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.
Election/Restrictions
Applicant’s election without traverse of Invention Group II (claims 23-40 and 42, drawn to a method of treating a subject for a condition mediated by a target RNA) and Species A (1) (a tat protein or active variant thereof), B (1) ( a trans-activating response element (TAR) or active variant thereof), C (1) (a precursor of an inhibitory ribonucleic acid, a siRNA, RNAi, shRNA or microRNA), and D(1) (a viral target RNA of a pathogenic virus, SARS-CoV-2 or influenza virus) in the reply filed on 10/21/2025 is acknowledged.
Claims 34 and 41-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/21/2025.
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Application Status
Preliminary amendment to claims filed 07/25/2023 are hereby acknowledged. Claims 1-22 are cancelled. Claims 26, 28-31, 35 and 42 are currently amended. Claims 23-42 are pending, however, claims 34 and 41-42 are withdrawn from consideration. Therefore, claims 23-33 and 35-40 are under consideration in this office action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/08/2023 is hereby acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
However, the listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, or are listed on a submitted IDS, they have not been considered.
Drawings
The drawings are objected to for the following reasons:
37 CFR 1.84 (u)(1) states “Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter.”
In the current case, the view numbers for the partial views for Figures 2A, 2B,
and 3B that appear on several sheets are followed by "Cont." instead of a capital letter such as FIG. 2A, FIG. 2B, FIG. 2C etc.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are
required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: The term
“TSG1010” should be “TSG101” (see page 7, line 19).
Appropriate correction is required.
The specification is objected to as failing to provide proper antecedent basis
for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: TAR-myc-shSupt4; TAR-myc-shRdRP; ARRDC1; ARMMs ( “Brief Description of the Figures”, page 2). Terms should be spelled out in full at their first use in the disclosure.
The disclosure is objected to because it contains an embedded hyperlink
and/or other form of browser-executable code (page 45, line 20-21). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the terms “RNAeasy” (page 66, line 21; page 67, line 12; page 68,
lines 8 and 16; page 69, lines 5 and 13), “iScript RT” (page 66, line 22; page 68, line 17; page 69, line 14), “Taqman” (page 68, line 10), which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 23 is objected to because of the following informalities: The claim recites “ a) a TSG101” instead of “a) a Tumor susceptibility gene 101 (TSG101)”. The first time an abbreviation is used, the term should be spelled out in full.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 23-33 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention:
Claim 23 recites:
“A method of treating a subject for a condition mediated by a target RNA, the method comprising:
administering to the subject an effective amount of a micro-vesicle comprising:
a) a TSG 101 associating protein capable of associating non-covalently with
TSG101;
b) an RNA-binding protein attached covalently to the TSG101 associating
protein; and
c) a cargo RNA complex comprising:
(i) a binding RNA bound non-covalently to the RNA-binding
protein; and
ii) a cargo prodrug RNA component;
to treat the subject for the condition.”
It is therefore expected the description of a specific microvesicle, with recitation of specific lipids or source of the microvesicle.
It is therefore expected a method of treating a condition mediated by a target RNA. Said target RNA can be any RNA that is mutated, not properly spliced and/or not translated. The cargo RNA can be an mRNA for gene replacement therapy, or an inhibitor RNA for inhibiting expression of a target RNA. The cargo RNA can also be an Antisense RNA (siRNA, shRNA, miRNA), a splice-switching RNA, or a guide RNA.
It is therefore expected that this method is capable of treating any condition that is related to any defect in gene expression. It is also expected that the condition being defined and linked to specific RNAs (target and cargo) with an enunciation of residues.
The State of the Art:
Ratajczak (Ratajczak, M. et al. “ Extracellular microvesicles/exosomes:
discovery, disbelief, acceptance, and the future?”. Leukemia, Vol. 34 (2020), pp: 3126-3135) teaches that the small, spheroidal vesicles released from cells, are described as microparticles, microvesicles, or exosomes. Ratajczak refers to these microparticles as “extracellular microvesicles” (ExMVs) (see abstract). Ratajczak teaches that the microvesicles can range from 100 to 1,000 nm in diameter, are composed of an outer lipid bilayer and thus can be considered as physiological liposomes (see page 3127, right column, “The process of ExMV formation and their characterization” section). Ratajczak teaches that ExMVs can be responsible for rendering tumor cells more metastatic (see page 3133, left column, first paragraph). Therefore it is important to know the source of microvesicles. Ratajczak concludes by stating that for therapeutic application in clinic, one should also consider potential “off target” side effects, including the risk of hypercoagulation in the case of ExMV isolated from platelets or other blood cells, or neoplastic transformation when isolated from iPSCs.
Shirmast (Shirmast, P. et al. “Delivering therapeutic RNA into the brain using extracellular vesicles”. Molecular Therapy: Nucleic Acids, Vol. 35, No. 4 (2024), p: 102373) teaches that RNA are different and belong essentially to two classes, coding and non-coding, requiring different pathways for their activities (see Figure 2). Shirmast also teaches that the length of these RNAs differ, from 18-25 nt for a miRNA to 100-300 nt for a snRNA (see Figure 2).
Shirmast also teaches the challenges in delivering RNA therapeutics to the brain with the Blood Brain Barrier (BBB) restricting nearly 98% of small molecules and drugs (see page 10, left column, second paragraph). Shirmast teaches that naked RNAs can trigger immune responses, therefore using extracellular vesicles (EVs) and using specific motifs on RNA can mitigate the risks. However, developing reliable and efficient methods for large scale production remains a challenge (see page 10, right column, second paragraph). Shirmast also teaches that EVs loaded with long non-coding antisense RNA targeting SARS-CoV2 can be used against COVID-19, since found not immunostimulatory, even with an 800bp RNA material. However, the concerns include possible thrombogenicity, especially if the EVs are platelet-derived, with long-term consequences of repeated administration (see pages 10-11, “Challenges with EV-based therapies” section).
Therefore, it is expected in the disclosure a description of microvesicles used, their source, the description of an example, representative for each species of RNA to be used, with corresponding RNA-binding protein, and the specific disease it is meant to treat.
Wang (Wang, Q. et al. “ARMMs as a versatile platform for intracellular delivery of
macromolecules”. Nature Communications, Vol. 9 (2018), p: 960; cited as NPL# 2 on IDS filed 05/08/2023) teaches that microvesicles known as Arrestin domain containing protein 1 [ARRDC1]-mediated microvesicles (ARMMs), are capable of packaging a myriad of macromolecules such as p53 protein, RNAs and a genome-editing CRISPR-Cas9/guide RNA complex (see abstract, page 1).
Therefore, according to Wang, the macromolecules have to be covalently linked to a recombinant ARRDC1 as a fusion protein (see Figure 1a):
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Therefore, whenever there is a need to correct a condition needing protein replacement therapy for having an RNA target that is defective and not translated, the microvesicle might be modified and may not require all the component listed in claim 23.
When the condition requires targeting and correcting the target RNA, Wang teaches that the replacement RNA can be attached covalently as follow (see Figure 2a):
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When the condition requires targeting the target RNA using a CRISPR/Cas9 and gRNA complex, Wang teaches non-covalent packaging as follow (see Figure 3a):
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Therefore, it is expected that for each condition that necessitate targeting an RNA, that Applicant provides an example of disease and/or an example of attachment of specific macromolecule or specific complex to be carried within the microvesicle.
Groot (Groot, M. et al. “Sorting mechanisms for MicroRNAs into extracellular vesicles and their associated diseases”. Cells, Vol. 9 (2020), p: 1044) teaches that RNA-binding proteins are diverse and associate specifically to RNAs to assist with the sorting process into exosomes (see page 2, section 2). Each miRNA binds to a specific RNA-binding protein to be selectively sorted and assembled within extracellular vesicles as shown in Figure 1 , and below:
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Therefore, it is expected that the RNA-binding protein be specific for each cargo RNA selected, and according to specific disease to be treated.
What the Specification does and does not teach:
The Specification does not teach the source of microvesicles.
The Specification teaches an example, i.e. preferred embodiment, of SARS-COV2 inhibitory RNA in Section “I. Microvesicle mediated RNA-silencing therapy for Coronavirus diseases” (see page 62). Applicant teaches specific shRNA, i.e. shRDRP-1 and shRDRP-8 (SEQ ID NOs: 9 and 10) for the purpose of targeting SARS-CoV-2 virus (see page 34, lines 24-31).
As shown in Figures 1-4, all the experimentation is made in cell culture:
FIGS. 1 A and 1 B provide results showing that constructs of TAR-myc-shSupt4
and TAR-myc-shRdRP are efficient to knock down target gene RNA abundance (it is
noted that the "myc" domain is a linker).
FIGS. 2A and 28 provide results showing that the interaction of TAT-TAR
enables ARRDC1 -mediated sh RNA packaging in ARMMs.
FIGS. 3A and 3B show that elevated amounts of shRNA is present in ARMMs
produced from 293 Dicer deficient cells as compared with 293 cells that contain a
normal Dicer gene.
FIGS. 4A to 4C show the protection of ARMMs producing cells from the toxicity
effect of Supt4 siRNA by using 293 dicer deficient cargo-producing cells.
There is no step for a method of treating a subject described with a specifically disclosed composition.
Applicant does not provide a specific step or specific composition, combining a specific RNA-binding protein to specific miRNA, mRNA or long non-coding RNA or CRISPR/Cas- guide RNA complex either. Applicant does not provide a composition responsible for treating in a subject in need thereof suffering from cancer, immune disease, metabolic disease, or from a specific brain disease. Delivery of cargo RNA to the brain is especially challenging according to the prior art. Applicant does not provide examples and recitation, enumeration in residues for miRNA, mRNA, siRNA, long non-coding RNA, guide RNA in complex with a CRISPR/Cas system, to be delivered to tissues, nor an example of condition other than COVID-19, while claiming any type of microvesicles, any type of target RNA, and any condition.
Conclusion:
Taking into consideration the factors outlined above, including the nature of the
invention, the state of the art, the guidance provided by the applicant and the specific example, it is the conclusion that Applicant does not possess the invention as claimed. There is no specific written example within the Specification that would lead one with ordinary skills in the art to a different conclusion.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 23, and 26-32 are rejected under 35 U.S.C. §102(a)(1) as being anticipated by Lu (Lu, Q. WO 2018/067546 A1, published April 12, 2018; previously cited).
Regarding claim 23, Lu teaches a micro-vesicle comprising:
a) a 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 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.
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 31 and 32, 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).
Claims 23, 31, 24, 25 and 33 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 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) and US Patent No. 9, 737,480 B2 ( published August 22, 2017; hereafter referred to as USPAT480).
It is noted that the elements of claims 23 and 31 are anticipated by Lu:
Regarding claim 23, Lu teaches a micro-vesicle comprising:
a) a 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 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.
Regarding claim 31, 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 does not teach all the elements of claims 24-25 and 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 potentsingle-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, 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.
Claims 23, and 35-39 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 Mulligan (Mulligan, R.C. WO 2021/236852 A1, published November 25, 2021, benefitting from priority of US Provisional Application No. 63/027,904 filed May 20, 2020).
It is noted that the elements of claim 23 are anticipated by Lu:
Regarding claim 23, Lu teaches a micro-vesicle comprising:
a) a 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 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.
Regarding claims 35-39, Lu does not teach a target RNA that is a viral target RNA. However, Mulligan teaches a target that is a viral RNA.
Mulligan teaches methods and compositions for treatment of viral infections and provides specifically for coronavirus infection, which is a respiratory disease that can be caused by the pathogenic coronavirus SARS-CoV-2 (see pages 1-2, “Background” section, [0004]-[0005], and see pages 213-215, claims 1-3, 15).
Mulligan teaches that his invention consists in delivering compositions comprised of polynucleotides or proteins, via delivery vehicles, said polynucleotides encoding or regulating expression of Chromosome 19 Open Reading Frame 66 (C19orf66) in a cell in a subject that is known or suspected of having the virus infection ([0006]). Therefore, Mulligan teaches an agent, a prodrug, that is targeting a viral RNA, and that agent can be administered as an mRNA encoding for C19orf66 (see [0041]-[0043]). C19orf66 is capable, once encoded, to inhibit viral replication and viral RNA processing (see [0044]).
Mulligan teaches that the vehicle for delivery can be a viral particle, a virus-like particle, a nanoparticle, a vesicle, a microvesicle, a membrane vesicle, an extracellular membrane vesicle (see [0239], [0277], [0503] and claim 23).
Mulligan also teaches a method to improve safety of vehicle by codon optimizing nucleotide sequences encoding the packaging components (see [0300]-[0301]). Mulligan discloses that codon optimization reduces homologous recombination between different constructs within the vector system ([0301]). Mulligan therefore teaches that there might be some safety issues ([0264], [0301], [0317]).
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 substitute the mRNA in Figure 2 with an mRNA encoding for C19orf66 as taught by Mulligan. One with ordinary skills in the art, motivated in avoiding reconstitution of an active and pathogenic virus complicating the coronavirus infection, and motivated in using a non-viral carrier/vehicle in the form of a microvesicle, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Claim 40 is 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 Mulligan (Mulligan, R.C. WO 2021/236852 A1, published November 25, 2021, benefitting from priority of US Provisional Application No. 63/027,904 filed May 20, 2020), as applied to claims 23, 35-39 above, and in further view of 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) and 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).
The rejections of claims 23 and 35-39 are described above. The elements of claims 23 and 35-39 are rendered obvious by the combination of references Lu and Mulligan. However, elements of claim 40, i.e., “the viral RNA target encodes RNA-dependent RNA polymerase (RdRP)” is not rendered obvious by Lu and Mulligan.
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).
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).
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 mRNA of C19orf66 taught by Lu modified by Mulligan, with a shRNA against RdRP nsp12 of SARS-CoV-2 virus. One with ordinary skills in the art, motivated in avoiding side-effects from known antiviral agents, could have performed this modification with a reasonable expectation of success and would arrived at the claimed invention.
Conclusion
No Claim is allowed.
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/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636