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
The instant application is a national stage entry of PCT application PCT/US21/39716, filed 12/16/2022 under 35 USC 371. Acknowledgement is made of the applicant’s claim for benefit to prior-filed U.S. provisional patent applications 63/045,551, which was filed 06/29/2020.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 91-99, drawn to a plurality of engineered extracellular vesicles comprising a higher amount of miR-345, in the reply filed on 12/24/2025 has been acknowledged. Claims 91-99 have been considered on the merits. Claims 100-110 are withdrawn from consideration pursuant 37 CFR 1.142(b).
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g. p33, L28). 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.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 91-99 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “substantially” in claims 91-94 and 96 is a relative term which renders the claims indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In instant case, it is not clear what amount of microRNA is considered substantially higher/lower than the amount of said microRNA in non-engineered extracellular vesicles.
Claims 95 and 97-99 depend from, at least, claim 91, and thus inherit the deficiency and are rejected on the same basis.
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 91-94 and 98-99 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Williams et al. (WO 2018/039119 A1, published 03/01/2018).
Williams et al. teach improved methods and compositions for the systemic delivery of therapeutic exosomes to a subject in need thereof (Abstract).
Regarding claim 91, Williams et al. teach methods and compositions for the delivery of exosomes to a subject in need thereof. In certain aspects are methods of introducing exosomes to a
subject, the method comprising, administering to the subject a first dose comprising non-therapeutic exosomes and administering to the subject a second dose comprising therapeutic exosomes (Parag 0004). In certain embodiments, the therapeutic exosomes optionally comprise more than one distinct payload. In certain embodiments, the payload comprises more than one type of payload selected from the group consisting of: peptide, protein, DNA, RNA, siRNA, miRNA, shRNA, lncRNA, small molecule, large molecule biologic, polysaccharide, lipid, toxin and combinations thereof (parag 0008). In some embodiments, a nucleic acid payload can be engineered for specific trafficking from the producer cell into the exosome. In certain embodiments, a nucleic acid payload (e.g., mRNA or miRNA) can comprise a sequence in the coding or noncoding region that targets the nucleic acid to the exosome (parag 0112). A non- polypeptide payload (e.g., a nucleic acid, such as an RNA, e.g., siRNA, miRNA, shRNA, etc., a therapeutic small molecule or a toxin) can be i) expressed in the producer cell from an exogenous nucleic acid, ii) conjugated to the producer cell or the exosome, iii) loaded into or onto the producer cell or the exosome, and any combination of i), ii) and iii) (parag 0227). Williams et al. teach one or more miRNAs can be expressed as payload in exosomes in table 7 (see parag 0056 and p97), which including miR-345. Exosome is one type of extracellular vesicle (see parag 0026). The teachings above indicate exosomes overexpressing miR-345, which are engineered extracellular vesicles comprise miR-345, and the amount of miR-345 in the engineered extracellular vesicles is higher than an amount of miR-345 in non-engineered extracellular vesicles since miR-345 are loaded into or onto the exosome. Therefore the teachings above anticipate instant claim 91.
Regarding claims 92-94, following the discussion above, Williams et al. teach in some embodiments, the exosome comprises one or more of the miRNAs listed in Table 7 (parag 0056 and p97-98), miRNAs in Table 7 also include miR-146a and let-7b, in addition to miR-345.
Regarding claims 98 and 99, following the discussion above, Williams et al. teach the therapeutic exosomes optionally comprise more than one distinct payload (parag 0008). A non-polypeptide payload (e.g., a nucleic acid, such as an RNA, e.g., siRNA, miRNA, shRNA, etc., a therapeutic small molecule or a toxin) can be i) expressed in the producer cell from an exogenous nucleic acid, ii) conjugated to the producer cell or the exosome, iii) loaded into or onto the producer cell or the exosome, and any combination of i), ii) and iii) (parag 0227). Williams et al. also teach the term "producer cell" refers to a parental cell that produces the exosomes. The producer cells can be mammalian, human or non-mammalian. Parent producer cells can include, but are not limited to, reticulocytes, erythrocytes, megakaryocytes, leukocytes, platelets, neutrophils, mesenchymal stem cells, connective tissue cells, neural cells and tumor cells (parag 0043). This teaching reads on the extracellular vesicles (e.g., exosome) can be derived from mesenchymal stem cells and loaded with a payload (e.g., miRNA), as recited in instant claims 98 and 99.
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.
Claims 91-95 and 98-99 are rejected under 35 U.S.C. 103 as being unpatentable over Williams et al. (WO 2018/039119 A1, published 03/01/2018).
Williams et al. teach improved methods and compositions for the systemic delivery of therapeutic exosomes to a subject in need thereof (Abstract).
Regarding claim 91, Williams et al. teach methods and compositions for the delivery of exosomes to a subject in need thereof. In certain aspects are methods of introducing exosomes to a
subject, the method comprising, administering to the subject a first dose comprising non-therapeutic exosomes and administering to the subject a second dose comprising therapeutic exosomes (Parag 0004). In certain embodiments, the therapeutic exosomes optionally comprise more than one distinct payload. In certain embodiments, the payload comprises more than one type of payload selected from the group consisting of: peptide, protein, DNA, RNA, siRNA, miRNA, shRNA, lncRNA, small molecule, large molecule biologic, polysaccharide, lipid, toxin and combinations thereof (parag 0008). In some embodiments, a nucleic acid payload can be engineered for specific trafficking from the producer cell into the exosome. In certain embodiments, a nucleic acid payload (e.g., mRNA or miRNA) can comprise a sequence in the coding or noncoding region that targets the nucleic acid to the exosome (parag 0112). A non- polypeptide payload (e.g., a nucleic acid, such as an RNA, e.g., siRNA, miRNA, shRNA, etc., a therapeutic small molecule or a toxin) can be i) expressed in the producer cell from an exogenous nucleic acid, ii) conjugated to the producer cell or the exosome, iii) loaded into or onto the producer cell or the exosome, and any combination of i), ii) and iii) (parag 0227). Williams et al. teach one or more miRNAs can be expressed as payload in exosomes in table 7 (see parag 0056 and p97), which including miR-345. Exosome is one type of extracellular vesicle (see parag 0026). The teachings above indicate exosomes overexpressing miR-345, which are engineered extracellular vesicles comprise miR-345, and the amount of miR-345 in the engineered extracellular vesicles is higher than an amount of miR-345 in non-engineered extracellular vesicles since miR-345 are loaded into or onto the exosome.
Regarding claims 92-94, following the discussion above, Williams et al. teach in some embodiments, the exosome comprises one or more of the miRNAs listed in Table 7 (parag 0056 and p97-98), miRNAs in Table 7 also include miR-146a and let-7b, in addition to miR-345.
Regarding claims 98 and 99, following the discussion above, Williams et al. teach the therapeutic exosomes optionally comprise more than one distinct payload (parag 0008). A non-polypeptide payload (e.g., a nucleic acid, such as an RNA, e.g., siRNA, miRNA, shRNA, etc., a therapeutic small molecule or a toxin) can be i) expressed in the producer cell from an exogenous nucleic acid, ii) conjugated to the producer cell or the exosome, iii) loaded into or onto the producer cell or the exosome, and any combination of i), ii) and iii) (parag 0227). Williams et al. also teach the term "producer cell" refers to a parental cell that produces the exosomes. The producer cells can be mammalian, human or non-mammalian. Parent producer cells can include, but are not limited to, reticulocytes, erythrocytes, megakaryocytes, leukocytes, platelets, neutrophils, mesenchymal stem cells, connective tissue cells, neural cells and tumor cells (parag 0043). This teaching reads on the extracellular vesicles (e.g., exosome) can be derived from mesenchymal stem cells and loaded with a payload (e.g., miRNA), as recited in instant claims 98 and 99.
Regarding claim 95, Williams et al. do not specifically point out the amounts of miR-345 in the engineered extracellular vesicles are at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, or 20-fold higher than the amounts of miR-345 in non-engineered extracellular vesicles. However, Williams et al. teach the administration of suitable exosomes in an amount effective to substantially deliver the payload to the target cell or tissue, thereby preventing or treating the disease, disorder or condition (parag 0276). The term "substantially" or "substantial" refers, e.g., to the presence, level, or concentration of an entity in a particular space, the effect of one entity on another entity, or the effect of a treatment. For example, an activity, level or concentration of an entity is substantially increased if the increase is 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 50-fold, 100-fold, or 1000-fold relative to a baseline (parag 0050). Moreover, it is not inventive to find optimal workable ranges by routine experimentation, for instance, find an optimal level of miR-345 expressed in exosomes (i.e., by overexpression of miRNAs) in order to achieve the goal of preventing or treating the disease, disorder or condition. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." See Jn re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claims 91-99 are rejected under 35 U.S.C. 103 as being unpatentable over Williams et al. (WO 2018/039119 A1, published 03/01/2018) in view of Kim et al. (Cancer Res. 2016 Nov 1;76(21):6424-6435).
The teaching of Williams et al. is set forth above.
Regarding claims 96 and 97, Williams et al. do not teach the amount of miR-10b in the engineered extracellular vesicles is substantially lower than the amount of miR- 10b in non-engineered extracellular vesicles derived from the cells , and will be at least 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, or 20-fold lower. However, this was disclosed by Kim et al. at the time of instant invention.
Kim et al. report the generation of miR-10b–deficient mice, in which miR-10b is shown to be largely dispensable for normal development but critical to tumorigenesis (Abstract).
Regarding claim 96, Kim et al. teach genetic deletion of miR-10b does not cause substantial developmental defects, it impedes mammary tumor initiation, progression, and metastasis in a polyomavirus middle T (PyMT) model of breast cancer (p6424, left column). Kim et al. also teach miR-10b is secreted by metastatic breast cancer cells via exosomes and, upon uptake, induces invasiveness
of nonmalignant mammary epithelial cells (p6424, left column).
Regarding claim 97, Kim et al. teach generating miR-10b–deficient mice to determine
the role of miR-10b in normal development and tumor progression (p6424, right column and p6425, left column), “miR-10b–deficient” indicates no miR-10b expression in the cell, as well as the exosome secreted by the cell, which reads on the amount of miR-10b in the engineered extracellular vesicles is at least 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, or 20-fold lower than the amount of miR-10b in non-engineered extracellular vesicles derived from the cells, as recited in instant claim.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Williams et al.’s therapeutic exosomes comprising miR-345, and decrease/eliminate the amount of miR-10b in the engineered extracellular vesicles as taught by Kim et al.. The skilled artisan would have been motivated to decrease the amount of miR-10b in the engineered extracellular vesicles since Kim et al. teach deletion/reduction of miR-10b does not cause substantial developmental defects, but delays oncogene-induced mammary tumorigenesis and suppresses epithelial–mesenchymal transition, intravasation, and metastasis (Abstract). There would be a reasonable expectation of success of decrease the amount of miR-10b in the engineered extracellular vesicles since Kim et al. teach miR-10b–deficient mice which have miR-10b–deficient cells and cell-derived exosomes (see p6425, left column).
Conclusion
No claims are allowed.
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/Q.G./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699