issues. In the interest of compact prosecution, preferably is interpreted as exemplary and optional, not required. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 6 recites the broad recitation the average molecular weight of the polymer is 2000-25000 Da , and the claim also recites 5000-20000 Da which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claim 6 is rejected for those reasons. Claims 7-8 are rejected because they depend from Claim 6 and don’t remedy the issues. In the interest of compact prosecution, the narrower range of 5000-20000 Da is interpreted as exemplary and optional, not required. Claim 8 recites the broad recitation 20-60% , and the claim also recites 30-50% and 30-35% which are narrower statements of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claim 8 is rejected for those reasons. In the interest of compact prosecution, the narrower ranges of 30-50% and 30-35% are interpreted as exemplary and optional, not required. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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 (i.e., changing from AIA to pre-AIA) 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. 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-20-02-aia AIA This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. 07-21-aia AIA Claim (s) 1-9 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application Publication No.: US 2020/0299697 (“App697”, published 24 September 2020, of record on IDS ) and Ewe (et al. 2016. A novel tyrosine-modified low molecular weight polyethylenimine (P10Y) for efficient siRNA delivery in vitro and in vivo. J. Contr. Rel. 230:13-25 , “Ewe”, of record on IDS ) . App697 teaches (§Abstract) toxic RNAi active seed sequences that preferentially target and inhibit the expression of multiple essential genes for cell survival and/or growth through a process called “death-induced by survival gene elimination” or “DISE.” App697 discloses (same §) their toxic RNAis can be (double-stranded) dsRNAs and either strand can be the guide strand that initiates RNA interference (RNAi). Regarding Claim 1, App697 teaches (Figs. 2-3; ¶57, ¶69-77) a dsRNA comprising two 21-mer strands, wherein each strand comprises a 3’ overhang. A relevant excerpt of Fig. 3 is shown here: PNG media_image1.png 131 1177 media_image1.png Greyscale An artisan would readily recognize that the terminology “A” strand or “B” strand is arbitrary and can applied to either strand, especially since (§Abstract) teaches that either strand can be the guide strand. Therefore one can interpret the figure below as showing that the bottom strand is the “A” strand and positions A02-A07 count from the 5’end of the bottom strand, as shown in the marked up modified Fig. 3: PNG media_image2.png 356 1177 media_image2.png Greyscale The figure shows a DNA overhang on each 3’end. Therefore App697 teaches limitations of Claim 1(1). Regarding Claims 2-4, App697 teaches (¶9, ¶58, Fig. 3) the B strand comprises 2’-OMe modifications at positions B01 and B02. That is shown above in the marked up Fig. 3. Therefore App697 teaches limitations of Claims 2-4. Regarding Claim 19, App697 teaches (¶24) their invention encompasses pharmaceutical compositions comprising a pharmacologically effective amount of a toxic RNA and/or extracellular particles comprising the toxic RNA and a pharmaceutically acceptable carrier for delivering the toxic RNA to target cells or tissues. That ¶ teaches using the particles comprising the toxic RNA to manage a cell proliferation disorder. App697 teaches (¶60) the RNA can be delivered via nanoparticles. App697 teaches (¶127) administering the pharmaceutical composition to a subject. Therefore App697 teaches limitations of Claim 19. App697 does not teach using a polyamine-based polymer (Claim 1[2]), that the dsRNA and polyamine-based polymer are present in polyplex particles (Claim 5), that the polyamine-based polymer is polyethyleneimine (PEI), wherein the PEI can be linear or branched, and wherein the average molecular weight of the PEI is 2-25 kDa (Claim 6); that the PEI is modified with tyrosine (Claim 7), wherein 20-60% of the primary amines in the PEI are modified with tyrosine (Claim 8), or wherein the composition further comprises a lipid component, wherein the dsRNA and PEI are present in lipopolyplexes (LPP) (Claim 9). However, Ewe, drawn to a novel tyrosine-modified low molecular weight PEI (P10Y) for efficient siRNA delivery in vitro and in vivo, teaches (§Abstract) delivery of siRNA for inducing RNAi is a hurdle to using siRNA in vivo. Ewe teaches (same §) they synthesized a new tyrosine-modified low molecular weight (MW) PEI called P10Y that delivers enhanced knockdown (KD) efficiency and no appreciable cytotoxicity. Ewe discusses that (§1. Introduction ¶2) cytotoxicity is a hindrance to in vivo use. Ewe teaches (§1. Introduction, final¶) the tyrosine-modified low MW weight 10 kDa branched PEI has improved in vitro properties and excellent applicability in mice in vivo. Regarding Claim 1(2), Ewe teaches (§2. Material and methods-2.4. Complex preparation, cell culture and transfection) they produced P10Y-siRNA complexes. Ewe describes (§2. Material and methods-2.6. Photon correlation spectroscopy [PCS] and phase analysis light scattering [PALS]) measuring characteristics of the particles , which indicates the P10Y and siRNA formed particles; therefore App697 teaches limitations of Claim 1(2). Regarding Claim 5, Ewe teaches (§2. Material and methods-2.3 Cell culture ¶2) they seeded cells with the P10Y polyplexes and discusses (§2. Material and methods-2.14. In vivo tumor therapy and analysis of adverse effects [determination of liver enzymes and markers of immunostimulation/immunophenotyping] ¶1) the P10Y/siRNA polyplexes. That indicates Ewe teaches the dsRNA and PEI were present in polyplexes (i.e., limitations of Claim 5). Regarding Claim 6, Ewe teaches (§2. Material and methods-2.2. Chemical synthesis of tyrosine-modified PEI and NMR analysis) the PEI is branched and has a MW of 10 kDa and (§2. Material and methods-2.4. Complex preparation, cell culture and transfection ¶1) the P10Y complexes were prepared at different polymer/siRNA mass ratios… on the basis of an average MW of the siRNAs of 13,300 g/mol . An artisan would recognize that MW is equivalent to 13.3 kDa. Both 10 kDa and 13.3 kDa are within the range of 2-25 kDa; therefore Ewe teaches limitations of Claim 6. Regarding Claims 7-8, Ewe teaches (§2. Material and methods-2.2. Chemical synthesis of tyrosine-modified PEI and NMR analysis) they chemically synthesized tyrosine-PEI and calculated 30% tyrosine grafting . Ewe further describes (§3. Results-3.1. Synthesis and analysis of the tyrosine-modified PEI derivative P10Y ¶1) they coupled tyrosine to PEI nitrogens, and 1 H NMR analysis of the P10Y revealed a 30% degree of substitution . That indicates that Ewe teaches tyrosine-modified PEI wherein 20-60% of the primary amines in the PEI are modified with tyrosine; therefore Ewe teaches limitations of Claims 7-8. Regarding Claim 9, Ewe discusses that (§4. Discussion ¶1) PEI comprising phospholipids support cellular uptake and endosomal escape . Therefore Ewe indicates including lipids in the polyplexes is of benefit. An artisan would understand that polyplexes comprising a phospholipid would constitute the claimed LPP; therefore Ewe teaches limitations of Claim 9. Ewe discusses (Fig. 1 and caption; Fig. 5 and caption; §4. Discussion, entire § and ¶4) many positive outcomes associated with their P10Y-siRNA polyplexes, including increased KD efficacy (vs. parent 10 kDa PEI/siRNA complexes), reduced cytotoxicity, longer circulation in blood, delivery to tumors, profound anti-tumor effects based on specific knockdown of their target gene, and (§5. Conclusions) teaches their P10Y is an efficient and promising platform for siRNA delivery in vitro and in vivo. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the “toxic” siRNA of App697 with the tyrosine-modified 10 kDa PEI and other teachings of Ewe for the benefit of more effectively/efficiently delivering the toxic siRNA to cells and tissues in vivo. One would have been motivated to do so with a reasonable expectation of success because App697 teaches (¶127-128) administering their toxic RNAs to subjects to treat cancer and Ewe teaches (§1. Introduction ¶1-2) issues such as nuclease degradation and poor cellular uptake and insufficient lysosomal release hinder translating siRNA to in vivo use, that PEI nanoparticles can help overcome those issues, and (e.g., Fig. 1) tyrosine modified PEI (P10Y)-siRNA complexes more increase KD efficacy vs. PEI-siRNA complexes without tyrosine modification. One would have been motivated because Ewe teaches (§Abstract, §5. Conclusions) using siRNA-P10Y polyplexes to effectively deliver siRNA as a therapeutic in vivo. Therefore all the limitations of Claims 1-8 and 19 would have been obvious in view of App697 and Ewe. An artisan would have added Ewe’s phospholipid to the P10Y for the benefit of supporting cellular uptake and endosomal escape. They would have been motivated to do so with a reasonable expectation of success because Ewe indicates (§4. Discussion) including a phospholipid in particles for siRNA delivery was routine and conventional. Therefore all the limitations of Claim 9 would have been obvious in view of App697 and Ewe . 07-22-aia AIA Claim (s) 1-12 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over App697 and Ewe as applied to Claim s 1-9 and 19 above, and further in view of Schafer (et al. 2010. Liposome–polyethylenimine complexes for enhanced DNA and siRNA delivery. Biomaterials 31:6892-6900 , “Schafer”) and International Patent Application Publication No.: WO 2017/112852 (“WO852”, published 29 June 2017) . The teachings of App697 and Ewe as applicable to Claim(s) 1-9 and 19 have been described above. App697 and Ewe teach a composition comprising “toxic” dsRNA having one strand that comprises GGGGGC at positions 2-7 from the 5’end, wherein each strand comprises a 3’ overhang; and wherein the “toxic” dsRNA is in complex with and forms a polyplex with tyrosine-modified PEI. Ewe teaches their PEI had a MW of 10 kDa. Ewe teaches polyplexes comprising a phospholipid component. Ewe further teaches (§1. Introduction ¶2) PEI can be linear or branched and either kind of PEI is routinely used in nucleic acid delivery. App697 and Ewe do not teach the specific lipid component dipalmitoylphophatidylcholine (DPPC). However, Schafer teaches (§Abstract) using lipid-PEI complexes called lipopolyplexes (LPP) to effectively deliver nucleic acids to induce RNAi. Schafer teaches (same §) their studies indicate incorporating certain lipids into the LPP improves delivery and KD of a target gene. Schafer teaches (§1. Introduction ¶4) lipids help protect nucleic acids from degradation and increase endocytosis and endosomal escape. Schafer teaches (§1. Introduction ¶6) they tested a variety of lipid-PEI combinations to determine which produce the optimal properties. Schafer teaches (§3. Results-3.3. DNA transfection efficacies of PEI F25-LMW/DNA lipopolyplexes; -3.4. siRNA-mediated knockdown efficacies; -3.5. Toxicity of various PEI F25-LMW/DNA lipopolyplexes, entire §s; Figs. 4-5) PEI complexes formulated with DPPC (or DPPC and another lipid[s]) result in particles that have the best gene KD efficacy in combination with the lowest cytotoxicity (i.e., compared with formulations without DPPC). App697, Ewe, and Schafer do not explicitly teach the PEI can be linear or branched or that the average molecular weight of the PEI is 10 kDa. However, WO852, drawn to modified PEI and uses thereof, teaches (§Abstract, ¶4) formulations comprising PEI that are used for delivering RNA to cells. WO852 teaches (¶5) drawbacks to using a PEI as the payload delivery agent include that certain of these polymers are cytotoxic, and the cytotoxicity increases as the PEI’s MW increases. WO852 teaches (¶27, ¶29) producing PEI delivery particles wherein the PEI has a number average MW of 10 kDa. WO852 teaches (¶50, 52) their particles can be used to deliver RNA or dsRNA. WO852 teaches (¶118) the 10 kDa PEI can be branched or linear. WO852 teaches (¶152, ¶160) the PEI can be combined with lipids to form the particles and that lipids can be used to target the particles to certain cell types or to promote endocytosis or phagocytosis of the particles. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the composition comprising dsRNA having one strand comprising GGGGGC at positions 2-7 from the 5’end, wherein each strand comprises a 3’ overhang; wherein the dsRNA forms a polyplex with tyrosine-modified PEI of App697 and Ewe with the teachings of Schafer and WO852 for the benefit of producing optimized siRNA-LPPs that effectively KD a target gene, reduce cytotoxicity, and increase endocytosis and endosomal escape. It would have been obvious to incorporate Schafer’s DPPC lipid into the P10Y-based particle of App697 and Ewe because Ewe teaches that (§1. Introduction ¶2; Fig. 1 and caption; Fig. 5 and caption; §4. Discussion, entire § and ¶4) their lower MW P10Y comprising PEI with a MW of 10 kDa reduced cytotoxicity compared with polyplexes comprising higher MW PEI and because Schafer teaches (Figs. 4-5) incorporating DPPC into gene delivery particles improves gene KD and reduces cytotoxicity. One would have been motivated to produce the composition of App697 and Ewe wherein the LPP comprise DPPC and wherein the PEI has an average MW of 10 kDa with a reasonable expectation of success because Schafer teaches including DPPC in gene delivery particles improves gene KD and reduces cytotoxicity, and because Ewe (§1. Introduction ¶2) and WO852 (¶5) teach higher MW PEI is more toxic than lower MW PEI or PEI that has a MW of 10 kDa. One would have been motivated to use 10 kDa PEI with a reasonable expectation of success because Ewe teaches their P10Y particles comprising lower MW PEI are suitable for in vivo use and because WO852 teaches PEI having an average MW of 10 kDa is a suitable choice when producing siRNA-delivery particles. One would have been motivated to use either linear or branched PEI wherein the PEI has an average MW of 10 kDa with a reasonable expectation of success because WO852 teaches (¶118) using either such PEI is an acceptable design choice when producing particles for delivering RNA and Ewe teaches (§1. Introduction ¶2) using either linear or branched PEI is routine and conventional. Teachings in the cited art indicate varying the MW of PEI and the lipid composition of a delivery particle was routine and conventional and that doing so would produce known benefits as discussed. Therefore all the limitations of Claims 1-12 and 19 would have been obvious in view of App697, Ewe, Schafer, and WO852. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where 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. MPEP 2144.05 provides: It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions (In re Williams, 36 F.2d 436, 438 (CCPA 1929). Here, the focus is that general conditions are known in the prior art and changes in form or, possibly, substitution of equivalents, over the prior art that does the same thing as what is known in the prior art is not patentable. Substitution of equivalents or addition of known ingredients or modification of proportions of known ingredients as applied to optimizing the MW of PEI within known parameters, mixing variants known to “work”, or using branched or linear PEI, or combining known ingredients (i.e., tyrosine-modified PEI and DPPC) for optimal or better results (i.e., regarding nanoparticle formulation and gene delivery) is known in the prior art. Therefore using those known ingredients to produce gene delivery compounds cannot be considered inventive . 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 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-20 of U.S. Patent No. 11613754 (“US754”) in view of US Patent Application Publication No.: US 2020/0299697 (“App697”, published 24 September 2020, of record on IDS ), Ewe (et al. 2016. A novel tyrosine-modified low molecular weight polyethylenimine (P10Y) for efficient siRNA delivery in vitro and in vivo. J. Contr. Rel. 230:13-25 , “Ewe”, of record on IDS ), Schafer (et al. 2010. Liposome–polyethylenimine complexes for enhanced DNA and siRNA delivery. Biomaterials 31:6892-6900 , “Schafer”) and International Patent Application Publication No.: WO 2017/112852 (“WO852”, published 29 June 2017) . The instant claims are directed to a composition comprising (1) a dsRNA having a first strand … 5’-A01-A02-A03-A04-A05-A06-A07-…A21-3’ … wherein the region A02-A07 of the dsRNA is GGGGGC …, wherein the A and B strands comprise 3' overhangs; and (2) a polyamine-based polymer, wherein the dsRNA is in complex with the polyamine-based polymer and forms particles; wherein either strand can be modified, modified at positions B01 and B02, including with 2’-OMe; wherein the dsRNA and the polymer are present in polyplex particles; wherein the polymer can be linear or branched PEI and can having a MW of 2-25 Da or an average MW of 10 kDa; wherein the PEI can be modified with tyrosine, including wherein 20-60% of the primary amines in the PEI are modified with tyrosine; wherein the composition can include a further lipid component and wherein the dsRNA and polymer are in LPP; wherein the lipid component can be DPPC; and to a pharmaceutical composition comprising the composition. The patented US754 claims are directed to a polynt comprising a dsRNA, wherein the nt at positions 2-7 on one strand can be 5’-GGGGGC-3’ ; wherein the dsRNA can comprise 3’ overhangs; to a nanoparticle comprising the polynt, wherein the nanoparticle can be formed from lipoproteins; to a pharmaceutical composition comprising the polynt; and to methods of using polynt. Both claim sets are directed to dsRNAs wherein the nt at positions 2-7 on one strand are 5’-GGGGGC-3’ and wherein the dsRNA comprises 3’ overhangs. The patented claims don’t recite the 2’-OMe modification, that the polymer is specifically PEI or tyrosine-modified PEI, that it is specifically PEI with an average MW of 10 kDa, the % of amines modified with tyrosine, the DPPC, or the other limitations of the instant claims. However, all those limitations were known in the art of producing nanoparticles for delivering RNA: App697 teaches (§Abstract, Figs. 2-3; ¶57, ¶69-77, ¶9, ¶58, ¶24, ¶60, ¶127) the modifications. Ewe teaches (§Abstract, §1. Introduction ¶2, final¶; §2. Material and methods-2.2. Chemical synthesis of tyrosine-modified PEI and NMR analysis, -2.3 Cell culture ¶2, -2.4. Complex preparation, cell culture and transfection; -2.6. PCS and PALS, -2.14. In vivo tumor therapy and analysis of adverse effects ¶1; §3. Results-3.1. Synthesis and analysis of the tyrosine-modified PEI derivative P10Y ¶1; §4. Discussion ¶1, ¶4; Figs. 1 and 5 and captions; §5. Conclusions) using a novel tyrosine-modified low molecular weight PEI (P10Y) for efficient siRNA delivery in vitro and in vivo, the 10 kDa PEI, that 20-60% of the primary amines in the PEI are modified with tyrosine, and that their tyrosine-modified low MW weight 10 kDa branched PEI has improved in vitro properties and excellent applicability in mice in vivo. Schafer teaches (§Abstract, §1. Introduction ¶4,6; §3. Results-3.3. DNA transfection efficacies of PEI F25-LMW/DNA lipopolyplexes; -3.4. siRNA-mediated knockdown efficacies; -3.5. Toxicity of various PEI F25-LMW/DNA lipopolyplexes, entire §s; Figs. 4-5) using lipid-PEI complexes called LPP and which comprise the lipid DPPC to effectively deliver nucleic acids to induce RNAi and reduce cytotoxicity. WO852 teaches (§Abstract, ¶4, ¶5, ¶27, ¶29, ¶50, ¶52, ¶118, ¶152, ¶160) PEI toxicity increases as its MW increases, producing PEI delivery particles wherein the PEI has a number average MW of 10 kDa, and the PEI can be branched or linear. It would have been obvious to use the polynt comprising GGGGGC at positions 2-7 of the patented claims and modify it with modifications of App697, the delivery particle comprising 10 kDa tyrosine PEI of Ewe, the DPPC-PEI of Schafer, and the PEI wherein the average MW is 10 kDa and the PEI can be branched or linear of WO852, for the benefit of optimizing delivery and KD and reducing cytotoxicity. One would have been motivated to do so with a reasonable expectation of success because the cited prior art teaches benefits of making those modifications. Therefore all the limitations of the instant claims would have been obvious in view of the patented US754 claims and App697, Ewe, Schafer, and WO852 . 08-36 AIA Claim s 1-12 and 19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1-2 of U.S. Patent No. US 11959082 (“US082”) in view of US Patent Application Publication No: US 2018/0320187 (“App187”, published 08 November 2018, of record on IDS ), Ewe, Schafer, and WO852 . The instant claims are directed to a composition comprising (1) a dsRNA having a first strand … 5’-A01-A02-A03-A04-A05-A06-A07-…A21-3’ … wherein the region A02-A07 of the dsRNA is GGGGGC …, wherein the A and B strands comprise 3' overhangs; and (2) a polyamine-based polymer, wherein the dsRNA is in complex with the polyamine-based polymer and forms particles; wherein either strand can be modified, modified at positions B01 and B02, including with 2’-OMe; wherein the dsRNA and the polymer are present in polyplex particles; wherein the polymer can be linear or branched PEI and can having a MW of 2-25 Da or an average MW of 10 kDa; wherein the PEI can be modified with tyrosine, including wherein 20-60% of the primary amines in the PEI are modified with tyrosine; wherein the composition can include a further lipid component and wherein the dsRNA and polymer are in LPP; wherein the lipid component can be DPPC; and to a pharmaceutical composition comprising the composition. The patented US082 claims are directed to a polynt comprising a dsRNA, wherein the nt at positions 2-7 on the B strand are 5’-GGGGGC-3’ and to a pharmaceutical composition comprising the polynt; and to methods of using polynt. An artisan would realize that which strand is called the A or B strand is arbitrary and that what matters is the structure that is 5’-GGGGGC-3’ at positions 2-7. Therefore, one would recognized that both claim sets are directed to dsRNAs wherein the nt at positions 2-7 on one strand are 5’-GGGGGC-3’ . The patented claims don’t recite the 3’ overhangs, the 2’-OMe modification, that the polymer is specifically PEI or tyrosine-modified PEI, that it is specifically PEI with an average MW of 10 kDa, the % of amines modified with tyrosine, the DPPC, or the other limitations of the instant claims. However, all those limitations were known in the art of producing nanoparticles for delivering RNA: App187 teaches (¶8) dsRNAs comprising (§Abstract) toxic RNAi active seed sequences [that] preferentially target and inhibit the expression of multiple essential genes for cell survival and/or growth through a process called “death-induced by survival gene elimination” or “DISE.” App187 teaches (¶169) the siRNA has 3’ overhangs on both strands. App187 teaches (¶43) 2’-OMe modifications at positions 1 and 2 of the passenger strand. Since the strand comprising the seed sequence binds to a target, that is the “guide strand” and corresponds to the instantly claimed “A” strand. That means the other strand corresponds to the “B” strand and those 2’-OMe modifications would be at positions that corresponds to the instantly claimed “positions B01 and B02”. Ewe teaches (§Abstract, §1. Introduction ¶2, final¶; §2. Material and methods-2.2. Chemical synthesis of tyrosine-modified PEI and NMR analysis, -2.3 Cell culture ¶2, -2.4. Complex preparation, cell culture and transfection; -2.6. PCS and PALS, -2.14. In vivo tumor therapy and analysis of adverse effects ¶1; §3. Results-3.1. Synthesis and analysis of the tyrosine-modified PEI derivative P10Y ¶1; §4. Discussion ¶1, ¶4; Figs. 1 and 5 and captions; §5. Conclusions) using a novel tyrosine-modified low MW PEI (P10Y) for efficient siRNA delivery in vitro and in vivo, the 10 kDa PEI, that 20-60% of the primary amines in the PEI are modified with tyrosine, and that their tyrosine-modified low MW weight 10 kDa branched PEI has improved in vitro properties and excellent applicability in mice in vivo. Schafer teaches (§Abstract, §1. Introduction ¶4,6; §3. Results-3.3. DNA transfection efficacies of PEI F25-LMW/DNA lipopolyplexes; -3.4. siRNA-mediated knockdown efficacies; -3.5. Toxicity of various PEI F25-LMW/DNA lipopolyplexes, entire §s; Figs. 4-5) using lipid-PEI complexes called LPP and which comprise the lipid DPPC to effectively deliver nucleic acids to induce RNAi and reduce cytotoxicity. WO852 teaches (§Abstract, ¶4, ¶5, ¶27, ¶29, ¶50, ¶52, ¶118, ¶152, ¶160) PEI toxicity increases as its MW increases, producing PEI delivery particles wherein the PEI has a number average MW of 10 kDa, and the PEI can be branched or linear. It would have been obvious to use the polynt comprising GGGGGC at positions 2-7 of the patented US082 claims and modify it with the 3’ overhangs and modifications of App187, the delivery particle comprising 10 kDa tyrosine PEI of Ewe, the DPPC-PEI of Schafer, and the PEI wherein the average MW is 10 kDa and the PEI can be branched or linear of WO852, for the benefit of optimizing delivery and KD and reducing cytotoxicity. One would have been motivated to do so with a reasonable expectation of success because the cited prior art teaches benefits of making those modifications. Therefore all the limitations of the instant claims would have been obvious in view of the patented US754 claims and App187, Ewe, Schafer, and WO852. Conclusion No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET). 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, Ram R Shukla can be reached at (571)272-0735. 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. RUTHIE S ARIETI Examiner (Ruth.Arieti@uspto.gov) Art Unit 1635 /RUTH SOPHIA ARIETI/Examiner, Art Unit 1635 /NANCY J LEITH/Primary Examiner, Art Unit 1636 Application/Control Number: 18/176,126 Page 2 Art Unit: 1635 Application/Control Number: 18/176,126 Page 3 Art Unit: 1635 Application/Control Number: 18/176,126 Page 4 Art Unit: 1635 Application/Control Number: 18/176,126 Page 5 Art Unit: 1635 Application/Control Number: 18/176,126 Page 6 Art Unit: 1635 Application/Control Number: 18/176,126 Page 7 Art Unit: 1635 Application/Control Number: 18/176,126 Page 8 Art Unit: 1635 Application/Control Number: 18/176,126 Page 9 Art Unit: 1635 Application/Control Number: 18/176,126 Page 10 Art Unit: 1635 Application/Control Number: 18/176,126 Page 11 Art Unit: 1635 Application/Control Number: 18/176,126 Page 12 Art Unit: 1635 Application/Control Number: 18/176,126 Page 13 Art Unit: 1635 Application/Control Number: 18/176,126 Page 14 Art Unit: 1635 Application/Control Number: 18/176,126 Page 15 Art Unit: 1635 Application/Control Number: 18/176,126 Page 16 Art Unit: 1635 Application/Control Number: 18/176,126 Page 17 Art Unit: 1635 Application/Control Number: 18/176,126 Page 18 Art Unit: 1635 Application/Control Number: 18/176,126 Page 19 Art Unit: 1635 Application/Control Number: 18/176,126 Page 20 Art Unit: 1635 Application/Control Number: 18/176,126 Page 21 Art Unit: 1635 Application/Control Number: 18/176,126 Page 22 Art Unit: 1635