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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in
37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 26, 2026 has been entered.
Claim Status
Claim listing filed on May 26, 2026 is pending. Claims 1-62, 64-65, 68-69, 73, and 78 are canceled. Claims 63, 66-67, 76-77, and 79-81 are amended. Claims 82-89 are new. Claims 63, 66-67, 70-72, 74-77, and 79-89 are examined upon their merits.
Information Disclosure Statement
The information disclosure statements filed on 02/13/2026 and 05/26/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Withdrawn Claim Rejections
Applicant’s cancelation of Claims 64-65, 68, 73, and 78 have rendered all previous rejections directed to these claims moot.
Claim Objections (New, necessitated by amendment)
Claim 63 is objected to because of the following informalities: “N6-methyladenosine (m6A), or pseudouridine” in line 6 does not require a comma as it is not a list and should be corrected to “N6-methyladenosine (m6A) or pseudouridine.” Appropriate correction is required.
Applicant is advised that should Claim 87 be found allowable, Claim 88 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. Claim 87 depends from Claim 85 which requires that the composition comprising the modified circular RNA molecule is administered by intravenous administration. Claim 88 depends from Claim 87 and repeats the same limitation (the composition comprising the modified circular RNA molecule is administered by intravenous administration). Therefore, Claims 87 and 88 are substantial duplicates. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112 (New, necessitated by amendment)
Claims 84-89 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 84 recites the limitation "the modified nucleoside" in line 12. There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, "the modified nucleoside" is interpreted as the adenosines replaced with m6A. Appropriate action is required.
Claim Rejections - 35 USC § 102 (Maintained)
The rejection of Claims 63, 66-67, 70-72, 74-75, 79-80, and 82-84 under 35 U.S.C. 102(a)(2) as being anticipated by Kahvejian et al. WO 2020/023655 (of record) is maintained. Note, the 102(a)(2) rejection of record applied to Claims 63-68, 70-75, and 78-80 and now applies to Claims 63, 66-67, 70-72, 74-75, 79-80, and 82-84 due to Applicant’s amendments.
The teachings of Kahvejian as they apply to Claims 63, 66-67, 70-72, 74-75, 79-80, and 82-84 are of record in the final office action filed 03/26/2026. Note, it is of record that Kahvejian teaches BJ cells transfected with unmodified circular RNA or modified circular RNA (paragraph [0488]) which reads on instant Claim 79 wherein “naked RNA” is interpreted as free RNA that is not complexed with a delivery system such as a nanoparticle.
Applicant's arguments filed May 26, 2026 have been fully considered but they are not persuasive. Applicant argues that Kahvejian only discloses circular RNAs that are modified with a combination of pseudouridine and methylcytosine, and Kahvejian does not teach that pseudouridine modification in the absence of methylcytosine can reduce immunogenicity of a circular RNA. The language of Claim 63 recites “wherein the modified circular RNA molecule comprises modified nucleoside of N6-methyladenosine (m6A) or pseudouridine” (emphasis added). MPEP § 2111.03.I states that the transitional term “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. Therefore, the circular RNA with reduced immunogenicity taught by Kahvejian that comprises methylcytosine nucleoside modifications in addition to the pseudouridine nucleoside modifications reads on the instant claims. Further, Kahvejian must be interpreted in light of the state of the art at the time of filing. One of ordinary skill would have understood that the pseudouridine nucleoside modifications of Kahvejian contributed to the reduced immunogenicity because it was well-understood in the art at the time of filing that pseudouridine modifications render mRNA non-immunogenic as single modifications (Kariko et al. Mol Ther. 2012; Abstract, Introduction paragraphs 3 and 5, Fig. 2E) and in combination with 5-methylcytidine (Kariko et al. Nucleic Acids Res. 2011; Figs. 3C-D and 4A, Results paragraph 5). Note, Kariko 2012 and Kariko 2011 are cited solely in response to Applicant’s arguments and not as a new ground of rejection.
Applicant argues that Kahvejian teaches that circular RNA not completely modified with m6A (i.e. less that 100% m6A modification) does not reduce the immunogenicity of the modified circular RNA. Instead, Kahvejian states that m6A hybrid modified circular RNA showed “similar levels” of immune proteins as compared to the unmodified circular RNA (Kahvejian paragraph [0494]). It is of record in the final office action filed 03/26/2026 that “reduce” is interpreted to encompass any reduction, even a statistically insignificant change, wherein “immune response” can be quantified by any means known in the art prior to the time of filing (final office action page 2). Under this interpretation of “reduce,” the teachings of Kahvejian read on the instant claims. Specifically, Kahvejian teaches that the expression of immune proteins was decreased in the m6A hybrid modified circular RNA as compared to the unmodified circular RNA at the 72-hour timepoint across RIG-I, MDA5, and IFN-b proteins (as shown below in Fig. 11 comparing the solid arrows (unmodified) to the dotted arrows (m6A hybrid modified)). Applicant’s arguments have been considered but are not persuasive, and the rejection is maintained.
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Claim Rejections - 35 USC § 103 (Maintained)
The rejection of Claims 63, 66-67, 70-72, 74-77, 79-80, and 82-89 under 35 U.S.C. 103 as being unpatentable over Kahvejian et al. WO 2020/023655 (of record) in view of Pandolfi et al. US 2017/0298347 (of record) is maintained. Note, the 103 rejection of record applied to Claims 63-68, 70-77, and 78-80 and now applies to Claims 63, 66-67, 70-72, 74-77, 79-80, and 82-89 due to Applicant’s amendments.
Applicant's arguments filed May 26, 2026 have been fully considered but they are not persuasive. Applicant argues that Pandolfi does not cure the deficiencies of Kahvejian. The alleged deficiencies of Kahvejian are addressed above, and the rejection is maintained.
The rejection of Claims 63, 66-67, 70-72, 74-75, and 79-84 under 35 U.S.C. 103 as being unpatentable over Kahvejian et al. WO 2020/023655 (of record) in view of Rosenkranz et al. Russ. Chem. Bull. 2015 (of record) is maintained. Note, the 103 rejection of record applied to Claims 63-68, 70-75, and 78-81 and now applies to Claims 63, 66-67, 70-72, 74-75, and 79-84 due to Applicant’s amendments.
Applicant's arguments filed May 26, 2026 have been fully considered but they are not persuasive. Applicant argues that Rosenkranz fails to cure the deficiencies of Kahvejian. The alleged deficiencies of Kahvejian are addressed above, and the rejection is maintained.
Claim Rejections - 35 USC § 103 (New, necessitated by amendment)
Claims 63, 66-67, 70-72, 74-75, 79-80, and 82-84 are rejected under 35 U.S.C. 103 as being unpatentable over Kahvejian et al. WO 2020/023655 (of record) in view of Kariko et al. Immunity. 2005. MPEP § 2120.I states that when the propriety of a 35 U.S.C. 102 rejection depends on a particular interpretation of a claim (such as the interpretation of “reduce” in the maintained 102 rejection above), then in the interest of compact prosecution, such rejections should be backed up by the best other art rejections available.
The teachings of Kahvejian as they apply to Claims 63, 66-67, 70-72, 74-75, 79-80, and 82-84 are of record in the final office action filed 03/26/2026. Specifically, Kahvejian teaches that the circular RNA can include from about 1% to about 100% modified nucleotides (paragraph [0290]; of record). The circular RNA can be completely m6A modified (100%) or partially m6A modified (less than 100% but greater than 1%) (paragraph [0485] and Fig. 9A; of record). Kahvejian teaches that m6A completely modified circular RNAs showed reduced levels of MDA5, OAS and IFN-beta immune protein expression as compared to unmodified circular RNA transfected cells (paragraph [0489] and Fig. 10; of record). Kahvejian further teaches that unlike the completely modified circular RNA, m6A hybrid modified circular RNA showed “similar levels” of RIG-I, MDA5, IFN-beta and OAS immune protein expression as compared to unmodified circular RNA transfected cells (paragraph [0494] and Fig. 11). From these results, Kahvejian concludes that modification of circular RNA, as compared to unmodified circular RNA, as well as the level of modification had an impact on activating immunogenic related genes (paragraph [0494]; emphasis added).
While Kahvejian summarizes that the level of m6A modification in circular RNA effects the level of immunogenicity, Kahvejian fails to directly compare how increasing or decreasing the percent m6A modification impacts the level of immunogenicity.
Kariko 2005 teaches that suppression of RNA-mediated immune stimulation is proportional to the number of modified nucleosides present in RNA (page 168, col. 2). The presence of an increasing amount of modified nucleosides proportionally inhibited the capacity of RNA to induce TNF-α (page 169, col. 1). The presence of 0.2%-0.4% m6A or pseudouridine was sufficient to cause detectable inhibition of cytokine secretion, 1.7%-3.2% m6A or pseudouridine maintained half its capacity to induce expression of TNF-α, and ~90% m6A or pseudouridine inhibited about 100% of TNF-α expression (page 169, col. 1 and Figs 5A-C).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was filed, that increasing the percentage of m6A modified nucleosides in the circular RNA of Kahvejian would decrease the level of immunogenicity based on the teachings of Kariko which show that the number of modified nucleosides is directly proportional to the suppression of immune stimulation. Although the specific hybrid m6A circular RNA of Kahvejian showed “similar levels” of immune protein expression as compared to unmodified circular RNA, one of ordinary skill would understand that increasing the percentage of modified nucleosides would reduce immunogenicity with a reasonable expectation of success. From the teachings of Kariko, it is clear that less than 100% of m6A modified nucleosides is still capable of reducing immunogenicity. The motivation to increase or decrease the level of m6A modification (between 1% and 100%) is to obtain the desired level of RNA immunogenicity.
Conclusion
No claim is allowed.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675
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