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 .
Priority
Applicant’s claim to priority from International Application PCT/US2021/047262 filed 08/24/2021 and from Provisional Application No. 63/071,018 filed 08/27/2020 is hereby acknowledged.
Application Status
Amendment to claims filed 04/21/2026 are hereby acknowledged. Claims 1-22, 31-32, 34 and 43-87 are cancelled. Claims 88-92 are newly added. Claims 23 and 33 are currently amended.
Therefore, claims 23-30, 33, 35-42 and 88-92 are pending, however, claims 41-42 are still withdrawn from consideration. Therefore, claims 23-30, 33, 35-40 and 88-92 are under consideration in this office action.
Any objection or rejection not reiterated herein has been overcome by amendments and is therefore withdrawn.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follows.
Drawings
Replacement sheets for Drawings filed 04/21/2026 are hereby acknowledged and are acceptable.
Specification
Amendments to Specification filed 04/21/2026 are hereby acknowledged.
The following rejections are new and necessitated by Applicant’s amendments filed 04/21/2026:
Claim Rejections - 35 USC § 103
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.
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.
Claims 23-30, 33 and 88-90 are rejected under 35 U.S.C. § 103 as being unpatentable over Lu (Lu, Q. WO 2018/067546 A1, published April 12, 2018; previously cited), in view of US Patent No. 9,737,480 B2 ( published August 22, 2017; hereafter referred to as USPAT480; previously cited) and Fellmann (Fellmann, C. et al. “Functional identification of optimized RNAi triggers using a massively parallel sensor assay”. Molecular Cell, Vol. 41, No. 6 (2011), pp: 733-746; previously cited) .
Regarding claim 23, Lu teaches a micro-vesicle comprising:
a) a Tumor susceptibility gene 101 (TSG101) associating protein capable of associating non-covalently with TSG101 (see [0003]). Lu teaches that ARRDC1 is a TSG101 associating protein;
b) a RNA-binding protein attached covalently to the TSG101 associating protein (see [0004]: "as one example, a cargo RNA fused to a TAR element can associate with an ARRDC1 protein that is fused to an RNA binding protein, such as a Tat protein";
c) a cargo RNA complex comprising:
(i) a binding RNA bound non covalently to the RNA-binding protein (see
abstract: "In some aspects, ARMMs containing binding RNAs associated with cargo RNAs are provided." And see [0022] "In certain embodiments, the cargo RNA is associated with a binding RNA, either covalently or non-covalently";
(ii) a prodrug cargo RNA component (see [0009], "The ARMM may then
be delivered to an ARMM target cell, where the cargo RNA fused to the TAR is released into the cytoplasm of the target cell. The cargo RNA may then be translated into a protein, for example, if the RNA is an mRNA".).
See also Figure 2:
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Lu also teaches that the composition of the invention is used for treating a disease of choice (see [00196]). Lu teaches contacting a target cell comprising a target RNA with a micro-vesicle ARMMs (see [00166]).
Lu also teaches that in some embodiments, the cargo RNA to be delivered is a mRNA, a snoRNA, a guide RNA, a splice leader RNA, a crRNA, a long non-coding RNA, a diagnostic agent, a prophylactic agent, an imaging agent that is and in others is not biologically active (see [00126]-[00127]). Therefore, Lu also teaches RNA or agents that are pro-drugs.
Lu teaches that the RNA can be pre- and/or post-processing, i.e. a precursor RNA or a post-processing RNA (see [0032]). Lu also teaches that the cargo RNA can be an RNA that inhibits expression of one or more genes in a cell, and can be a miRNA, siRNA, an antisense RNA (asRNA), a cis natural antisense sequence (cis-NAT) (see [00125]-[00126] and claims 24 and 33).
Lu teaches that ARMMs (ARRDC1-mediated microvesicles) are distinct from exosomes, and are produced by direct plasma membrane budding (DPMB) mediated by TSG101 (see page 1, [0003]).
Regarding claim 26, Lu teaches a TSG101 associating protein comprising an ARRDC1 component ( see figure 2 and [0073], [0077] and [00171]).
Regarding claim 27, Lu teaches an ARRDC1 component comprising a fusion protein comprising the RNA-binding protein, e.g., Tat (see Figure 2 and [00171], [00173]-[00176]).
Regarding claim 28, Lu teaches that the RNA-binding protein can be one of the following : “a trans-activator of transcription (Tat) protein, or variant thereof, a Rev protein, or variant thereof, an MS2 phage coat protein, or variant thereof, a P22 N protein, or variant thereof, a λ N protein, or variant thereof, a φ21 protein, or variant thereof, or a HIV-1 nucleocapsid protein, or variant thereof” (see claim 9, page 94).
Regarding claim 29, Lu teaches that the binding RNA comprises : “a transactivating response element (TAR), or variant thereof, a Rev response element (RRE), or variant thereof, an MS2 RNA sequence or variant thereof, a P22 boxB RNA sequence or variant thereof, a λ boxB RNA sequence or variant thereof, a φ21 boxB RNA sequence or variant thereof, or a SL3 ψ RNA sequence or variant thereof”.(see claim 10, page 94).
Regarding claim 30, Lu teaches the RNA binding protein comprises a trans-activator of transcription (Tat) protein, or variant thereof (see claims 11, 12 and 14, page 94).
Regarding claims 23, 26-30, Lu also teaches that the RNA can be pre- and/or post-processing, i.e. a precursor RNA or a post-processing RNA (see [0032]).
However, Lu does not teach a cargo prodrug RNA component comprising a precursor of an inhibitory ribonucleic acid, wherein the inhibitory ribonucleic acid is a shRNA configured to target the target RNA.
USPAT.’480 teaches that some embodiments of their invention provide ARMMs comprising an agent that can be a nucleic acid, an RNA, and that the RNA can be a shRNA (see column 2, lines 58-67). USPAT.’480 also reminds that shRNA may be a precursor of siRNA (see column 20, lines 15-18).
Therefore, it would have been obvious to one with ordinary skills in the art, before the effective filing date of the claimed invention to have substituted the RNA cargo taught by Lu with a shRNA taught by USPAT.’480. One with ordinary skills in the art, motivated in inhibiting the expression of a gene responsible for a disease condition could have targeted the mRNA of encoding for a pathological protein with a shRNA as taught by USPAT.’480 with a reasonable expectation of success and would arrived at the claimed invention.
Regarding claims 24-25 and 33, Lu does not teach all the elements of claims 24-25 and 33, i.e., a micro-vesicle comprising a plurality of distinct cargo RNA complexes each containing different cargo prodrug RNA components that target different sequences of the RNA target (claim 24), a micro-vesicle comprising 2 to 10 distinct cargo RNA complexes each containing different cargo prodrug RNA components that target different sequences of the RNA target (claim 25), or, a cargo RNA component comprising a double-stranded ribonucleic acid that is 30 nt or longer that is capable upon processing of binding to a sequence in an RNA target (claim 33).
However, Fellmann’s and USPAT480’s teachings render elements of claims 24, 25 and 33 obvious.
Regarding claim 24, Lu teaches that some aspects of the invention provide in vitro cell culture systems having at least two types of cells: microvesicle producing cells, and target cells that take up the microvesicles produced.” And “such co-culture systems allow for the expression of a gene product or multiple gene products generated by the microvesicle producing cells in the target cells without genetic manipulation of the target cells” (see [00170]). Lu also teaches that “In some embodiments, the microvesicle-producing cell comprises a plurality of expression constructs encoding a plurality of the proteins, fusion proteins, and or RNAs provided herein” (see [00172]).
Lu does not teach “a plurality of distinct cargo RNA complexes each containing different cargo prodrug RNA components that target different sequences of the RNA target.”
However, Fellmann states that “ while powerful, RNAi technology has some limitations. Besides suppressing the intended target gene, synthetic RNAi triggers can evoke off-target effects by suppressing unintended transcripts due to sequence homologies of either the sense or the antisense strand. Generally, the potential for misinterpreting such false positive results can be minimized through the use of several independent RNAi triggers targeting the same transcript. In addition, high intracellular levels of synthetic small RNAs can result in toxicities related to saturation of the RNAi machinery ( ). Such effects can be reduced by the use of microRNA-based RNAi triggers ( ) and, in principle, would be eliminated through the use of shRNAs that effectively repress gene expression at low concentrations.” (see page 734, “Introduction” section, left column, first paragraph).
Fellmann teaches that using a single shRNA is not efficient. Fellmann teaches that tiling shRNA sequence to target the mRNA (e.g., Trp53 mRNA) is more efficient with a high number of shRNAs (see Figure 3). Fellmann teaches that potent single-copy shRNAs are surprisingly rare, with a frequency ranging from 0.5% (Trp53) and 4.4% (Pcna) across the surveyed transcripts (see page 744, left column, lines 4-10).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Lu with the teachings of Fellmann, and modified the method of treating a condition using the microvesicle comprising a TSG101 associating protein, an RNA-binding protein attached covalently to the TSG101 associating protein, and a cargo RNA complex, as taught by Lu, by modifying the cargo prodrug RNA component, adding multiple shRNAs in cargo complexes, wherein the plurality of distinct cargo RNA complexes each contains different cargo prodrug RNA components that target different sequences of the RNA target. One motivated in increasing the efficiency and potency of the composition at inhibiting the expression of the target RNA, at lower concentrations to avoid toxicity, could have performed this modification with a reasonable expectation of success and would arrived at the claimed invention.
Regarding claim 25, the combination of Lu and Fellmann does not teach a microvesicle comprising 2 to 10 distinct cargo RNA complexes each containing different cargo prodrug RNA components that target different sequences of the RNA target.
The teachings of Fellmann suggest a plurality of shRNAs is more efficient and more potent, but does not provide with a minimum number of shRNAs.
USPAT480 teaches that “In some embodiments, an RNAi-inducing agent is an “RNAi-inducing vector,” which refers to a vector whose presence within the cell results in production of one or more RNAs that self-hybridize or hybridize to each other to form an RNAi agent (e.g., siRNA, shRNA, and/or miRNA)….whose presence within the cell results in production of one or more RNAs…” (see column 19, lines 5-17).
In KSR Int 'l v. Teleflex, the Supreme Court, indicated that “The principles underlying [earlier] cases are instructive when the question is whether a patent claiming the combination of elements of prior art is obvious. When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability”. KSR Int'l v. Teleflex lnc., 127 S. Ct. 1727, 1740 (2007).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify Lu, in view of the teachings of Fellmann and USPAT480 to include multiple, one or more, i.e. two, or more, shRNAs capable of providing siRNAs after processing, to inhibit the same RNA target as disclosed in Fellmann and USPAT480, since the claimed invention is merely a combination of old elements. One with ordinary skills in the art through routine experimentation, could have added 2 or more shRNAs to the cargo RNA complexes to test for inhibition of target gene expression . One with ordinary skills in the art, motivated in increasing the efficiency and the potency of the cargo RNA complex, and testing the minimum number of achievable additions, could have performed these modifications with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 33, USPAT480 teaches that “As used herein, the term “RNA interference” or “RNAi” refers to sequence-specific inhibition of gene expression and/or reduction in target RNA levels mediated by an RNA, which RNA comprises a portion that is substantially complementary to a target RNA (see column 18, lines 19-23). USPAT further states: “In some embodiments, an RNAi agent may comprise a blunt-ended (i.e., without overhangs) dsRNA which is ≥ 25 base pairs length” (see column 18, lines 54-60).
The obviousness of the combination of references Lu, Fellmann and USPAT480 is described above.
Regarding claims 88-90, Lu teaches a target RNA can be an mRNA that encodes a therapeutic protein. Alternatively, the cargo RNA may be a siRNA that inhibits expression of a protein (e.g., a transcription factor, metastasis suppressor, a growth factor, a metastasis promoter, an oncogene…) (see [0072]).
Therefore, Examiner interprets that the cargo RNA can be targeting an RNA that is associated with a disease such as cancer.
Lu teaches the contacting of a target cell with a ARMM for a cargo RNA to be delivered ( [00166], [00167], see claims 37-40). Lu teaches that the contacting can be done in vitro by administering the ARMM to the target cell in a culture dish, or in vivo by administering the ARMM to a subject ( [00166]). Lu teaches treating a disease, disorder, or condition administering the composition comprising the ARMM and cargo RNA ( [0046], [00161]-[00162]).
USPAT.’480 also teaches an invention providing methods of delivering an agent to a target cell comprising contacting the target cell with a microvesicle with an agent or administering microvesicles or microvesicles-producing cells to a subject (see column 4, lines 12-42).
The obviousness of the combination of references Lu, Fellmann and USPAT480 is described above.
Claims 35-40 are rejected under 35 U.S.C. § 103 as being unpatentable over Lu (Lu, Q. et al. WO 2018/067546 A1, published April 12, 2018; previously cited) in view of US Patent No. 9,737,480 B2 ( published August 22, 2017; hereafter referred to as USPAT480; previously cited) and Fellmann (Fellmann, C. et al. “Functional identification of optimized RNAi triggers using a massively parallel sensor assay”. Molecular Cell, Vol. 41, No. 6 (2011), pp: 733-746; previously cited), as applied to claim 23 above, and further in view of Zhang (Zhang, Y. et al. “Silencing SARS-COV Spike protein expression in cultured cells by RNA interference”. FEBS Letters, Vol. 560 (2004), pp: 141-146; previously cited) and Machitani (Machitani, M. et al. “ RNA-dependent RNA polymerase, RdRP, a promising therapeutic target for cancer and potentially COVID-19”. Cancer Science, Vol. 111 (August 17, 2020), pp: 3976-3984; previously cited).
It is noted that the elements of claim 23 is rendered obvious by the combination of Lu, USPAT.’480 and Fellmann. The rejection of claim 23 is described above.
Regarding claims 35-39, the combination of references teaches RNA interference ([0002]). Lu teaches that the delivery of ribonucleic acids (e.g., therapeutic RNAs) to cells is limited by a number of factors, including the immunogenicity of viral delivery systems as well as the ability to target a specific cell type when using viral or non-viral transduction methods ([0002]).
But the combination of references does not teach a target RNA that is a viral target RNA. However, Zhang teaches a target that is a viral RNA.
Zhang teaches RNA interference targeting the S gene in SARS-CoV-infected cells (see title and abstract). Zhang teaches that that up to date (2004), there was no specific therapeutic method to treat patients suffering from SARS-CoV infection, and that using an siRNA targeting a viral RNA for degradation is possible, as it was shown for other viruses infections such as HIV and hepatitis C/B virus infections (see abstract).
Therefore, it would have been obvious to one of ordinary skills in the art before the effective filing date of the claimed invention to have modified the cargo RNA taught by Lu, and have substituted the mRNA in Figure 2 with a shRNA, precursor drug for siRNA, targeting the SARS-CoV S gene as taught by Zhang. One with ordinary skills in the art, motivated in inactivating a pathogenic virus such as the coronavirus SARS-CoV, and motivated in using a non-viral carrier/vehicle in the form of a micro-vesicle to avoid the immunogenicity of a viral delivery system and to have the ability of targeting specific cells, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 40, Zhang teaches that RNAi is feasible in SARS-CoV context (see title and abstract). Zhang teaches the making of a hairpin cDNA annealing complementary synthetic oligos (see page 142, left column, section 2.1; see Figure 1). Zhang teaches infecting Vero E6 cells with SARS-CoV and transfect them with the construct containing the hairpin cDNA (see section 2.8). Zhang teaches that siRNA against mRNA of Spike protein was obtained and are effective against the virus (see page 145, left column, section 3.6).
However, the elements of the claim, i.e., “the viral RNA target encodes RNA-dependent RNA polymerase (RdRP)” is not rendered obvious by the combination of references Lu, USPAT480, Fellmann and Zhang.
However, Machitani teaches that a RdRP plays a pivotal role in infection and represents a promising target for therapeutic strategies against COVID-19 (see title and abstract). Machitani also teaches RdRP inhibitors such as nucleoside analogs antiviral remdesivir are efficient in treating filovirus infection and likely effective on COVID-19 (see page 3982, section 5.1, left column). However, Machitani also teaches that RdRP inhibitors such as ribavirin and favipiravir are teratogenic (see section 5.3, page 3982). Machitani’s teachings suggest searching for other inhibitors against RdRP. Machitani states that RdRP nsp12 has attracted much attention (see section 5.1, page 3982, left column).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the shRNA, prodrug for siRNA targeting SARS-CoV S gene in the ARMM delivery system taught by Lu modified by USPAT.’480, Fellmann and Zhang, with a shRNA against RdRP nsp12 of SARS-CoV-2 virus as taught by Machitani. It would have been a substitution of a shRNA targeting a SARS-CoV gene with another shRNA targeting a promising SARS-CoV target, that can also be used as an anticancer therapeutic agent. One with ordinary skills in the art, motivated in developing therapeutic agents with dual functionality, could have performed this modification with a reasonable expectation of success and would have arrived at the claimed invention.
Response to Arguments
Applicant's arguments filed 04/21/2026 have been fully considered but they are not persuasive.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Lu relies on the teachings of USPAT.480 and incorporate the WIPO publication from which USPAT.’480 claims priority, i.e., WO2013/119602 published August 15, 2013 (see first page of USPAT.480) and Lu’s “Summary of the Invention” ([0003], page 1) states that “the entire contents of which are incorporated herein by reference. Therefore, Lu relies upon USPAT.480’s content directly, and the elements presented in the amended claim 23 are already known in the prior art USPAT. 480.
Regarding Applicant’s arguments against Fellmann, stating that Fellmann teaches away from the claimed element: “a plurality of distinct cargo RNA complexes each containing different cargo prodrug RNA components that target different sequences of the RNA target.”
Fellmann teaches that potent single-copy shRNAs are surprisingly rare, with a frequency ranging from 0.5% (Trp53) and 4.4% (Pcna) across the surveyed transcripts (see page 744, left column, lines 4-10). Fellmann’s teachings also suggest that using multiple shRNAs to target an open reading frame is a known practice. Fellmann states that “ while powerful, RNAi technology has some limitations. Besides suppressing the intended target gene, synthetic RNAi triggers can evoke off-target effects by suppressing unintended transcripts due to sequence homologies of either the sense or the antisense strand. Generally, the potential for misinterpreting such false positive results can be minimized through the use of several independent RNAi triggers targeting the same transcript. Fellmann teaches the making of a library of shRNA (see page 744, “Experimental Procedures” section, “Vectors and Library construction” paragraph).
Thus, the end-result of Fellmann’s experiments is not the point of combining the references; it is the established technical knowledge and the motivation of one with ordinary skills in the art to tile multiple shRNAs over the length of an mRNA of interest, that renders the elements claimed obvious.
Also, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Allowable Subject Matter
Claims 91-92 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No Claim is allowed.
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 ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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