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 .
Claim Status
Claims 1-22 pending.
Claims 1-15 and 17-20 are withdrawn from examination as being part of nonelected inventions.
Claims 16 and 21-22 are being examined.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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 16 and 21-22 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.
Claim 16 recites, “the composition has an antioxidant capacity”. The claim does not make clear what substance is providing this functional property. Further, it is unclear whether or not such a substance(s) is/are within the nanovesicles.
It is suggested to amend the claim by inserting, “wherein the nanovesicles comprise at least one antioxidant, and”, in line 2 after “to cells,”.
Claim 21 recites, “The method of Claim 16, wherein the nanovesicles are extracted from a mixture comprising:
- Citrus Lemon in a percentage between 23% and 27%,
- Citrus Sinensis in a percentage between 23% and 27%,
- Citrus Sinensis (Magnolopsida cultivar) in a percentage between 32% and 38%,
- Citrus Paradisi in a percentage between 4% and 6%,
- Citrus Bergamia in a percentage between 4% and 6% - Mangifera Indica in a percentage between 4% and 6%.
There is no “and” or “or” between line 6 and 7. It is not clear to the Examiner if all the five components or any one of the five components need(s) to be present in the claim.
Similarly, there is no “and” or “or” between line 5 and 6 in claim 22. It is not clear to the Examiner if all the three components or any one of the three components need(s) to be present in the claim.
Thus, the meets and bounds of claims 21-22 are not clear.
Claim 22 recites the limitation "second composition" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 22 depends on claim 16. Claim 16 recites “a composition” in line 2 but does not recite any “second composition”. It is not clear what is implied by “second composition” in claim 22.
Claim Rejections - 35 USC § 112(a)
Written Description
Claim 16 is 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 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.
Claim 16 recites, “…the composition has an antioxidant capacity equal to 1777.0 ± 150 mM per 6 x 109 nanovesicles in the composition...”
Applicant describes quantification of nanovesicles (number) using "Bradford assay" and "Nanoparticle Tracking Analysis" (NTA) (spec, page 13, para 2, line 1-2). The Applicant also describes, “using a commercial kit (PAO kit) to measure the total antioxidant activity of our both micro and nanovesicle” (page 15, para 2, line 4-6). Instant description teaches, “the NTA analysis demonstrated the integrity of the vesicles and allowed the evaluation of the concentration, size and distribution of the vesicles derived from the extracted juice” (page 13, para 2, line 3-7).
Claim 16 comprises all types of antioxidants and not just protein. Bradford assay is a standard method in the art used to quantify total protein concentration,(not just specific proteins which are considered antioxidant, in a solution. Antioxidants are diverse in chemical property and prevent oxidation of diverse metabolic and/or cellular substrates (inducing polynucleotides, phenols, and lipids) caused by free radicles. Many, if not most, of the (known) antioxidants, e.g., ascorbic acid present within the nanovesicles (spec, page 17, para 1, line 1-3), are not proteins and cannot be detected by the Bradford assay.
Shahidi et al. (Measurement of antioxidant activity, Journal of functional foods, 2015, 18:757–781) teaches that oxidation itself comprises autoxidation, photooxidation, thermal oxidation and enzymatic oxidation, most of which involve free radicals and/or other reactive species as the intermediate (page 757, right column, para 2, line 1-4). It also describes that antioxidant activity can be monitored by a variety of assays (page 760, Table 1) with different mechanisms, including hydrogen atom transfer (HAT), single electron transfer (ET), reducing power, and metal chelation, among others (Abstract). Understanding the mechanisms, advantages and limitations of the measurement assays is important for proper selection of method(s) for valid evaluation of antioxidant potential in desired applications (Abstract). The Examiner broadly and reasonably interprets “antioxidant capacity” as “antioxidant activity”, as described by Shahidi et al.
It is apparent that the antioxidant activity varies depending on the specific assay used. The Applicant does not how the generic Bradford assay measures specific proteins with antioxidant capacity/activity. The Applicant also does not describe which process (e.g., hydrogen atom transfer (HAT), single electron transfer (ET), reducing power, metal chelation, etc., as described by Shahidi et al.) the commercial kit (PAO kit) uses to measure antioxidant activity. The Applicant also does not describe if Bradford assay can specifically measure enzymes and proteins that have antioxidant activity.
The Applicant also does not describe if the specific number (6x109) of nanovesicles (of a defined diameter size range) and/or the antioxidant capacity of 1777±150 mM is/are critical to achieve the claimed function of slowing cell aging.
An invention described solely in terms of a method of making and/or its function would lack written descriptive support where there is no described (in the specification) or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. See MPEP § 2163.
Considering the breadth of the claims, uncertainty regarding quantification of “antioxidant capacity”, and lack of structure function relationship of the broad genus claimed, the Applicant does not appear to have been in possession of the claimed genus at the time this application was filed.
Response to Applicant’s Arguments: The argument set forth in the Applicant’s reply on 01/26/2026 has been considered but is not found fully persuasive.
The Applicant argues, “”Antioxidant capacity" was a well-known term of art at the time of filing of the present application, see, e.g., Ghiselli, Andrea, et al.” (response, page 6, last para, line 1-2)”.
The Examiner acknowledges that the term “Antioxidant capacity" was a well-known term of art at the time of filing of the present application” (response, page 6, last para, line 1-2). As discussed in the rejection, antioxidant capacity of a given sample will have differing measurements depending on the assay used. Shahidi et al. describes different methods, and Ghiselli et al. (Total antioxidant capacity as a tool to assess redox status: critical view and experimental data, 2000, Free Radical Biology & Medicine, 29:1106–1114; cited by Applicant in the response) describes yet another method, Total Radical-trapping Antioxidant Parameter (TRAP) assay (page 1107, right column, last para) and a modified method based on the TRAP assay (page 1108, right column, para 1, line 1-4). The specification does not indicate what assay was used to obtain the antioxidant capacity recited in claim 16. The specification mentions a Bradford assay, nanoparticle tracking analysis (NTA), and an identified “PAO” commercial kit. As discussed above, Bradford assay is a standard method in the art used to quantify total protein concentration in a solution and not antioxidant or not limited to specific proteins with antioxidant activity. The NTA analysis demonstrated “the integrity of the vesicles and allowed the evaluation of the concentration, size and distribution of the vesicles derived from the extracted juice” (page 13, para 2, line 3-7) and does not quantify antioxidant capacity. As discussed above, the Applicant also does not describe the commercial kit in terms of the actual process (or, actual assay) and what exactly does the kit measure.
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.
Claims 16 and 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over Buachan et al. in view of Stanly et al.
Claim 16 is drawn to a method of slowing cell aging by administering a composition comprising 6x109 nanovesicles of 80nm to 200 nm in size and derived from plants and containing 1777.0 ± 150 mM antioxidant.
Buachan et al. teaches that cytoprotective action including delaying ageing by citrus fruits is enhanced by the antioxidants including vitamin C, phenolics, carotenoids and flavonoids (title; abstract, line 13; page 1619, para 3, line 4-5) present there. High intake of citrus fruit pummelo (pomelo), Citrus maxima (CM), lowers the risk of cardiovascular disease (CVD) and stroke (abstract, line 3-4). It implies that all the antioxidants are present in bio-available form (as recited in claim 1) to the cells and/or the animal to impart its effect. In CVD, the endothelium is the main target of Reactive Oxygen Species (ROS) induced tissue injury, leading to endothelial dysfunction and premature aging (page 1619, para 2, line 4-5). Administering CM at 10-1000µg/ml (page 1620, para 3, last line) delays onset of aging (abstract, line 12), which reads on to “slowing cell aging”, as recited in claim 16. Buachan et al. describes that gallic acid is a common antioxidant besides ascorbic acid and citrus flavonoids like Hesperidin and Naringin (abstract, line 8; page 1620, para 7, line 1-2).
However, Buachan et al. does not describe 6x109 nanovesicles containing 1777.0 ± 150 mM antioxidant wherein the nanovesicles are between 80nM to 200nM in size.
Stanly et al. describes several types of biomembrane-enclosed plant derived vesicles including nanovesicles that can transport or store bioactive molecules and other metabolites (page 1, para 1). Vesicle populations present in citrus juice comprises nanovesicles between 50 and 80 nM diameter in size (page 2, para 3, line 11-13). Stanly et al. also describes citrus species comprising orange (C. sinensis) and grapefruit (C. paradisi) (as recited in claim 21) that specifically inhibit the proliferation of lung, skin and breast cancer cells, with no substantial effect on the growth of non-cancer cells (abstract). Nanovesicles (NVS) present in grapefruit juice exhibit a high relative amount of organic acids that include the antioxidants (Fig. 4). Stanley also describes the presence of approximately 600–800 proteins in each sample including many antioxidant enzymes such as catalase, superoxide dismutase and glutathione reductase (which is known to be involved in production and recycle of an important biological antioxidant, glutathione1), as recited in claim 22.
Before the effective filing date of the invention, it would have been obvious to an ordinarily skilled artisan to administer a composition comprising antioxidants like gallic acid, ascorbic acid, Hesperidin, and Naringin derived from citrus plants (e.g. Citrus maxima), as described by Buachan et al., encapsulated in nanovesicles, as described by Stanly et al., with a realistic goal to slow down aging in animal including human cells, as described by Buachan et al.
Buachan et al. teaches a method of slowing cell aging by administering a mixture of antioxidants present in 10-1000µg/ml freeze dried citrus juice (page 1620, para 3, line 3-6). Buachan et al. measures antioxidant capacity by Ferric Reducing Antioxidant Power (FRAP) assay (page 1620, para 5, line 1-2). However, Buachan et al. does not describe any specific number of nanovesicles or antioxidant capacity/amount in terms of molarity (mM). However, the description of the instant invention does not teach if the number of nanovesicles (6x109) and/or the molarity (1777.0 ± 150 mM) is a critical parameter in the invention to slow cell aging.
The Applicant is reminded that differences in number of nanovesicles and “antioxidant capacity” (mM) do not support the patentability of the subject matter encompassed by the prior arts unless there is evidence indicating such number (of nanovesicles) and/or “antioxidant capacity” is/are 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.
Before the effective filing date, an ordinarily skilled artisan would have been motivated to administer a composition comprising antioxidants like gallic acid, ascorbic acid, hesperidin, and naringin derived from citrus plants (e.g. Citrus maxima) in nanovesicles made up of lipid membranes with a realistic objective to slow down aging in animal including human cells.
Response to Applicant’s Arguments: The Applicant argues, “Stanly provides no teaching or suggestion regarding what, if any, effects the isolated vesicles described therein may have on cellular Aging” (page 7, para 9, last 3 lines) and “Buachan et al. provides no teaching or guidance regarding isolated plant vesicles” (page 8, para 1, line 1-2). The Examiner disagrees. Buachan et al. teaches that cytoprotective action including delaying ageing by citrus fruits is enhanced by the antioxidants including vitamin C, phenolics, carotenoids and flavonoids (title; abstract, line 13; page 1619, para 3, line 4-5) present in fruit juice from several citrus spp., while Stanley et al. describes vesicle populations present in citrus juice comprises nanovesicles between 50 and 80 nM diameter in size (page 2, para 3, line 11-13), as discussed above.
Applicant is reminded that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
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.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAY CHATTERJEE whose telephone number is (703)756-1329. The examiner can normally be reached (Mon - Fri) 8.30 am to 5.30 pm..
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bratislav Stankovic can be reached at (571) 270-0305. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Jay Chatterjee
Patent Examiner
Art Unit 1662
/Jay Chatterjee/ Examiner, Art Unit 1662
/BRATISLAV STANKOVIC/ Supervisory Patent Examiner, Art Units 1661 & 1662
1 Couto et al. (The role of glutathione reductase and related enzymes on cellular redox homoeostasis network, 2016, Free Radical Biology and Medicine, 95:27–42) provides the evidence that glutathione reductase is involved in production and recycle of an important biological antioxidant, glutathione (abstract, line 2-4; page 29, right column, para 4, line 1-5).