DETAILED ACTION
Claims 1-20 are pending in the instant application.
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 claims priority to the U.S. Provisional Application Serial No. 63/627,124 filed January 31, 2024.
Information Disclosure Statement
The information disclosure statement (IDS) submitted are in compliance with the provisions of 37 CFR 1.97, except where noted. Accordingly, the information disclosure statement was considered by the examiner. Please see attached initialed Forms 1449.
Claim Objections
Claims 2, 6 and 11 are objected to because of the following informalities: “according claim 1”. It should be fixed to “according to claim 1”; “anesthetic tetrodotoxin” in claim 6 should be fixed to “anesthetic is tetrodotoxin”. Claim 11 is missing the degree symbol in front of the C; it should be fixed to “when stored at 4 °C”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 2 and 10 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. Claims 2 and 10 contain acronyms that must be spelled out when first used in a claim.
Claims 2, 7, and 9 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. Claims 2, 7, and 9 blur the metes and bounds of the claims due to words in parentheses. The examiner cannot determine if they are exemplary or limited to one or more of these terms.
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 1-4, 9 and 19-20 are rejected under 35 U.S.C. 102(a)(1)(a)(2) as being anticipated by Yuk (US 2020/0046647 A1).
Yuk discloses an exosome-based nanoparticle composite and a method for preparing the same (Abstract). The drug loaded into the exosome cores is not limited to a particular type and examples include poorly soluble drugs, ionic drugs, and others. Examples of ionic drugs include bupivacaine hydrochloride ([0033-0035]). The exosome can be injected ([0046]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Yuk (US 2020/0046647 A1), Rutman et al. (JP 2013519653 A translated), Tan et al. (Clinical applications of stem cell-derived exosomes, Springer Nature, 12 January 2024)
Yuk discloses an exosome-based nanoparticle composite and a method for preparing the same (Abstract). The drug loaded into the exosome cores is not limited to a particular type and examples include poorly soluble drugs, ionic drugs, and others. Examples of ionic drugs include bupivacaine hydrochloride ([0033-0035]). The exosome can be injected ([0046]). The use of the cell line-derived exosomes contributes to a considerable improvement in a biocompatibility; cell lines are preferably macrophage or cancer cell lines ([0041]). RAW264.7 macrophage cell line may be used which is derived from mouse ([0042]). Yuk discloses a method for preparing a core/shell nanoparticle composite, including (a) isolating exosomes from a cell line by centrifugation, (b) mixing the isolated exosomes with a drug to load the drug into the exosomes, and (c) mixing the drug-loaded exosomes with an aqueous solution of a copolymer followed by freeze-drying ([0048]). The nanoparticle composites had particle diameters of ~500 nm ([0063]).
Yuk does not explicitly mention tetrodotoxin.
Rutman discloses sodium channel blocker (SCB) for treatment of human; SCB can be tetrodotoxin (pg 2, Claims). A pharmaceutical composition wherein SCB is contained in a liposome or microemulsion includes exosome (page 3, claim 15). The SCB can be injected via an injection to a human or another mammal (page 3, claims 16-17).
Above references do not explicitly mention mammalian embryonic stem cell.
Tan discloses Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency (Abstract). Stem cell-derived exosomes inherit similar therapeutic effects from their parental cell of origin, e.g., tissue regeneration, anti-inflammation and immunomodulation (pg 3, left col 1st paragraph).
Yuk discloses exosomes containing an anesthetic agent such as bupivacaine HCL. Rutman discloses that SCBs such as tetrodotoxin can be contained in a liposome or exosome. Tan discloses the advantages of using stem-cell derived exosomes. Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to create a composition comprising an anesthetic encapsulated in a stem cell-cerived exosome. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claims 2-4, bupivacaine is taught above.
Regarding claims 5-6, CCB such as tetrodotoxin is taught above.
Regarding claim 7, Yuk discloses paring exosomes – 10 mg of exosomes were isolated from RAW264.7 cell line. Then the exosomes were mixed with 10 mg of doxorubicin HCl. One of ordinary skill in the art would envisage that doxorubicin HCl could be replaced by other ionic drugs such as bupivacaine HCl. One of ordinary skill in the art would further experiment with different concentration of ionic drugs to create exosome compositions.
Regarding claim 8, stem cell is taught above.
Regarding claim 9, diameter is taught above.
Regarding claim 10, Yuk discloses the nanoparticle composite can be mixed with phosphate-buffered saline (PBS) ([0065]).
Claims 11-20 are rejected under 35 U.S.C. 103 as being unpatentable over Yuk (US 2020/0046647 A1), Rutman et al. (JP 2013519653 A translated), Tan et al. (Clinical applications of stem cell-derived exosomes, Springer Nature, 12 January 2024) as applied to claims 1-10 above, and further in view of Levy et al. (Impact of storage conditions and duration on function of native and cargo-loaded mesenchymal stromal cell extracellular vesicles, cytotherapy, 2023) and Hettich et al. (Encapsulation of Hydrophilic Compounds in Small Extracellular Vesicles: Loading Capacity and Impact on Vesicle Functions, Adv. Healthcare Mater. 2022).
Levy discloses impact of storage conditions and duration on function of native and cargo-loaded mesenchymal stromal cell extracellular vesicles (title). Here the authors add to the understanding of storage effects on EV activity with a focus on human bone marrow-derived MSC (BDMSC) EVs. Specifically, the authors’ data showed that the anti-inflammatory and pro-angiogenic effects of MSC EVs were retained for up to 28 days after storage at 20°C, 80°C and room temperature (RT) following lyophilization (pg 503, left col, 1st paragraph). Isolated bone marrow-derived MSC (BDMSC) EVs were aliquoted and stored in their respective conditions and time points before assessing total protein content using a BCA assay. Although storage at 20°C and 80°C generally preserved total protein content, the authors observed a slight trend of decreasing protein content over up to 28 days when stored at RT and 4°C (pg 504, right col, last paragraph). Levy discloses that a significant aspect of the therapeutic potential associated with EVs lie in their use as drug carriers (pg 506, left col, 1st paragraph). Overall, the authors’ data suggest that both storage conditions and duration may have a consequential effect on the therapeutic efficacy of bioactive MSC EVs—including those loaded with therapeutic cargo (pg 508, Conclusion).
Hettich discloses that different methods are exploited to incorporate hydrophilic non-membrane permeable compounds into stem cell-derived small EV, and to assess the vesicle characteristics after the different loading processes. When comparing several methods head-to-head, the loading capacity increases in the order saponin ≤ sonication ≤ fusion ≤ freeze-thawing ≤ osmotic shock (Abstract). Hettich discloses that active ingredient (pyranine) was added to hypotonic EV and the mixture was dialyzed against water. EVs were recovered by diluting the mixture in hypertonic buffer to reach a final osmolality of 300 mOsmol/kg (pg 8, left col 3rd paragraph).
Therefore, it would have been obvious to one of ordinary person in the art before the effective filing date of the claimed invention to have combined teachings of above to carefully consider both the storage conditions and duration to optimize the stability of EV formulations as well as osmolality. This is taking some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Regarding claim 12, a method of making a composition comprising an exosome is taught above.
Regarding claim 13, Rutman discloses that a pharmaceutical composition containing SCB can be in an amount of 0.01 to 1000 ug/ml (or 1 mg/ml) (page 3, claim 10). Furthermore, one of ordinary skill in the art would routinely experiment with different concentrations of an active ingredient within an exosome composition.
Regarding claim 14, Tan discloses that there are various cargo loading techniques including pre-production loading methods (e.g., freeze-thaw cycles) (pg 5, left col, 2nd paragraph). One of ordinary skill in the art would routinely use freeze-thaw cycles to encapsulate active ingredients within exosomes.
Regarding claims 15, one of ordinary skill in the art would routinely experiment with different freeze-thaw cycle methods to encapsulate an active agent within an exosome.
Regarding claim 16, Levy discloses that BDMSC EVs loaded with miR-146a-5p were stored and subjected to one or five freeze-thaw cycles (pg 506, right col, last paragraph). Likewise, one of ordinary skill in the art would routinely experiment with various freeze-thaw cycles.
Regarding claim 17, a method of creating exosomes is well-known in the field as discussed above. One of ordinary skill in the art would routinely experiment with the amount of water, therapeutic agent, and buffer to create exosomes.
Regarding claim 18, a composition is taught above.
Regarding claims 19-20, an injection to a patient is taught above.
Conclusion
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/JOHN SEUNGJAI KWON/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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