RNA-GUIDED CAS NUCLEASES AND USES THEREOF IN DIAGNOSTICS AND THERAPY

§101 §102 §103 §112 §DP

DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Claims 1-11 and 12-17 are pending. Election/Restrictions Applicant’s election of the invention of Group II, drawn to methods, and the species proliferative disorders in the reply filed on 26 August 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Claims 1-4, 6-8, and 16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 26 August 2026. Claims 5, 9-11, 13-15, and 17 are examined. Claims 1-3 are examined to the extent they are required by the dependent claims. Information Disclosure Statement The Spec. cites references. 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. The IDS(es) has been considered. Drawings The drawings are objected to because of the following informalities: Fig. 5: the photo of the blots should be clearer. Fig. 9: The grayscale isn’t clear enough to determine which column corresponds to which treatment. In Fig. 9A is SuCasΩ the middle column? 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. Specification The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See p. 2 L2-3. 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. Claim Objections Claims 5, 10, 15, and 17 are objected to because of the following informalities: Claim 5 should specify that steps (a) and (b) require providing… to a cell. Claim 10 should recite a non-coding RNA… Claim 15 should recite a semicolon between contaminant and wherein: …from an undesired contaminant; wherein said method…. That will clarify that the wherein clause should follow each for clause. Claim 15 will be better if it recites: …wherein said method comprises administering the complex according to claim 1. Claim 17 will be better if it recites: the method according to claim 14, wherein the disease is an infection, a genetic disorder, a proliferative disorder, or an autoimmune disease. Appropriate correction is required. Claim Interpretation Claim 5 recites a method comprising steps (a)-(e). Steps (c)-(e) are interpreted as outcomes that occur as an inevitable result of steps (a)-(b). The claims are interpreted that way because active steps (a) and (b) recite providing compounds comprising certain structures and steps (c)-(e) will occur as a result of those structures being provided. Claims 9 and 10 recite methods comprising step (c). Step (c) is interpreted as an outcome that occurs as an inevitable result of step (a). (There is no step [b].) The claim is interpreted that way because active step (a) recites contacting a cell/tissue/cellular nucleus/sample with at least one complex… and step (c) will occur as a result of that complex being provided. Claim 10 recites a method for editing the sequence of at least one target RNA. The Spec. doesn’t clarify what is meant by editing. “Editing” is interpreted to encompass any form of changes, including deletion of a sequence or part of a sequence. That interpretation is based on the plain meaning of “editing”. Note about Citations to Page and Paragraph Number The following style is used for citations to page and paragraph number (for documents that don’t have ¶ #s, including the Spec.): p. # refers to PDF p. #. ¶1 refers to the first complete ¶ on a page. ¶0 refers to a partial ¶ that is the first ¶ on a page. Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Claims 5, 9-11, 13-15, and 17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. Claim 5 recites: a method for cleaving a nucleic acid molecule selected from dsDNA, ssDNA, and RNA, comprising the steps of a) providing at least one CasΩ nuclease enzyme, b) providing at least one preselected guide RNA, c) forming a complex between the least one CasΩ nuclease enzyme and the at least one preselected guide RNA, d) binding of the complex of c) to a target RNA based on the at least one preselected guide RNA, and e) cleaving said nucleic acid molecule selected from dsDNA, ssDNA, and RNA by the at least one CasΩ nuclease enzyme. Claim 11 recites: the method according to claim 5, wherein the at least one target RNA comprises a nucleic acid sequence that is specific for a disease state, such as, for example, for cells selected from the group consisting of cells exhibiting a genetic disorder, cells exhibiting a proliferative disorder, such as cancer cells, immune cells that produce autoantibodies, cells infected with bacterial or viral pathogens, bacterial pathogens, protozoan pathogens, cells of microbiota, and contaminating bacteria or archaea. [emphasis added.] Claim 9 recites: a method for modulating expression of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample, wherein said at least one target RNA is selected from an mRNA, non-coding RNA and a viral RNA molecule, said method comprising: a) contacting said cell, tissue, cellular nucleus, and/or sample with at least one complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, further bound to a target RNA molecule having a sequence that is at least 90% complementary to said guide RNA, and c) binding the complex of b) to the at least one target RNA and thereby altering the stability, processing, or translation of the at least one target RNA, whereby the binding in c) modulates the expression of at least one target RNA in the cell, tissue, cellular nucleus, and/or sample. Claim 10 recites: a method for editing the sequence of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample, wherein said at least one target RNA is selected from an mRNA, non-coding RNA and a viral RNA molecule, said method comprising: a) contacting said cell, tissue, cellular nucleus, and/or sample with at least one complex between at least one modified and catalytically inactive CasΩ nuclease enzyme complexed with at least one RNA-modifying enzyme and at least one preselected guide RNA, wherein said at least one preselected guide RNA comprises a sequence that is at least 90% complementary to the at least one target RNA, and c) binding the complex of b) to the at least one target RNA, and editing of the at least one target RNA by said at least one RNA-modifying enzyme. Claim 13 recites: A method for specifically inactivating an undesired cell or virus, comprising contacting said cell or virus with a complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, wherein said guide RNA is specifically selected for said undesired cell or virus to be inactivated. Claim 14 recites: a method for preventing and/or treating a disease comprising administering to a subject in need of such prevention and/or treatment an effective amount of a complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, wherein said guide RNA comprises a sequence selected to be specific for a bacterium, a sequence selected to be specific for a virus, a sequence selected to be specific for a fungus, a sequence selected to be specific for a protozoan, a sequence selected to be specific for a genetic disorder, and/or a sequence selected to be specific for a proliferative disorder. Claim 17 recites: the method according to Claim 14, used to prevent and/or treat an infection, a genetic disorder, a proliferative disorder, or an autoimmune disease. Claim 15 recites: A method for cleaving a nucleic acid molecule selected from dsDNA, ssDNA, and RNA; for detecting at least one target RNA in a cell, tissue, cellular nucleus, and/or sample; for modulating expression of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample; for editing the sequence of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample; for specifically inactivating an undesired cell or virus, or for decontaminating a preparation from an undesired contaminant wherein said method comprises the use of a complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA. All of the claims recite a complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA or a guide RNA specifically selected…. The claimed characteristics are not markedly different from the product’s naturally occurring counterpart in the natural state. This judicial exception is not integrated into a practical application because the claims do not provide a modified form of the complex comprising a CasΩ and at least one guideRNA that will bind at least one target RNA that is markedly different from its naturally occurring counterpart. Step 1 – Statutory Category: The claimed invention is a process. Under 35 USC 101, the claimed invention must be “any new and useful process, machine, manufacture, or composition of matter.” The methods that require providing/administering/contacting a cell with the complex comprising a CasΩ nuclease and a guide RNA can be considered useful process. Therefore, the methods fall under one of the statutory categories identified in 35 USC 101. Step 2A Judicial Exception – Prong 1 (Nature of the claim recitation & Markedly different characteristics analysis): Prong 2A asks whether the claim recites an abstract idea, law of nature, or natural phenomenon (product of nature or natural process). Even a useful process may not be patent-eligible if it falls under a judicial exception. Processes that are natural phenomena that fall within the judicial exception can include 1) naturally occurring processes or 2) those that are not naturally occurring but have characteristics that are not markedly different from a naturally occurring counterpart. The Federal Circuit in University of Utah Research Foundation v. Ambry Genetics (Fed. Circ. December 2014) held claimed synthetically made primers that have the identical nucleotide sequences as portions (i.e., fragments) of naturally occurring nucleic acids are ineligible nature-based products. The court reasoned that simply being synthetic or non-naturally created is not enough for eligibility when the identical sequences occur in nature. In the limited situation where a process claim reciting a nature-based product is drafted in such a way that there is no difference in substance from a product claim, the claim is subject to the markedly different analysis for the recited nature-based product. These types of claims are drafted in a way that focuses on the product rather than the process steps. For example, consider a claim that recites, in its entirety, "a method of providing an apple." Under the broadest reasonable interpretation, this claim is focused on the apple fruit itself, which is a nature-based product. Similarly, claims to detecting naturally occurring cell-free fetal DNA (cffDNA) in maternal blood were held to be directed to the cffDNA, because the "existence and location of cffDNA is a natural phenomenon [and thus] identifying its presence was merely claiming the natural phenomena itself." Rapid Litig. Mgmt., 827 F.3d at 1048, 119 USPQ2d at 1374, (explaining the holding in Ariosa Diagnostics, Inc. v. Sequenom, 788 F.3d 1371, 115 USPQ2d 1152 (Fed. Cir. 2015)). The instantly claimed invention is a process but recites method steps that occur, exactly as recited, in Nature: methods of cleaving a nucleic acid molecule selected from dsDNA, ssDNA, and RNA wherein the cell is infected with a viral pathogen (Claims 5 and 11), modulating expression of a target RNA wherein the target RNA is a viral RNA (Claim 9), editing the sequence of a target RNA wherein the target RNA is a viral RNA (Claim 10), inactivating a virus (Claim 13), treating a disease or infection by targeting a viral RNA sequence (Claims 14 and 17). In each claim, the method provides (Claims 5 and 11), contacts a cell (Claims 9-10, 13), administers (Claims 14 and 17), or uses (Claim 15) a complex comprising at least one CasΩ nuclease and a guide RNA. The complex encompassed by the claims exists as or encompasses a naturally occurring complex because the claimed composition exists within bacteria in vivo. Then, each of the claimed processes occurs within a bacterium. For example, Bravo (et al. 2023. RNA targeting unleashes indiscriminate nuclease activity of CRISPR–Cas12a2. Nature 613:582-587; “Bravo”) and Dmytrenko (et al. 2023. Cas12a2 elicits abortive infection through RNA-triggered destruction of dsDNA Nature 613:588-594; “Dmytrenko”) teach that CasΩ exist in nature in complex with a guideRNA, a target RNA, and wherein the target RNA is flanked by a PAM. It is noted that both papers refer to “CasΩ” as “Cas12a2”, but these are different names for the same Cas nuclease because Dmytrenko Suppl. Fig. 1 shows nucleases called Cas12a2 and they are the same nucleases as the instant Spec.’s Fig. 1. Bravo (§Abstract) teaches Cas12a2 is a CRISPR-associated nuclease that performs RNA-guided, sequence nonspecific degradation of single-stranded RNA, ssDNA and dsDNA following recognition of a complementary RNA target. Therefore, Bravo teaches the CasΩ nuclease, the guideRNA that is complementary to a target, and the target. In order for cutting to occur, the nuclease/guideRNA would need to come into contact with each other and with the target, which constitutes a complex. Therefore, the claimed process occurs in Nature. Bravo (§Structure of Cas12a2 binary complex ¶1) teaches that they purified a binary complex consisting of catalytically active Cas12a2 and a mature crRNA and determined the structure using cryo-EM. Bravo teaches (§Structure of Cas12a2 binary complex ¶4) the requirement of a PAM differentiates Cas12a (requires a PAM to recognize target) from CasΩ/Cas12a2 (doesn’t require a PAM). Still, Dmytrenko teaches that (§Discussion ¶2) CasΩ has a more flexible target recognition system and could further serve as a back-up mechanism if precise recognition and clearance of DNA targets by Cas12a fails which indicates that CasΩ forms a complex with target RNAs flanked by a PAM if Cas12a has failed to do so. Dmytrenko teaches that (§Cas12a2 exhibits targeting flexibility ¶3) collectively, the distinct activities of Cas12a2 compared with Cas12a suggested that tandem systems possessing both nucleases (Fig. 1d) may act cooperatively to broaden the effectiveness against foreign viruses and plasmids. This teaches that the nucleases target viruses and since the guide RNA must be complementary to the target, the guideRNA must comprise a sequence selected to be specific for the targeted virus. Although Bravo describes (§Complex formation for cryo-EM) adding crRNA to the Cas12a2, the crRNA was added for the purpose of investigating how/where binding occurs in the natural product. Therefore, the process as recited in the claims is not different from the naturally-occurring process and does not amount to significantly more. Regarding the claims’ requirements that the guideRNA be “selected”, the guide RNAs were “selected” by the natural process of evolution. Regarding each claimed process, Bravo (§Discussion ¶3, §Introduction ¶3, Fig. 2g) and Dmytrenko (§Abstract) explain that after Cas12a2 recognizes its RNA target, it cleaves target RNA, ssRNA, ssDNA, and dsDNA. That cleaving modulates target RNA expression (Claim 9), inactivates a cell or virus (Claim 13 and 15), and can be considered a kind of editing (Claim 10). Bravo teaches (§Discussion ¶3) the process confers population-level antiphage defense which can be considered a form of treating an infection (Claims 14 and 17). Since the phage, a virus, is the natural target, the process targets a virus RNA and occurs in bacteria infected with a viral pathogen (Claim 11). Therefore, the limitations of Claims 5, 11, 9-10, 13, 14, 17, and 15 exist in Nature. Even if the process is synthetically administered, it would be identical to and can be considered equivalent to the naturally occurring process because the claims do not recite any specific sequence or structure or element that is not present in nature. CasΩ nucleases occur in nature in complex with a guideRNA that evolutionary processes selected to bind to at least one target RNA which can be a virus RNA and which can contain a PAM. Bravo (cited above) teaches a natural process wherein the complex comes together with its viral RNA target and cleaves it. That cleaving can be considered a form of editing, and it modulates expression, destroys a cell, etc. Therefore, the claimed inventions that are methods are directed to natural phenomena, have no markedly different characteristics, and therefore fall within the judicial exception category. Step 2A Judicial Exception – Prong 2 (Judicial exception is integrated into a practical application): Prong Two asks whether a claim recites additional elements that integrate the judicial exception into a practical application. No practical application is listed and in any case the function of the complex is a feature inherent to its structure (see MPEP 2106.04(c)(II)(C)(2)), and the function of the complex is part of a natural process as discussed. The courts have found that linking the use of a judicial exception to a particular technological environment or field of use do not integrate a judicial exception (see MPEP 2106.04(d)(I)). Therefore, there is no practical application beyond how the natural phenomenon/natural process operates in its natural environment. Step 2B Significantly More: The “significantly more” analysis determines that a claim is patent eligible if the claims recite additional elements that contribute an “inventive concept”, which requires an additional element in the claim to apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Claims 5 and 15 recite a method for cleaving a nucleic acid molecule; as discussed above nothing in this claim contributes an inventive concept. Claim 11 recites a method for cleaving a nucleic acid molecule that is specific for a disease state such as a cell infected with a viral pathogen; as discussed above nothing in this claim contributes an inventive concept. Claims 9 and 15 recite a method for modulating expression of a target RNA and Claims 10 and 15 recite a method of editing a target RNA; as discussed above the claimed process requires a complex that exists in nature, the claimed expression modulation and target editing occur when the cell expresses the components of the complex, so nothing in these claims contributes an inventive concept. Claim 13 recites the method inactivates an undesired virus; as discussed above, that is exactly how the process operates in a phage-infected bacterium, so nothing in this claim contributes an inventive concept. Claims 14 and 17 recite a method for preventing or treating a disease that can be an infection; as discussed above, Bravo teaches the natural function of Cas12a2 confers population-level antiphage defense, so the limitation provides no inventive concept. As discussed above, if a synthetic process has the same steps and comprise a complex comprising the exact same structure as a naturally occurring product, it will have the same properties or characteristics. Each claim fails to meet patent subject matter eligibility requirements. The limitations of Claims 5, 9-11, 13-15, and 17 do not recite any meaningful additional limitations, modification(s) or transformation(s) that distinguish the claimed process from a naturally occurring phenomenon present in bacteria, and therefore do not recite any limitations significantly more than the judicial exception. Therefore, Claims 5, 9-11, 13-15, and 17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon and does not meet patent subject matter eligibility requirements. In the interest of compact prosecution, it’s noted that amending the claims to specify that the method requires administering the complex to a eukaryotic cell and/or that the guide RNA comprises a modified nucleotide (see Spec. p. 26 ¶0 and p. 4 ¶1 and p. 49 ¶3, see specifically §Guide Modifications in cited document US10266887, which is incorporated by reference, Col 43 starting at L60). Claim Rejections - 35 USC § 112 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. Claims 11, 13-15, and 17 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 11 recites: a method for cleaving a nucleic acid molecule selected from dsDNA, ssDNA, and RNA, comprising the steps of a) providing at least one CasΩ nuclease enzyme, b) providing at least one preselected guide RNA, c) forming a complex between the least one CasΩ nuclease enzyme and the at least one preselected guide RNA, d) binding of the complex of c) to a target RNA based on the at least one preselected guide RNA, and e) cleaving said nucleic acid molecule selected from dsDNA, ssDNA, and RNA by the at least one CasΩ nuclease enzyme; wherein the at least one target RNA comprises a nucleic acid sequence that is specific for a disease state. [emphasis added.] Claims 13 and 15 recite inactivating an undesired dell or virus using a guideRNA specifically selected for said undesired cell or virus. Claim 14 recites a method for preventing and/or treating a disease comprising administering to a subject in need of such prevention and/or treatment an effective amount of a complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, wherein said guide RNA comprises a sequence selected to be specific for a bacterium, a sequence selected to be specific for a virus, a sequence selected to be specific for a fungus, a sequence selected to be specific for a protozoan, a sequence selected to be specific for a genetic disorder, and/or a sequence selected to be specific for a proliferative disorder. Claim 17 recites the method used to prevent and/or treat an infection, a genetic disorder, a proliferative disorder, or an autoimmune disease. [emphasis added.] Those broad claims encompass the large genus of target RNAs specific for a disease state (Claim 11), that occur in an “undesired cell or virus” (Claims 13 and 15), and the large genera of guide RNAs that can be used to treat or prevent any disease or any infection, genetic disorder, proliferative disorder, or autoimmune disease (Claims 14 and 17). Any kind of target RNA specific for a disease state or guide RNAs that can be used to treat or prevent any disease/any infection, genetic disorder, proliferative disorder, or autoimmune disease would be encompassed by the claims as instantly presented. There is a written description (WD) problem because the claims encompass target RNAs and guide RNAs whose structure cannot be envisioned because the claims encompass generic target and guide RNAs defined solely by their functions of being specific for a disease state or being able to be used to treat or prevent any disease/any infection, genetic disorder, proliferative disorder, or autoimmune disease. 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. The Spec. discusses target RNA and guide RNA at pp. 22-23 ¶4-1, p. 28 ¶1, pp. 29-30 ¶1-3, pp. 36-37 ¶3-1, p. 39 ¶2, pp. 40-43 ¶3-1, pp. 44-45 ¶4. However, those passages merely mention target RNAs, guide RNAs, and undesired RNAs. Nothing in those passages discloses what structure(s) is encompassed by each term. Regarding what structure(s) is encompassed by any of the target RNAs specific for any disease state, guide RNAs that can be targeted to prevent or treat a disease, and undesired RNAs specific to an undesired cell or virus—all the RNAs that are encompassed by the claims—the Spec. does not provide information describing its features. The Spec. does not disclose what physical structure is responsible for each of the claimed functions. The Spec. does not disclose or discuss how to associate any disease state, any genetic disorder, proliferative disorder, or autoimmune disorder with a target RNA. The Spec. doesn’t disclose the structure of an undesired cell or virus that can be targeted, or of the guide RNA that would target it. The Spec. hasn’t disclosed a target nucleic acid specific for any disease state, so Applicant has not demonstrated possession of methods of using a complex comprising a guide RNA targeting such a target. Even if an artisan knew what disease-specific gene to target for each of the vast number of diseases, the Spec. hasn’t demonstrated possession of a method that results in the claimed outcomes of treating or preventing. Applicant’s examples and prophetic examples show (Fig. 5) an undisclosed guide RNA degrades nontarget nucleic acids only in the presence of its RNA target. Other examples disclose guide RNA that targets (p. 58, Fig. 9) E. coli, (p. 59) SARS-COV2 RNA, (p. 59) an unedited locus (presumable mRNA transcribed from an unedited locus), and (pp. 62-63) GAPDH and MALAT1 in mammalian cells. None of those examples disclose the guide RNA sequence. Altogether, those examples are not sufficient to provide written description support for a representative number of species within the broad genera claimed. Although the claims claim the functional characteristics (i.e., target RNAs specific for a disease state, target RNAs that occur in an “undesired cell or virus”, guide RNAs that can be used to treat or prevent any disease or any infection, genetic disorder, proliferative disorder, or autoimmune disease), each functional characteristic is not coupled with any known structure. Although the Specification teaches the examples discussed above, it does not identify a core structure necessary for performing the claimed function(s). 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 an RNA specific for a disease state, being an RNA that occurs in an “undesired cell or virus”, or being a guide RNA that can be used to treat or prevent any disease or any infection, genetic disorder, proliferative disorder, or autoimmune disease in such a way to demonstrate possession of the full invention as claimed at time of filing. The claimed guide RNAs do not share any core structure. The specification teaches they used only a few guide RNAs within the claimed genus/genera (i.e., guide RNAs that target E. coli, SARS-COV2 RNA, GAPDH, and MALAT1), and none of those guide RNAs have any disclosed structure. Altogether, those are only a paltry number compared with the breadth of what is claimed. The number of species disclosed by complete structure is not sufficient to provide the written description support for the huge genera and subgenera that are encompassed by the claims. Nor does the Spec. disclose a representative number of target RNA sequence–disease relationships, instructions for determining which portion of a disease-associated RNA to target, or that targeting those RNAs is capable of treating any disease. 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 11, 13-15, and 17 are rejected for failing to demonstrate possession of the claimed invention. Claims 17 is rejected because it depends from Claim(s) 14 and does not remedy the issues. Claims 14 and 17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating a disease wherein a known RNA–disease relationship is demonstrated and methods of treating an infection or proliferative disorder wherein a known RNA–disease relationship is demonstrated, do not reasonably provide enablement for preventing any disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection. The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the specification; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. The breadth of the claims and the nature of the invention: With respect to claim breadth, the standard under 35 U.S.C. §112(a) entails determining what the claims recite and what the claims mean as a whole. Methods of Claims 14 and 17 recite a method for preventing and/or treating a disease… (Claim 14) and the method… used to prevent and/or treat an infection, a genetic disorder, a proliferative disorder, or an autoimmune disease (Claim 17). The broadest reasonable interpretation (BRI) of the method of Claim 14 is that the method can be used to prevent and/or treat any disease. The BRI of Claim 17 is that the method can be used to prevent and/or treat any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease. The nature of the invention is a method for preventing or treating any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease. A skilled artisan would not be able to use the method as claimed with a reasonable expectation of success based solely on what is disclosed in the specification. The state of the art and prior art, the level of one of ordinary skill, and the level of predictability in the art: The art and prior art discusses that it is not possible to prevent any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease. Regarding preventing infectious disease, Drexler (2010. What You Need to Know About Infectious Disease. Washington (DC): National Academies Press, Institute of Medicine, “IOM”) teaches (§IV Prevention and Treatment ¶1) infectious disease may be an unavoidable fact of life, but there are many strategies available to help us protect ourselves from infection and to treat a disease once it has developed. That indicates that infection by infectious disease is an unavoidable fact of life and can’t be prevented. Regarding preventing any genetic disorder, Cleveland Clinic (2021 and 2024. “Genetic Disorders” and “Autoimmune Diseases”. Available online at my.clevelandclinic.org. Accessed on 21 September 2026, “Cleveland”) teaches (Genetic Disorders §Prevention) there is often little you can do to prevent a genetic disorder and suggests genetic counseling to inform the likelihood of passing on a disorder. That indicates it is not possible to prevent any genetic disorder. Regarding preventing any proliferative disorder, cancer is one kind of proliferative disorder. Cancer Research UK (2025. Can cancer be prevented? How to reduce your risk of cancer. Available online at cancerresearchuk.org. Accessed on 23 September 2026, “CRUK”) teaches (§Can cancer be prevented? ¶1) not all cancers can be prevented but you can take steps to reduce your risk. That indicates it is not possible to prevent any proliferative disorder. Regarding preventing any autoimmune disease, Cleveland teaches (Autoimmune Diseases §Prevention) there might not be any way to prevent autoimmune diseases because experts aren’t sure what causes them. That indicates it is not possible to prevent any autoimmune disease. Although the skill level of an artisan is high, altogether the art teaches using any method to prevent any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease would be unpredictable. The amount of direction provided by the specification and the existence of working examples: What is enabled by the working examples and what is known in the art is narrow compared to the breadth of the claims. The Spec. discusses target RNA and guide RNA at pp. 22-23 ¶4-1, p. 28 ¶1, pp. 29-30 ¶1-3, pp. 36-37 ¶3-1, p. 39 ¶2, pp. 40-43 ¶3-1, pp. 44-45 ¶4. Applicant’s examples and prophetic examples show (Fig. 5) an undisclosed guide RNA degrades nontarget nucleic acids only in the presence of its RNA target. Other examples disclose guide RNA that targets (p. 58, Fig. 9) E. coli, (p. 59) SARS-COV2 RNA, (p. 59) an unedited locus (presumable mRNA transcribed from an unedited locus), and (pp. 62-63) GAPDH and MALAT1 in mammalian cells. The examples show at least one experiment where they targeted and killed a cell comprising a target RNA. That indicates that if an RNA–disease relationship were known and if an artisan knew the sequence of an RNA that underlies a disease, they could use the claimed methods to kill at least some cells comprising that RNA. That indicates it is theoretically possible to treat some diseases. However, nothing in the Spec. discusses any example of preventing any disease and, in conflict with the claims, the art teaches it is not possible to prevent any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease. Although the level of an artisan is high, the art of treating diseases is unpredictable. The art teaches it is not possible to prevent any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease and the specification does not provide any guidance as how to prevent any disease. For example, Cleveland discussed genetic counseling and testing can inform the risk of a genetic disorder or passing one on to one’s offspring, but nothing in that reference or the art generally discusses preventing a genetic disorder. Similarly, since the cause of any autoimmune disease isn’t known, it is not possible to say that the disease can be prevented. Therefore, the methods could not be used as claimed to prevent any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease as recited by the claims. The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution. Given that the art teaches it is not possible to prevent any disease, any infection, any genetic disorder, any proliferative disorder, or any autoimmune disease, an artisan of ordinary skill would not be able to use the invention as claimed with a reasonable expectation of success. The amount of experimentation required for enabling guidance commensurate in scope with what is claimed goes beyond what is considered “routine” within the art and constitutes undue further experimentation in order to successfully use the methods or preventing any disease with a reasonable expectation of success. In conclusion, the specification provides enablement for methods of treating a disease wherein a known RNA–disease relationship is demonstrated. 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. Claims 5, 9-11, 13-15, and 17 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. A 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. In the present instance, Claims 5, 9-11, 13-15, and 17 recite or depend from a claim that recites “CasΩ nuclease”. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. CasΩ is not a term of the art, and the term has no clear meaning in the art or Spec.. It is not clear what constitutes or does not constitute a “CasΩ”. Furthermore, the Spec. does not provide clarifying guidance on this issue because it doesn’t provide any definition of CasΩ. The Spec. describes (p. 10 ¶2) some features of CasΩ but that § is still unclear because (a) requires a single RuvC motif but (b) and (c) conflict because they require additional RuvC motifs. Furthermore, those additional RuvC motifs are described to comprise certain AA insertions or deletions, but those AA insertions and deletions are not disclosed. Claims 5, 9-11, 13-15, and 17 are rejected for those reasons. Claims 11 and 17 are rejected because they depend from Claims 5 and/or 14 and do not remedy the issues. In the interest of compact prosecution, the term “CasΩ” is interpreted as any nuclease comprising any of the sequences disclosed in the Spec., namely SEQ ID NOs 1-67. In addition, CasΩ is interpreted as a Cpf1 enzyme. The Spec. discloses (p. 3 ¶2) Cas12 a (type V) disclosed in US9790490B2 corresponds to CasΩ according to the present invention, as shown in this excerpt of the Spec.: PNG media_image1.png 86 681 media_image1.png Greyscale Claims 5, 9-11, 13-15, and 17 recite “preselected guide RNA”. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear what constitutes a “preselected guide RNA”, who preselected it, or when in time it was “preselected” in comparison to. Claims 5, 9-11, 13-15, and 17 are rejected for those reasons. Claims 11 and 17 are rejected because they depend from Claims 5 and/or 14 and do not remedy the issues. In the interest of compact prosecution, the term “preselected guide RNA” is interpreted as a guide RNA that has been designed to bind any target RNA of interest. Claim 9 recites “a) contacting said cell, tissue… with at least one complex [comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, wherein the complex is bound to a target RNA molecule having a sequence that is at least 90% complementary to said guide RNA], and c) binding the complex of b) to the at least one target RNA …”. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear how the complex of Claim 2, which is already bound to a target RNA molecule, can then be used in Step (c) to bind the complex to the target RNA. The first recitation (a)… the complex according to Claim 2 indicates the binding has already occurred. Therefore, it is not clear how step (c) can be accomplished. In the interest of compact prosecution, the claim is interpreted as reciting … a) contacting said tissue… with at least one complex [comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, wherein the complex is bound to a target RNA molecule having a sequence that is at least 90% complementary to said guide RNA], wherein binding of the complex to the at least one target RNA alters the…. Claims 9-10 recite the limitation "the complex of b)" in L8 and L9. There is insufficient antecedent basis for this limitation in the claim because neither those claims nor the claims from which they depend recite any “complex of b)” or anything that could possibly be interpreted as a complex of b). In the interest of compact prosecution, the claims are interpreted as reciting “the complex of a)”—because that is the only complex that makes sense in the context of the rest of each claim—meaning the complex comprising the CasΩ nuclease (Claim 9) or catalytically inactive CasΩ nuclease (Claim 10) that is complexed with a guide RNA. Claim 10 recites “…a) contacting said cell, tissue… with at least one complex between at least one modified and catalytically inactive CasΩ nuclease enzyme complexed with at least one RNA-modifying enzyme and at least one preselected guide RNA, wherein said at least one preselected guide RNA comprises a sequence that is at least 90% complementary to the at least one target RNA, and c) binding the complex of b) to the at least one target RNA, and editing of the at least one target RNA by said at least one RNA-modifying enzyme”. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear what is meant by: with at least one complex between at least one modified and catalytically inactive caseΩ nuclease enzyme complexed with at least one RNA-modifying enzyme. In the interest of compact prosecution, the claim is interpreted as reciting: …a) contacting said cell, tissue… with a complex comprising at least one modified and catalytically inactive CasΩ nuclease enzyme complexed with at least one RNA-modifying enzyme and at least one preselected guide RNA, wherein said at least one preselected guide RNA comprises a sequence that is at least 90% complementary to the at least one target RNA, and c) binding the complex of b) to the at least one target RNA, and editing of the at least one target RNA by said at least one RNA-modifying enzyme. Regarding Claim 11, the phrases "such as" and “for example” render the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). In the interest of compact prosecution, the limitations following the phrase are interpreted as merely exemplary and not a required part of the claimed invention. Claims 11 and 15 recite “contaminating bacteria or archaea” (Claim 11) and “for decontaminating a preparation from an undesired contaminant”. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear what constitutes a “contaminating bacteria or archaea” or “an undesired contaminant”, so the scope of the claim would vary depending on the eye of the beholder. Claims 11 and 15 are rejected for those reasons. In the interest of compact prosecution, the terms are interpreted as any bacteria or archaea or contaminant who comprises any target RNA of interest wherein the guide RNA has been designed to bind that target RNA. The term “undesired” in Claims 13 and 15 is a relative term which renders the claim indefinite. The term “undesired” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what is or isn’t an undesired cell or virus and the scope of the claim would vary depending on the eye of the beholder. In the interest of compact prosecution, the claims are interpreted as meaning: …a target cell or virus that is targeted by the guide RNA… Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite in that it fails to point out what is included or excluded by the claim language. This claim is an omnibus type claim. Claim 15 recites a method for cleaving…; for detecting…; for modulating…; for editing…; for specifically inactivating…; or for decontaminating…, wherein said method comprises the use of a complex according to Claim 1. The claim(s) are considered indefinite because there is a question or doubt as to what are the metes and bounds of the claim. It is not clear whether Claim 15 is a method claim or a use claim (which isn’t allowed and would be subject to a 101 or 112 rejection). Claim 15 recites no method steps and only a use. "Use" claims that do not purport to claim a process, machine, manufacture, or composition of matter fail to comply with 35 U.S.C. 101. In re Moreton, 288 F.2d 708, 709, 129 USPQ 227, 228 (CCPA 1961)("one cannot claim a new use per se, because it is not among the categories of patentable inventions specified in 35 U.S.C. § 101 "). In Ex parte Dunki, 153 USPQ 678 (Bd. App. 1967), the Board held the following claim to be an improper definition of a process: "The use of a high carbon austenitic iron alloy having a proportion of free carbon as a vehicle brake part subject to stress by sliding friction." In Clinical Products Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966), the district court held the following claim was definite, but that it was not a proper process claim under 35 U.S.C. 101: "The use of a sustained release therapeutic agent in the body of ephedrine absorbed upon polystyrene sulfonic acid." Although a claim should be interpreted in light of the specification disclosure, it is generally considered improper to read limitations contained in the specification into the claims. See In re Prater, 415 F.2d 1393, 162 USPQ 541 (CCPA 1969) and In re Winkhaus, 527 F.2d 637, 188 USPQ 129 (CCPA 1975), which discuss the premise that one cannot rely on the specification to impart limitations to the claim that are not recited in the claim. In the interest of compact prosecution, the “use” claim is interpreted as a method claim that requires the step of administering to a cell or subject the complex of Claim 1. Applicant is required to reword their “use” claims to make it a method claim. See MPEP §2173.05(q). Claim Rejections - 35 USC § 102 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. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. Claim(s) 5, 9-11, 13-15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent No. 9790490, published 17 October 2017 (“US490”, of record). US490 discloses (§Abstract) systems, methods, and compositions for targeting nucleic acids, including RNA-targeting systems comprising an RNA-targeting CRISPR effector protein and at least one a guide RNA. US490 discloses (Col 2-4 L55-30) a Cpf1 CRISPR Cas protein that forms a complex with one or more nucleic acid components and upon binding of the complex to the locus of interest, induces a modification such as a strand break or genome (not RNA) editing. US490 discusses “Cpf1” and “Type V/Type VI” nucleases but doesn’t use the term “CasΩ nuclease”. However, as discussed above in §112(b), the Spec. discloses that US490’s Cpf1 nucleases correspond to the present invention’s CasΩ nuclease. Therefore, anything that US490 teaches is a property or characteristic of Cpf1 or Type V/Type VI nucleases is also a characteristic inherent to the claimed CasΩ nuclease. Regarding the RNA-targeting activity of CasΩ: US490 discloses (Col 34-35 L65-5) their nucleic acid-targeting system comprises an endogenous Type V/Type VI CRISPR system wherein the RNA-targeting Cas enzyme is Cpf1. US490 discloses (Col 37 L20-35) the RNA-targeting effector protein may direct cleavage of one or both nucleic acid strands, including either or both of DNA and RNA. US490 teaches (Col 44 L20-30) their system is used for methods for controlling gene expression involving RNA sequence targeting and their methods avoid off-target binding because their systems have a high degree of sequence specificity for a target RNA. US490 discloses (Col 29 L1-10): a RNA-targeting system is characterized by elements that promote the formation of a RNA-targeting complex at the site of a target RNA sequence… “target sequence” refers to a DNA or RNA sequence to which a DNA or RNA-targeting guide RNA is designed to have complementarity, where hybridization between a target sequence and a RNA-targeting guide RNA promotes the formation of a RNA-targeting complex. That indicates that US490’s RNA-targeting system has complementarity to a target RNA sequence and forms a complex with a target RNA. Therefore, US490 anticipates the RNA-targeting activity of Cpf1 that is recited in Claims 5, 9-11, 13-15, and 17. Regarding the guide RNA that is selected to be specific for a target RNA: US490 discloses (Col 3 L15-30 and Col 26 L8-25) a guide RNA is designed to have complementarity and hybridization to a target sequence such as RNA polynt. US490 discloses (Col 43-44 L5-30) the target RNA of an RNA-targeting complex can be any RNA endogenous or exogenous to a eukaryotic cell, including an RNA residing in the nucleus, an mRNA or pre-mRNA, or a “disease-associated” RNA. Regarding Claim 1, as discussed, US490 discloses (Col 2 l40-50) a method of modifying sequences associated with or at a target locus of interest, the method comprising delivering to said locus a Type V CRISPR-Cas effector protein (disclosed to include Cpf1) and a nucleic acid component, wherein the effector protein forms a complex with the nucleic acid component and upon binding of the complex to the locus of interest, the effector protein induces modification a sequence modification at the locus of interest, wherein the modification can be a strand break. Therefore, US490 anticipates Claim 5. Regarding Claim 9: US490 discloses (Col 41-44 L65-30) methods that include (Col 43 L1-55) using their complex to get any RNA sequence include mRNA or pre-mRNA, including modifying expression of an RNA in a eukaryotic cell. That § describes the RNA-targeting complex binds to a target RNA, inactivating it so the sequence isn’t translated. That would modulate expression of the target RNA. US490 describes (Col 32 L50-61) the guideRNA has about 80%, 90%, or more complementarity to a target. Regarding the viral RNA, US490 discloses (Col 234-235 L65-10) methods of targeting RNA viruses including Hepatitis C. Therefore, US490 anticipates Claim 9. Regarding Claim 10, US490 describes (Col 144 L20-35) using the complex for modifying a target polynt; they disclose deleting, inserting, translocating, inactivating, activating are some examples of modifying. US490 discloses (Col 41-44 L65-30) methods that include (Col 42 L1-10) modifying a target RNA in a multiplicity of cell types, and the modifying can include deleting, inserting, and other sorts of modifying those clearly read on the requirement of “editing” an RNA. As discussed above, US490’s guide RNAs can be at least 90% complementary to a target. Regarding the catalytically inactive RNA-modifying enzyme, US490 discloses (Col 50 L25-67) dead Cas enzymes and (Col 193 L5-15) functional domains linked to dead Cpf1 Cas proteins. US490 discloses (Col 38 L29-40) a complex comprising one or more effector proteins and (Col 80-81 L50-5) Cpf1 homo- and hetero-dimers. US490 teaches (Col 50 L35-62) a catalytically dead Cas nuclease can have increased binding affinity and specificity for a target nuclease. Since US490 teaches a complex comprising one or more effector proteins, functional domains linked to dead Cpf1 Cas proteins, and a catalytically inactive RNA-modifying enzyme, the sum teachings of US490 read on a complex comprising a catalytically inactive CasΩ complexed with an RNA-modifying enzyme and a guide RNA that has 90% complementarity to a target. Altogether, US490 anticipates Claim 10. Regarding Claim 11: US490 discloses (Col 42 L15-25) the method can be used to cleave a disease RNA in a cell. As discussed above regarding the viral RNA, US490 discloses (Col 234-235 L65-10) methods of targeting RNA viruses including Hepatitis C. Regarding proliferative disorders, US490 discloses (Col 152 L43) disease targets can be cancer and (Col 262 L50-60) modulating expression of a target nuclei acid sequence in connection with cancer treatment. Therefore, US490 anticipates Claim 11. Regarding Claim 13: US490 discloses (Col 242 L15-35) using their systems to induce bacterial cell death, including treatments that are pathogen-specific. That indicates that they intended their methods to be used to kill pathogenic bacterial, fungal, and parasitic pathogens, which would inactivate those cells, thereby anticipating Claim 13. Regarding Claims 14 and 17: the previous ¶ explained that US490 discloses treating a disease or infection with a complex comprising a Cas nuclease (including Cpf1 nuclease) and a guide RNA that is specific to a bacterium, HepC, or to treat cancer. Therefore, US490 anticipates Claims 14 and 17. Regarding Claim 15: the preceding ¶ explained that US490 discloses methods of cleaving a target RNA using a complex comprising a Cas nuclease (including Cpf1 nuclease) and a guide RNA that is specific to an RNA target. Therefore, US490 anticipates Claim 15. Claim Rejections - 35 USC § 103 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 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. 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. Claim(s) 5, 9-11, 13-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 9790490 (published 17 October 2017, “US490”, of record) as applied to Claims 5, 9-11, 13-15, and 17 in the 102 rejection above. The 102 rejection above explains how US490 anticipates each of the limitations in Claims 5, 9-11, 13-15, and 17. US490 describes (Col 144 L20-35) using their complex for modifying a target polynt; they disclose deleting, inserting, translocating, inactivating, activating are some examples of modifying. US490 discloses (Col 41-44 L65-30) methods that include (Col 42 L1-10) modifying a target RNA in a multiplicity of cell types, and the modifying can include deleting, inserting, and other sorts of modifying those clearly read on the requirement of “editing” an RNA. Regarding the catalytically inactive RNA-modifying enzyme, US490 discloses (Col 50 L25-67) dead Cas enzymes and (Col 193 L5-15) functional domains linked to dead Cpf1 Cas proteins. US490 discloses (Col 38 L29-40) a complex comprising one or more effector proteins and (Col 80-81 L50-5) Cpf1 homo- and hetero-dimers. US490 teaches (Col 50 L35-62) a catalytically dead Cas nuclease can have increased binding affinity and specificity for a target nuclease. Regarding Claim 10: US490 does not explicitly disclose a complex comprising at least one catalytically inactive CasΩ complexed with at least one RNA-modifying enzyme and at least one guide RNA. However, US490 teaches their Cas nuclease cleaves RNA; that cleavage can be considered a form of editing. US490 teaches a complex comprising one or more effector proteins, functional domains linked to dead Cpf1 Cas proteins, and a catalytically inactive RNA-modifying enzyme. US490 teaches a catalytically dead Cas nuclease can have increased binding affinity and specificity for a target nuclease. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that modifying the complex comprising more than one effector protein of US490 with the teaching about a dead Cpf1 Cas nuclease having increased binding affinity and specificity for a target nuclease would have the benefit of producing a complex that is highly specific for its target (i.e., binding via the increased-specificity dead Cpf1 Cas nuclease) and also capable of cleaving the target (i.e., a complex comprising a catalytically dead and a catalytically active Cpf1 Cas nuclease). Therefore, all the limitations of Claim 10 (and Claims 5, 9, 11, 13-15, and 17) would have been obvious in view of US490. Claim(s) 5, 9-11, 13-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 9790490 (published 17 October 2017, “US490”, of record) as applied to Claims 5, 9-11, 13-15, and 17 in the 102 rejection above, and further in view of International Patent Application Publication No. WO 2021/099996 (published 27 May 2021, “WO996”, of record). The 102 rejection above explains how US490 anticipates each of the limitations in Claims 5, 9-11, 13-15, and 17. US490 does not explicitly disclose the sequence of a Cas nuclease or Cpf1 Cas nuclease that indicates it is a CasΩ nuclease as claimed. However, WO996 teaches (p. 7 L5-15) the term Cms1 endonucleases or Cms1 polypeptides refers to…sequences set for [sic] in SEQ ID NOs 41-160… The instant Spec. teaches that (p. 15 L20-25) the subgroup of ca40CasΩ nucleases according to the present invention, in particular as shown in SEQ ID Nos. 1-15, as one distinguishing feature exhibits a unique AA composition between the RuvC-II and RuvC-III catalytic motifs, comprising a deletion of AAs compared to nonCasΩ nucleases, such as Cas12a. SEQ ID NO. 1 in the claimed invention is identical to WO996 SEQ ID NO 153, as shown by the following AA sequence alignment: Query Match 100.0%; Score 6184; DB 33; Length 1180; Best Local Similarity 100.0%; Matches 1180; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 MSDKNQSFSQFTNLYELSKTLRFELKPSEITFEKLENNKLFKVKDVESKIFSKNENGEIS 60 SEQ ID NO 1 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 MSDKNQSFSQFTNLYELSKTLRFELKPSEITFEKLENNKLFKVKDVESKIFSKNENGEIS 60 SEQ ID NO 153 Qy 61 EAEKKVKNYLFDINETELNNLVKKCDEKIEEIKKIKDFLEKNPDKLWQVWIDNEKIKIID 120 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 EAEKKVKNYLFDINETELNNLVKKCDEKIEEIKKIKDFLEKNPDKLWQVWIDNEKIKIID 120 [truncated for brevity] Qy 1081 IQRIEDIKELQKEDKKGGQLGNLIFVDPENTSKQCPNCLEIGQRKHSRPTHDFVKCKKCG 1140 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1081 IQRIEDIKELQKEDKKGGQLGNLIFVDPENTSKQCPNCLEIGQRKHSRPTHDFVKCKKCG 1140 Qy 1141 FDTRNDDTKKGFDFIDGGDTLAAYNIAKRGLKFLKEKNNL 1180 |||||||||||||||||||||||||||||||||||||||| Db 1141 FDTRNDDTKKGFDFIDGGDTLAAYNIAKRGLKFLKEKNNL 1180 Since the instant Spec. identifies SEQ ID NO 1 as a CasΩ and SEQ ID NO 1 is identical to WO996 SEQ ID NO 153, SEQ ID NO 153 has the same structure as a CasΩ nuclease, is a CasΩ nuclease and therefore inherently encompasses all the properties of a CasΩ nuclease. Since the Spec. discloses (p. 3, full ¶2) CasΩ is Cpf1, that means that WO996 SEQ ID NO 153 (called Cms1) is the same thing as Cpf1. Altogether, Cms1 = CasΩ = Cpf1. WO996 teaches (p. 4 L17-27) after Cpf1 hybridizes with its primary target it can cleave ssDNA in a non-sequence specific manner. WO996 teaches (pp. 26-27 L29-11, p. 38 L1-5) methods of using their SEQ ID NO 153 to kill bacterial cells. Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention that the invention of US490 comprising Cpf1 nucleases could be modified with the Cms1 enzyme comprising WO996’s SEQ ID NO 153 of WO996 for the benefit of testing whether the complex comprising WO996 SEQ ID NO 153 is as effective at killing non-bacterial cells as the nucleases disclosed in US490. One would have been motivated to do so with a reasonable expectation of success because WO996 discloses (pp. 42 points 10 and 11) using their invention to kill bacteria and shows (p. 38 L1-5) an example of doing so, but does not discuss using their invention to kill fungal cell or to treat a proliferative disorder. Therefore, all the limitations of Claims 5, 9-11, 13-15, and 17 would have been obvious in view of US490 and WO996. Alternatively, (1) WO996’s disclosure that their Cms1 nuclease comprising SEQ ID NO 153 is 100% identical to the claimed invention’s SEQ ID NO 1 and (2) the Spec.’s disclosure that US490 discloses CasΩ nucleases indicate that all the claim limitations of Claims 5, 9-11, 13-15, and 17 would have been inherently comprised by the methods disclosed in US490. Claim(s) 5, 9-11, 13-15, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. 9790490 (published 17 October 2017, “US490”, of record) as applied to Claims 5, 9-11, 13-15, and 17 in the 102 rejection above and further in view of Lall (2019. New CRISPR platform expands RNA editing capabilities. McGovern Institute at MIT. Available online at mcgovern.mit.edu. Dated 11 July 2019, “Lall”). The 102 rejection above explains how US490 anticipates each of the limitations in Claims 5, 9-11, 13-15, and 17. US490 describes (Col 144 L20-35) using their complex for modifying a target polynt; they disclose deleting, inserting, translocating, inactivating, activating are some examples of modifying. US490 discloses (Col 41-44 L65-30) methods that include (Col 42 L1-10) modifying a target RNA in a multiplicity of cell types, and the modifying can include deleting, inserting, and other sorts of modifying those clearly read on the requirement of “editing” an RNA. Regarding the catalytically inactive RNA-modifying enzyme, US490 discloses (Col 50 L25-67) dead Cas enzymes and (Col 193 L5-15) functional domains linked to dead Cpf1 Cas proteins. US490 discloses (Col 38 L29-40) a complex comprising one or more effector proteins and (Col 80-81 L50-5) Cpf1 homo- and hetero-dimers. US490 teaches (Col 50 L35-62) a catalytically dead Cas nuclease can have increased binding affinity and specificity for a target nuclease. Regarding Claim 10: US490 does not explicitly disclose a complex comprising at least one catalytically inactive CasΩ complexed with at least one RNA-modifying enzyme and at least one guide RNA. However, Lall teaches (¶3) Zhang (the lead inventor of US490) and his team used a deactivated Cas13 to guide RESCUE to targeted cytosine bases on RNA transcripts, and used a novel programmable enzyme to convert unwanted cytosine into uridine, thereby directing a change in the RNA instructions. 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 US490’s complex comprising dead Cpf1 Cas enzyme (which has increased binding affinity and specificity) with Lall’s teaching about using a deactivated Cas13 nuclease to guide an RNA-editing enzyme to a specific site on RNA. One would have done so for the benefit of using US490’s dead Cpf1 Cas enzyme—which US490 teaches has increased binding affinity and specificity for a target RNA—with Lall’s RESCUE enzyme to edit RNA to treat devastating diseases that affect the brain. One would have been motivated to do so with a reasonable expectation of success because US490 teaches their complex can comprise a dead Cpf1 Cas and other functional domains, and teaches that dead Cpf1 Cas nucleases can have increased binding affinity and specificity for a target RNA. One would have been motivated to do so with a reasonable expectation of success because Lall teaches their RESCUE enzyme was linked to another dead Cas enzyme and could be used (¶1) to treat devastating brain diseases, and it would have been a simple matter to swap the highly specific dead Cpf1 Cas of US490 for the dead Cas of Lall. Doing so would have produced a complex recited in Claim 10, and using it to edit a target RNA would have produced all the limitations of Claim 10. Double Patenting A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957). A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101. Claims 5 and 9-11 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 5 and 9-11 of copending Application No. 17335818 (reference application). This is a provisional statutory double patenting rejection since the claims directed to the same invention have not in fact been patented. # This application App. #17335818 5 a method for cleaving a nucleic acid molecule selected from dsDNA, ssDNA, and RNA, comprising the steps of a) providing at least one CasΩ nuclease enzyme, b) providing at least one preselected guide RNA, c) forming a complex between the least one CasΩ nuclease enzyme and the at least one preselected guide RNA, d) binding of the complex of c) to a target RNA based on the at least one preselected guide RNA, and e) cleaving said nucleic acid molecule selected from dsDNA, ssDNA, and RNA by the at least one CasΩ nuclease enzyme. A method for cleaving a nucleic acid molecule selected from dsDNA, ssDNA, and RNA, comprising the steps of a) providing at least one CasΩ nuclease enzyme, b) providing at least one preselected guide RNA, c) forming a complex between the least one CasΩ nuclease enzyme and the at least one preselected guide RNA, d) binding of the complex of c) to a target RNA based on the at least one preselected guide RNA, and e) cleaving said nucleic acid molecule selected from dsDNA, ssDNA, and RNA by the at least one CasΩ nuclease enzyme. 11 The method according to claim 5, wherein the at least one target RNA comprises a nucleic acid sequence that is specific for a disease state, such as, for example, for cells selected from the group consisting of cells exhibiting a genetic disorder, cells exhibiting a proliferative disorder, such as cancer cells, immune cells that produce autoantibodies, cells infected with bacterial or viral pathogens, bacterial pathogens, protozoan pathogens, cells of microbiota, and contaminating bacteria or archaea. The method according to claim 5, wherein the at least one target RNA comprises a nucleic acid sequence that is specific for a disease state, such as, for example, for cells selected from the group consisting of cells exhibiting a genetic disorder, cells exhibiting a proliferative disorder, such as cancer cells, immune cells that produce autoantibodies, cells infected with bacterial or viral pathogens, bacterial pathogens, protozoan pathogens, cells of microbiota, and contaminating bacteria or archaea. 9 A method for modulating expression of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample, wherein said at least one target RNA is selected from an mRNA, non-coding RNA and a viral RNA molecule, said method comprising: a) contacting said cell, tissue, cellular nucleus, and/or sample with at least one complex comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA, further bound to a target RNA molecule having a sequence that is at least 90% complementary to said guide RNA, and c) binding the complex of b) to the at least one target RNA and thereby altering the stability, processing, or translation of the at least one target RNA, whereby the binding in c) modulates the expression of at least one target RNA in the cell, tissue, cellular nucleus, and/or sample. A method for modulating expression of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample, wherein said at least one target RNA is selected from an mRNA, non-coding RNA and a viral RNA molecule, said method comprising: a) contacting said cell, tissue, cellular nucleus, and/or sample with at least one complex between at least one CasΩ nuclease enzyme and at least one preselected guide RNA, wherein said at least one preselected guide RNA comprises a sequence that is at least 90% complementary to the at least one target RNA, and c) binding the complex of b) to the at least one target RNA and thereby altering the stability, processing, or translation of the at least one target RNA, whereby the binding in c) modulates the expression of at least one target RNA in the cell, tissue, cellular nucleus, and/or sample. 10 A method for editing the sequence of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample, wherein said at least one target RNA is selected from an mRNA, non-coding RNA and a viral RNA molecule, said method comprising: a) contacting said cell, tissue, cellular nucleus, and/or sample with at least one complex between at least one modified and catalytically inactive CasΩ nuclease enzyme complexed with at least one RNA-modifying enzyme and at least one preselected guide RNA, wherein said at least one preselected guide RNA comprises a sequence that is at least 90% complementary to the at least one target RNA, and c) binding the complex of b) to the at least one target RNA, and editing of the at least one target RNA by said at least one RNA-modifying enzyme. A method for editing the sequence of at least one target RNA in a cell, tissue, cellular nucleus, and/or sample, wherein said at least one target RNA is selected from an mRNA, non-coding RNA and a viral RNA molecule, said method comprising: a) contacting said cell, tissue, cellular nucleus, and/or sample with at least one complex between at least one modified and catalytically inactive CasΩ nuclease enzyme complexed with at least one RNA-modifying enzyme and at least one preselected guide RNA, wherein said at least one preselected guide RNA comprises a sequence that is at least 90% complementary to the at least one target RNA, and c) binding the complex of b) to the at least one target RNA, and editing of the at least one target RNA by said at least one RNA-modifying enzyme. **Note that although there is a slight difference in wording between the two versions of Claims 9 (indicated by bolding/underlining), the scope of the claims is exactly the same. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Claims 5, 9-11, 13-15, and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5, 9-14, and17-18 of copending Application No. 17335818 (reference application, “App818”). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to complexes comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA. Both claim sets require a complex comprising CasΩ and a guide RNA. The instant claims recite methods for using the complex, including cleaving a nucleic acid, modulating expression of a target RNA, editing a target RNA sequence, and treating/preventing any disease. Those methods could not be used without the complex recited in the App818 claims. Both claim sets recite a method for specifically inactivating an undesired cell or virus, comprising contacting the cell or virus with a complex comprising a CasΩ nuclease and a guideRNA designed to bind at least one target RNA. Both claim sets require the same complex. It would not be possible to use the App818 invention without the instantly claimed methods. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Claims 5, 9-11, 13-15, and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-11, and 18 of copending Application No. 18872146 (reference application, “App146”) as evidenced by Dmytrenko (et al. 2022. Cas12a2 elicits abortive infection via RNA-triggered destruction of double-stranded DNA. BioRxiv, “Dmytrenko”, of record on IDS). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are directed to methods of using complexes comprising a CasΩ nuclease and at least one preselected guide RNA designed for binding to at least one target RNA. The App146 claims are directed to an isolated protein comprising Cas12a2 or a functional variant thereof, wherein said isolated protein is capable of indiscriminately cleaving a single stranded nucleic acid (which can be DNA or RNA) upon recognition of a specific complementary RNA target, and further wherein one or more residues are mutated such that double stranded nucleic acid cleavage is reduced or abrogated compared to native Cas12a2, including by 10% or more reduction; and to methods of using the Cas12a2. An artisan would not necessarily know that CasΩ and Cas12a2 are the same thing, but Dmytrenko provides evidence that is the case. Dmytrenko’s Fig. 1a shows that CasΩ is a kind of Cas12a2 because they are in the same area of the phylogenetic tree: PNG media_image2.png 402 450 media_image2.png Greyscale Therefore, both claims are inherently drawn to the same enzyme, and both claim sets require CasΩ, even if App146 calls it Cas12a2. Therefore, the invention of the App146 claims requires the claimed invention and the claimed invention would not be usable without a protein recited in the App146 claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. 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 Art Unit 1635 /RUTH SOPHIA ARIETI/Examiner, Art Unit 1635 /NANCY J LEITH/Primary Examiner, Art Unit 1636