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 .
Election/Restrictions
Claims 1-10 are pending.
Applicant’s election without traverse of Group III, claims 9-10, in the reply filed on 07/22/2026 is acknowledged. Claims 1-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/22/2026.
Claims 9, 10 are examined here.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant’s claim to priority to Chinese application 202311355319.1, filed on 10/18/2023, is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/14/2023 and 04/02/2026 were filed before the mailing date of the first Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because of the following informalities: the Brief Description of Figures for Fig. 4 is a confocal image of cells “before and after co-culture with the nanoparticle vector for RNA self-delivery” (par. 34). There is only one image, so it is unclear if the image is both of before and after, or just before or just after RNA delivery (presumably it is after RNA delivery).
Appropriate correction is required.
Claim Interpretation
Claim 9 first recites “nanoparticle vector is loaded with a bone tissue repair drug” then recites “the nanoparticle vector comprises β-cyclodextrin-RNA conjugate [β-CD-RNA], an adamantane-ligand conjugate [AD-Lig], and a cationic polymer”. It is assumed that the nanoparticle vector comprises all the materials: bone tissue repair drug, and β-CD-RNA, AD-Lig and cationic polymer and that the conjugated RNA can also be a bone tissue repair drug.
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 9 is rejected under 35 U.S.C. 103 as being unpatentable over Heidel et al. (2012, J of Drug Delivery, 2012, 1-17, “Heidel”) and Malhotra et al (2018, Eur. J of Pharmaceutical Sciences, 114, pg. 30-37 and Supp. material; “Malhotra”; although an earlier version of Malhotra NPL is provided, the published version will be added to the record and is cited in this rejection).
Heidel’s historical review paper discloses cyclodextrin-containing polymers (CDPs) to incorporate therapeutic payloads into nanoparticles, including by noncovalent inclusion of cationic CDPs to anionic, nucleic acid payloads, including siRNA (abstract). Heidel discloses forming an inclusion compound of a functionalized adamantane (AD)-PEG5000 conjugated to transferrin ligand (AD-PEG-Tf) protein (pg. 9). This inclusion compound stabilizes the CDP nanoparticles containing β-cyclodextrin with siRNA, i.e. minimize self-self (aggregation) and self-non-self (e.g., protein binding) interactions in vivo (pg. 9). Further the cyclodextrin can also be used to form a polymer, which is made by copolymerization of b-CD diamine and dimethylsuberimidate, imparting two amidine charge centers, which enhances the CDP to release intracellular release of siRNA and is a cationic polymer-based nanoparticle (pg. 7). For proof-of-concept studies, the delivery system was tested administering siRNA on a murine model of Ewing’s family of tumors – mesenchymal malignancies that arise in bone or soft tissues, siRNA targeting a oncogenic fusion protein and administered to the mice via systemic injection (pg. 11). The siRNA treatment demonstrated a “statistically significant reduction in tumor burden was observed only for those nanoparticles which contained (i) the anti-EWS-Fli 1 siRNA and (ii) the Tf targeting ligand” (pg. 11).
Since, Heidel discloses administering siRNA targeting a tumor that affects bone tissues, the CD-siRNA complex is considered a bone tissue repair drug.
Heidel does not disclose that the siRNA is conjugated to β-cyclodextrin nor the recited molar ratio of 1:1:1-200 (b-CD-siRNA; AD-Li; cationic polymer).
Malhotra discloses that CD is conjugated to siRNA (pg. 30), noting the direct conjugation would allow “modified functionalised cyclodextrin which would afford new ways of formulation and delivery” and synthesized cyclodextrin-RNA using disulfide or sulfanyl linker (pg. 31). Malhotra discloses using equimolar ratios of CD-siRNA conjugates and either targeted and untargeted adamantyl (i.e. with ligand or without ligand) derivatives prior to treatment (pg. 33, thus the molar ratio of CD-RNA and AD-lig is 1:1). Malhotra discloses testing a couple mass ratios of CD-siRNA/adamantyl-PEG or adamantyl-PEG-ligand (“RVG”) and a chitosan polycationic polymer at mass ratios of 10 and 1 (pg. 35). Malhotra disclose range of knockdown of target gene (40% and 75%) thus concluding results show that conjugation of an RNA to an amphiphilic cyclodextrin confers improved self-assembly and delivery properties on the RNA (par. 141). Fig. 5A illustrates the CD-RNA conjugate with AD-PEG-lig along with chitosan polycationic polymer, pg. 36, see below.
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A skilled artisan can determine the molar ratio based on the mass and molecular weight of the CD-siRNA and the cationic polymer used (e.g., for Malhotra’s 1:1 mass ratio, based on MW of CD-siRNA at 9264, see Table 1, pg. 35, and chitosan’s medium molecular weight (MW=~250K), thus the molar ratio is ~27:1 of siRNA conjugate:chitosan. Chitosan is a large molecule compared to the siRNA conjugate) . Malhotra teaches testing a couple of ratios of chitosan polycationic polymer with CD-siRNA/AD-lig.
MPEP provides that differences in concentration will not support the patentability of subject matter encompasses by the prior art unless there is evidence that indicating such concentration is critical. Thus, Malhotra teaches the components added at a particular ratio (noting both molar and mass ratios) and a skilled artisan can optimize the ratio of the components.
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the electrostatic interaction of CD-siRNA of Heidel in view of Malhotra and arrive at the claimed invention with a reasonable expectation of success. Based on the success of Heidel to reduce tumor burden following administration of CD-siRNA and AD-PEG-ligand bound in polycationic polymer to Ewing’s murine model and Malhotra demonstrating that conjugating siRNA to CD, which will allow for greater modification of the CD, and complexing it with ADA-PEG-ligand and a polycationic polymer to inhibit the expression of target gene, a skilled artisan would reasonably expect success by modifying the electrostatic interaction between the siRNA and CD of Heidel to conjugating a siRNA to the CD in a nanoparticle complex also comprising a polycationic polymer with AD-PEG-ligand that is administered to a subject in need of. Thus, cl. 9 is obvious.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Heidel et al. (2012, J of Drug Delivery, 2012, 1-17, “Heidel”) and Malhotra et al (2018, Eur. J of Pharmaceutical Sciences, 114, pg. 30-37 and Supp. material; “Malhotra”) as applied to claim 9 above, and further in view of Rodell et al. (2013, Biomacromolecules, 14, 4125-4134, “Rodell”) and Zhu et al. (2018, Small, 14, 1-10, “Zhu”, in IDS).
Regarding “ADA-PEG-ADA” of claim 10, ADA is understood to be adamantane as the claim recites “terminated with an adamantane molecule” as ADA flanks PEG and is terminal.
Disclosure regarding rejection of cl. 9 is noted above.
Heidel and Malhotra do not disclose the claimed RNA self-delivery formulated as an injectable gel comprising the nanoparticle vector, a hyaluronic acid (HA)-CD macromer, wherein the nanoparticle and the HA-CD macromer are linked by a linker molecule ADA-PEG-ADA terminated with an adamantane molecule to form a gel complex.
Rodell discloses that shear-thinning hydrogels afford direct injection to tissues without potential premature gel formation and delivery failure of therapeutic drug (abstract). Rodell discloses developing a shear-thinning hyaluronic acid (HA) hydrogel based on the guest-host interactions of adamantane modified HA (guest macromer, Ad-HA) and β-cyclodextrin-modified HA (host macromer; CD-HA) (abstract). The complementary guest-host macromers binding permitted both shear-thinning behavior for ease of injection and near-instantaneous reassembly for material retention at the target site (abstract) and exhibits improved recovery times (pg. 4125-4126). HA was chosen since it is found abundantly in tissues and is “widely investigated” (pg. 4126). Rodell discloses “[f]ormation of a hydrogel by simple mixing of the two macromer components in aqueous solutions”, and “the properties of the resulting hydrogel were dependent on cross-link density and network architecture which were separately controlled by macromer concentration and guest macromer modification” (pg. 4133). For all hydrogels, Rodell observed release beyond 60 days (pg. 4133).
Rodell does not disclose a ADA-PEG-ADA.
Zhu discloses a similar guest-host interactions, with the guest being an AD-PEG-AD macromer, and the host, a cyclodextrin containing moiety (polycaprolactone block copolymer, PCL-CD), that self-assemble by a cross-linking process, see Fig. 1, (pg. 2). Zhu demonstrates that self-assembly PCL-CD polymersomes demonstrate successful drug loading, immobilization in hydrogel via host-guest interaction and display shear thinning properties (pg. 8).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the nanoparticle complex comprising CD-RNA conjugate, AD-PEG-Lig, and cationic polymer of Heidel and Malhotra in view of Rodell and Zhu and arrive at the claimed invention with a reasonable expectation of success. Based on the success of Rodell’s injectable hydrogel via a guest-host interaction, i.e. a (AD-HA crosslinked CD-HA polymerosome) to deliver a drug for a quick release and long duration, and of Zhu demonstrating hydrogel with similar guest-host interaction, where the guest complex is an AD-HA-AD macromer, that successfully loads drug and displays shear thinning properties, a skilled artisan would reasonably expect success to substitute the guest-based macromer, comprising AD-HA, of Rodell with guest-based macromer of Zhu to deliver drug via an injectable gel comprising hyaluronic acid-cyclodextrin macromer of Rodell and is cross-linked with AD-PEG-AD of Zhu.
Thus, a skilled artisan would reasonably expect success to modify a polycationic polymer nanoparticle comprising a conjugated CD-siRNA and AD-ligand of Heidel and Malhotra with an injectable gel version comprising a nanoparticle with crosslinked CD-HA macromer and Ad-HA macromer of Rodell. The Ad-HA macromer of Rodell can be substituted with a ADA-PEG-ADA of Zhu for a similar gel formulation based on a guest-host mechanism as Rodell. Thus, cl. 10 is obvious.
Allowable Subject Matter
No claim is allowed.
Conclusion
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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