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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any rejection or objection not reiterated in this Action is withdrawn.
Election/Restrictions
Claims 6-9 and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 10, 2025.
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.
Claims 1, 2, 4, 5, 11-14, 19-23 and 25 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brown et al. (US 2017/0306332, of record).
Brown et al. teach compositions, and methods useful for reducing lactate dehydrogenase target RNA and protein levels via use of dsRNAs.
With regard to claims 1, 19-21 and 25, Brown et al. teach at paragraph 66 that diseases treatable by the disclosed methods include cancer and at paragraph 203 teach examples of cancer include breast cancer, melanoma, lung cancer and ovarian cancer, which are taught in the instant specification as expressing LDHC. At paragraph 99 Brown et al. teach the method includes administering an inhibitor of LDHC that may be an siRNA. Brown et al. teach at paragraph 168 the potency of an siRNA is most readily achieved at a formulated concentration that results in 30-70% knockdown activity on the target RNA. Brown et al. teach at paragraph 25 the nucleic acids of the invention can be chemically modified with modifications including 2′-fluoro (2′-F), 2′-OMethyl (2′-OMe), and/or bicyclic nucleobase analogs such as locked nucleic acids such as LNA or ENA. Brown et al. disclose numerous modified siRNAs in table 2 (per paragraph 486, underlined residues are 2’OMe modified) and in figures 7 and 9.
With regard to the limitation that modification is “to allow delivery of the naked siRNA into the subject's cells”, this is interpreted as an intended purpose of the modification that is not functionally limiting in terms of reciting a positive method step. The instant specification provides no disclosure regarding number or placement of modifications required to allow naked delivery to occur, therefore a single modification at any position within an oligonucleotide is considered to satisfy this limitation. The interpretation that naked delivery is not a method step is supported by claims 2 and 11-14, which recite use of delivery systems that would not provide “naked siRNA”.
With regard to claims 2 and 11-14, Brown et al. teach at paragraphs 198-199 that the siRNAs of the invention can be formulated with pharmaceutically acceptable carriers which may be micellar structures, such as liposomes or polymeric nanocapsules which facilitate transport and release of the encapsulated or bound dsRNA into the cell.
With regard to claim 5, Brown et al. teach at paragraph 155 the dsRNA may be an shRNA and at paragraph 583 teach the nucleic acid molecules of the invention can be inserted into expression constructs such as viral vectors.
With regard to claim 22, Brown et al. teach at paragraph 98 that the subject may be a human.
With regard to claim 23, Brown et al. teach at paragraph 575 systemic administration.
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.
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.
Claims 1, 2, 4, 5, 11-17, 19-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. as applied to claims 1, 2, 4, 5, 11-14, 19-23 and 25 above, and further in view of Shi et al. (US 2013/0315831, of record).
The teachings of Brown et al. as they relate to claims 1, 2, 4, 5, 11-14, 19-23 and 25 are detailed in the previous rejection. Brown et al. further teach at paragraph 560 that the dsRNA agents of the invention can be conjugated to moieties such as peptides or organic compounds (e.g., a dye, cholesterol, or the like). Modifying dsRNA agents in this way may improve cellular uptake or enhance cellular targeting activities of the resulting dsRNA agent derivative as compared to the corresponding unconjugated dsRNA agent, are useful for tracing the dsRNA agent derivative in the cell, or improve the stability of the dsRNA agent derivative compared to the corresponding unconjugated dsRNA agent. Brown et al. do not specifically teach targeting agents that are tumor homing peptides or a biologically responsive delivery system.
Shi et al. teach micro/nano-particles that can be used for delivery of active agents such as siRNAs (see paragraphs 5 and 14). The particles have excellent stability and high loading efficiency, and can encapsulate multiple agents. Further, the particles can include targeting agents.
With regard to claims 15-17 Shi et al. describe targeting agents at paragraphs 87-105 and specifically teach such agents include antibodies to MMP-1 through MMP-8 (a biosignal-responsive crosslinker as per paragraph 78 of the instant specification) and tumor targeting agents such as prostate-specific membrane antigen (a tumor homing peptide).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the siRNA formulations taught by Brown et al. with targeting agents that are a tumor homing peptide such as PSMA or a biosignal responsive crosslinker such as anti-metalloproteinase antibodies as taught by Shi et al. One of ordinary skill in the art would make such formulations because Brown et al. teach their siRNAs can be formulated with targeting agents and because Shi et al. teach the specific agents recited in claims 15-17.
Claims 1, 2, 4, 5, 10-14, 19-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. as applied to claims 1, 2, 4, 5, 11-14, 19-23 and 25 above, and further in view of Mei et al. (Nano Research 2015, of record).
The teachings of Brown et al. as they relate to claims 1, 2, 4, 5, 11-14, 19-23 and 25 are detailed in a previous rejection. Brown et al. teach the use of carriers such as polymeric nanostructures, but do not specifically teach use of DNA scaffolds as a delivery system.
Mei et al. teach that cancer chemotherapy has been limited by its side effects and multidrug resistance(MDR), the latter of which is partially caused by drug efflux from cancer cells and that targeted drug delivery systems that can circumvent MDR are needed.
With regard to claim 10, Mei et al. teach multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR cancer cells that circumvented MDR in both leukemia and breast cancer cell models. Nanoflower sizes are tunable (down to ~200 nm in diameter), and the densely packed drug-binding motifs and porous intrastructures endow NFs with a high drug-loading capacity. Although the nanoflowers are stable at physiological pH, drug release is facilitated under acidic or basic conditions. Nanoflowers deliver their payload into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. They also induce potent cytotoxicity in both target chemosensitive cells and MDR cells, but not in nontarget cells, thus concurrently circumventing MDR and reducing side effects. Mei et al. conclude that the DNA nanoflowers are promising tools for circumventing MDR in targeted cancer therapy.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the compositions of Brown et al. and formulate them with DNA nanoflowers as taught by Mei et al. One of ordinary skill in the art would do so because Brown et al. teach formulating siRNAs with various carriers and Mei et al. teach that DNA nanoflowers exosomes are a suitable carrier for delivering therapeutic agents to cancer cells while preventing drug efflux and enhancing drug retention.
Claims 1, 2, 4, 5, 11-14, 18-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. as applied to claims 1, 2, 4, 5, 11-14, 19-23 and 25 above, and further in view of Dell’accio et al. (US 2020/0360417, of record).
The teachings of Brown et al. as they relate to claims 1, 2, 4, 5, 11-14, 19-23 and 25 are detailed in a previous rejection. Brown et al. teach the use of micellar based carriers such as liposomes, but do not specifically teach use of exosomes as a delivery system.
However, it was well known to those of ordinary skill in the art that exosomes can be used to deliver siRNAs as evidenced by Dell’accio et al., who teach at paragraph 224, that electroporation, fusion, liposomes, extracellular vesicles (e.g. exosomes or microvesicles), colloidal polymeric particles, dendrimers and viral and non-viral vectors are suitable methods of delivering oligonucleotide sequences into cells.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the compositions of Brown et al. and formulate them with exosomes as taught by Dell’accio et al. One of ordinary skill in the art would do so because Brown formulating siRNAs with various carriers and Dell’accio et al. teach that exosomes are a suitable carrier for delivering oligonucleotides to cells.
Response to Arguments
Applicants traverse the 102 rejection over Brown by asserting this reference cannot anticipate claims 1 and 21 as amended because it fails to disclose "wherein the siRNA is chemically modified to allow delivery of the naked siRNA into the subject's cells" (emphasis added) as presently claimed.
This argument is not persuasive because Brown does disclose modified siRNAs that fall within the scope of the amended claims as set out in the revised rejection above.
Applicant’s arguments about the 103 rejections are based on the secondary references not remedying the deficiencies of Brown and are not persuasive because Brown is not deficient as described above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tracy Vivlemore whose telephone number is (571)272-2914. The examiner can normally be reached Mon-Fri 7:30-4:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Yvonne Eyler can be reached at 571-272-1200. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Tracy Vivlemore
Supervisory Primary Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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