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 .
1. Claims 2, 11, 13, 17, 24, 25, 29-35, and 37-43 have been cancelled. Claims 1, 3-10, 12, 14, 18-23, 27, 28, and 44 have been amended. Claims 45-48 are new.
Claims 1, 3-6, 8-10, 12, 14-23, 26-28, 36, and 44-48 are pending and under examination.
2. All rejections pertaining to claims 2 and 17 are moot because the claims were cancelled with the reply filed on 04/22/2026.
The objections to claims 9, 22, and 44 are withdrawn in response to the amendments filed on 04/22/2026.
The rejection to claims 10, 14, 23, and 27 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ) is withdrawn in view of the amendments to delete the phrase "such as" from claims 10 and 23; and to delete the recitations within parenthesis from claims 14 and 27.
Claim Objections
3. Claim 28 is objected to because of the recitation “a nucleic acid” in the preamble. Correction to “the nucleic acid” is required.
4. Claim 47 is objected to because of the recitation “a 5 end or a 3 end” in the preamble. Correction to “the 5 end or the 3 end” is required.
5. Claim 48 is objected to because of the recitation “and or” in the second line. Correction to “and/or” is required.
Claim Rejections - 35 USC § 103
6. 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 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.
7. Claims 1, 3, 4, 9, 12, 14, 16, 22, 26-28, 36, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (Chem. Commun., 2013, 49: 5462-5464), in view of both Kim et al. (Scientific Reports, 2015, 5: 1-9) and Zhang et al. (Drug Delivery, 2019, 26: 328-342; online 03/24/2019).
Wang et al. teach an RNA-DNA hybrid origami scaffold having a maximum dimension of less than 100 nm; the hybrid origami is obtained by using short DNA staples to fold a long RNA (scaffold sequence) into predefined higher order structures (ribbons, rectangles, and triangles). Wang et al. teach that, as opposed to attaching, programmed RNA self-assembly could integrate multiple functions into the nanostructure such that the nanostructure could perform complex activities (claims 1, 3, and 4) (see p. 5462; p. 5463, column 1 and Fig. 3; p. 5464, Fig. 4, column 1, first full paragraph, and paragraph bridging columns 1 and 2; Supplementary Material, Table S1 and Fig. S5).
Wang et al. do not teach that the single-stranded RNA is an mRNA (claims 1 and 16). Kim et al. teach that nanoparticles made entirely of mRNA (mRNA NPs) exhibit enhanced resistance to nucleases and could be used for effective gene delivery; the mRNA NPs slowly undergo translation into cells to provide continuous and prolonged gene expression (see Abstract; p. 4; p. 5, fifth paragraph). Based on these teachings, one of skill in the art would have found obvious to modify Wang et al. by using an mRNA in the RNA-DNA hybrid origami, to achieve the predictable result of obtaining nanoparticles capable of mediating effective gene delivery, when gene delivery was needed.
With respect to claims 9 and 22, Kim et al. teach that the mRNA NPs could be used for vaccination (see p. 5, sixth paragraph). Thus, using an antigen-encoding mRNA would have been obvious to one of skill in the art, to achieve the predictable result of obtaining a composition suitable for inducing immune responses. With respect to claims 28, 36, and 44, one of skill in the art would have found obvious to further formulate the composition with a pharmaceutically acceptable excipient and administer the resultant pharmaceutical composition to a subject in need of immunization, with the reasonable expectation that doing so would induce immune responses in the subject.
Wang et al. and Kim et al. do not teach a membrane binding moiety (claims 1, 12, 14, 26, and 27). Zhang et al. teach that cellular uptake is enhanced by decorating the nanoparticles with hydrophobic moieties (such as cholesterol and alkyl chains) which promote interaction with the phospholipid bilayer (see p. 329, paragraph bridging columns 1 and 2; p. 330, paragraph bridging columns 1 and 2; p. 331, column 1, first paragraph). Based on these teachings, one of skill in the art would have found obvious to decorate the mRNA-DNA hybrid origami with cholesterol or alkyl, to achieve the predictable result of enhancing its cellular uptake.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
8. Claims 1, 3, 4, 9, 12, 14, 16, 22, 26-28, 36, and 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with both Kim et al. and Zhang et al., in further view of Howorka et al. (WO 18/011603).
The teachings of Wang et al., Kim et al. and Zhang et al. are applied as above for claims 1, 3, 4, 9, 12, 14, 16, 22, 26-28, 36, and 44. Wang et al., Kim et al. and Zhang et al. do not teach dodecyl-beta-D-glucoside (claims 14, 27, 45, and 46). Howorka et al. teach that decorating nucleic acid nanostructures with dodecyl-beta-D-glucoside promotes interaction with the phospholipid bilayer (see p. 3, lines 18-20; p. 4, lines 38-40; p. 14, lines 27-36). Replacing cholesterol/alkyl with dodecyl-beta-D-glucoside would have been obvious to one of skill in the art to achieve the predictable result of enhancing the cellular uptake of the mRNA-DNA hybrid origami.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
9. Claims 1, 3, 4, 9, 10, 12, 14, 16, 22, 23, 26-28, 36, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with both Kim et al. and Zhang et al., in further view of Fiedler et al. (Recent Results in Cancer Research, 2016, 209: 61-85; Abstract).
The teachings of Wang et al., Kim et al. and Zhang et al. are applied as above for claims 1, 3, 4, 9, 12, 14, 16, 22, 26-28, 36, and 44. Wang et al., Kim et al. and Zhang et al. do not teach that the antigen is a tumor-associated antigen (TAA) (claims 10 and 23). Fiedler et al. teach treating cancer by immunizing with mRNAs encoding TAAs (see Abstract). Thus, specifically using a TAA-encoding mRNA would have been obvious to one of skill in the art, to achieve the predictable result of obtaining a composition suitable for treating cancer.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
10. Claims 1, 3-9, 12, 14, 16, 18-22, 26-28, 36, 44, 47, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. taken with both Kim et al. and Zhang et al., in further view of both Andersen et al. (Nature, 2009, 459: 73-76) and Veneziano et al. (Science, 2016, 352: 1-8).
The teachings of Wang et al., Kim et al. and Zhang et al. are applied as above for claims 1, 3, 4, 9, 12, 14, 16, 22, 26-28, 36, and 44. Wang et al., Kim et al. and Zhang et al. do not teach second and third scaffolds (claims 5-8 and 18-21). However, Wang et al. teach that RNA-DNA hybrid origami provide the potential for integration of diverse RNAs and functions into a single nanomachine (see p. 5464, column 2, last paragraph). Andersen et al. teach obtaining a DNA cubic higher-order structure (nanobox having a lid functionalized with a DNA dual lock-key) for the controlled release of cargoes of interest; the nanobox is obtained by using edge staples to assemble six DNA origami sheets into a cuboid structure; the lid and one facet of the main box each comprise two double-stranded DNA staples terminated with sticky ends (i.e., unpaired nucleotide extension at the 5’ or 3’ end); the lid is closed via the hybridization of the sticky ends present on the lid and facet (see Abstract; p. 73, Fig.1b-c; paragraph bridging p. 73 and 74; paragraph bridging p. 74 and 75; p. 75, Fig. 4a-b and paragraph bridging columns 1 and 2; p. 76, column 1, first paragraph; see the attached Supplementary Information, Fig. 1).
While Anderson et al. do not specifically teach vertex staples, Veneziano et al. teach using both edge and vertex staples to obtain 3-D higher-order structures (see p. 2, column 1, last paragraph and Fig. 1; Supplemental Materials, p. 3, Fig. S1 and p. 6, last paragraph). Based on these teachings, one of skill in the art would have found obvious to use the teachings of Wang et al., Kim et al. and Zhang et al. to fold an mRNA (scaffold sequence) encoding a protein of interest into six origami sheets and further assembling the sheets into the nanobox structure taught by Andersen et al. by using edge and vertex staples, with the reasonable expectation that doing so would result in a nanobox suitable to be used for continuous and prolonged expression of the protein of interest and also as a device for controlled release of agents of interest, when the delivery of the combination between proteins and agents of interest was needed. By doing so, one of skill in the art would have obtained a cuboid comprising vortex staples, each holding three facets together (i.e., a plurality of staples hybridizing with a region of a first, second, and third scaffold sequences, as recited in claims 5, 7, 18, and 20) and double-stranded DNA staples terminated comprising unpaired nucleotide extensions at the 5’ or 3’ end (claims 47 and 48).
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
11. The arguments addressing the references individually are not found persuasive because none of the references has to teach every claim limitation.
The applicant argues that, by teaching that RNA-DNA hybrid origami structures are less stable than the DNA origami, Wang teaches away from using the RNA-DNA hybrid origami for stability-critical applications.
This is not found persuasive. Wang teaches that the RNA itself is less stable than DNA, hence a lower RNA origami yield (see p. 5464, column 2, last paragraph). Wang does not teach or even suggest that the assembled origami are unsuitable for stability-critical applications. There is no such teaching or suggestion in the prior art as a whole. It was common knowledge in the prior art that RNA (including RNA origami) could be introduced into cells via encapsulation and stabilization into liposomes. See for example Afonin (ACS Nano, 2015, 9: 251-259), who teaches using lipofectamine to introduce RNA origami into cells (p. 252).
The argument that Wang and Kim are incompatible is not found persuasive because it is just an argument not supported by any evidence. Kim was only cited for providing the motivation to use an mRNA to make Wang’s RNA-DNA hybrid origami, which is compatible with Wang.
Thus, the applicant did not demonstrate that the combination of Wang, Kim, and Zhang does not teach the limitations of claims 1 and 16.
The argument that Fiedler, Andersen, Veneziano, and Howorka do not cure the deficiencies of Wang, Kim, and Zhang is not found persuasive because there is no deficiency to be cured in the combined teachings of Wang, Kim, and Zhang.
Conclusion
12. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Afonin (ACS Nano, 2015, 9: 251-259) was cited in response to the argument that Wang teaches away from using the RNA-DNA hybrid origami for stability-critical applications. Afonin provides evidence against the argument of teaching away.
13. Applicant's amendment necessitated the new ground(s) of rejection (specifically, including the new claims in the grounds of the rejections) presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ILEANA POPA/Primary Examiner, Art Unit 1633
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