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 .
Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 11/13/2025 is acknowledged.
Claims 43-44 and 50-62 are being examined on the merits.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on October 20, 2023 and November 13, 2025 are being considered by the examiner. The signed IDS forms are included with the instant office action.
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 43-44 and 50-62 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 55-56 recites the limitation "one or more beneficial cellular response factor" in line 1. There is insufficient antecedent basis for this limitation in the claim because the claims from which they depend (claim 43) does not recite this limitation or require any beneficial cellular response factor.
The phrase “substantially free” in claims 43 and 44 is a relative term which renders the claim indefinite. The term “substantially free” 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. It is unclear what can or cannot be included in the composition when the applicant recites “substantially free” and therefore the limitation is indefinite and the metes and bounds are unknown. None of the claims which depend from this claim fix this issue and are also rejected for being indefinite.
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 43-44, 50-52, and 57-62 are rejected under 35 U.S.C. 103 as being unpatentable over Yousra Hamdan et. al. (Exosomes and Micro-RNAs in Aging Process, biomedicines 2021, 9, 968) and Steven Braithwaite (from IDS, WO2018200560).
Regarding claim 43-44 and 51,Hamdan teaches “exosomes are the main actors of intercellular communications and have gained great interest in the new cell-free regenerative medicine. These nanoparticles are secreted by almost all cell types and contain lipids, cytokines, growth factors, messenger RNA, and different noncoding RNA, especially micro-RNAs (mi-RNAs). Exosomes’ cargo is released in the neighboring microenvironment but is also expected to act on distant tissues or organs. Different biological processes such as cell development, growth and repair, senescence, migration, immunomodulation, and aging, among others, are mediated by exosomes and principally exosome-derived mi-RNAs. Moreover, their therapeutic potential has been proved and reinforced by their use as biomarkers for disease diagnostics and progression. Evidence has increasingly shown that exosome-derived mi-RNAs are key regulators of age-related diseases, and their involvement in longevity is becoming a promising issue. For instance, mi-RNAs such as mi-RNA-21, mi-RNA-29, and mi-RNA-34 modulate tissue functionality and regeneration by targeting different tissues and involving different pathways but might also interfere with long life expectancy. Human mi-RNAs profiling is effectively related to the biological fluids that are reported differently between young and old individuals.” (see abstract).
Hamdan teaches enriching exosomes with miRNAs: “Moreover, exosome secretion levels can be increased, and their cargo can be enriched in specific proteins or mi-RNA by using genome editing” (see page 5, first para.) and teaches that the miRNA influencing aging are indeed found within human fluids such as saliva, plasma and urine (see page 10 2nd para.) and that “exosomes can be isolated from several sources: cultured cells, cell culture conditioned media, tissues, and biological fluids” (see page 15, para. 3). Hamdan describes purification steps: “nevertheless, different characterizations and validation methods have been developed whereby exosome purification and drug delivery are improved” (see page 2).
Regarding claims 43 and 52, “Interestingly, adipose tissue-derived exosomes from rats and pork have shown that xenogeneic injection of exosomes between these two species induced tissue repair and regeneration proving then their low immunogenicity” (see 15, 1st para.).
Regarding claims 58, Hamdan teaches, “another point of view is that aging is associated with the reduction of the regenerative and reparative activity in organs and tissues, leading to the increase of senescent cells. Different findings have highlighted the interaction of aging with exosomes’ composition. Exosomes from young donors appeared more proliferative, promoting osteogenic differentiation and maturation of MSCs through the enriched protein Galectin-3 being decreased in plasma exosomes of aged individuals [155]. During aging, senescent cells are negatively impacted in their exosome composition of mi-RNAs and proteins, including transforming growth factors (TGF-), growth differentiation factor-11 (GDF-11), interleukin-6 (IL-6), toll-like receptor 2 (TLR-2), TLR-4, tumor necrosis factor-(TNF-alpha), insulin-like growth factor (IGF), hepatocytes growth factor (HGF), and IL-1 (see page 9, 3rd para.).
Nevertheless, inflammatory cytokine secretion and release, including TNF-, IL-6, and IL-1, induced the secretion of larger and irregular-shaped exosomes from stem cells. Therefore, these signaling pathways are involved in the modulation of different gene expression and signaling molecules involved in the cell cycle arrest, including MAPK, VEGF, Wnt, NF-kB, JNK, CD4/6, SIRT1, Cyclin D1, E2F, PI3K-AKT, and IL-6 [53,68,147,148,158–161]. These interaction mechanisms might explain the changes induced by inflammatory cytokines in biological aging, also called inflamm-aging (see last para. page 9).
Hamdan does not specifically describe that the composition is substantially free from immunogenic components, and is non-immunogenic such that it can be transferred from one species to another, but Hamdan teaches wherein this transferring from one species to another has been done from rats to pigs and was done with low immunogenicity and so this limitation is implied and made obvious. Persons having ordinary skill in the art would know to remove any immunogenic components that would react when transferring exogenous components.
Hamdan teaches that during aging, senescent cells are negatively impacted in their exosome composition of mi-RNAs and proteins, including transforming growth factors (TGF-), growth differentiation factor-11 (GDF-11) and interleukin-6 (IL-6), because these inflammatory cytokines can change gene expression and increase inflammation of their environment creating something called inflamm-aging. Targeting these inflammatory markers for reduction is also obvious.
Although Hamdan teaches it is known to purify exosomes, Hamdan does not teach purifying plasma.
Braithwaite is relied upon to specifically teach concentrated, purified plasma fractions being useful for treating age-related diseases.
Braithwaite teaches using concentrated blood plasma fractions for treating age-related conditions (see abstract and claim 1) and teaches wherein the plasma is purified (see 3. Plasma fractions, 1st para.).
Therefore it would have been obvious to persons having ordinary skill in the art to determine the amount of purified plasma (containing the exosomes) to that of the purified RNA fraction to be in a ratio of about 1:1 to about 1:100 because this is well within the purview of any skilled artisan. One would also want to find the optimal ratio of which encapsulation of RNA species into the exosomes would be for the most efficacious administration.
Hamdan does not specifically teach using an in vitro transcribed RNA, however designing a synthetic RNA that mimics in vivo RNA would have been prima facie obvious given the prior art as Yousra teaches that different RNA species are useful for treating age-related diseases. To synthetically create a transcribed RNA one can do this in a lab through a common practice of in vitro transcription, wherein RNA is synthesized from a DNA template.
Creating the instant invention would have been obvious given the Handan’s and Braithwaite’s art and there would have been a reasonable expectation of success in doing so.
Claims 44 and 53-54 are rejected under 35 U.S.C. 103 as being unpatentable over Yousra Hamdan et. al. (Exosomes and Micro-RNAs in Aging Process, biomedicines 2021, 9, 968) and Steven Braithwaite (from IDS, WO2018200560) as applied to claims 43-44, 50-52, 57-62 above, and further in view of Anton Wyss-Coray et. al. (From IDS, US20150157664A1).
Hamdan and Braithwaite teach the instant invention however is silent on wherein the young animal used for obtaining the plasma fraction containing the enriched RNA is from at most half of the young animal's expected lifted span.
Wyss-Coray’s general disclosure is to methods and compositions for treating aging-associated conditions by administering a young plasma-comprising blood product to an individual in need thereof (see abstract and claim 1).
Wyss-Coray teaches “non-limiting examples of plasma-comprising blood products suitable for use in the subject methods include whole blood treated with anti-coagulant (e.g., EDTA, citrate, oxalate, heparin, etc.), blood products produced by filtering whole blood to remove white blood cells (“leukoreduction”), and blood product consisting essentially of purified plasma” (see 0043).
Regarding claim 53 Wyss-Coray teaches ““young individual” may refer to a subject that is between the ages of 0 and 40, e.g., 0, 1, 5, 10, 15, 20, 25, 30, 35, or 40 years old” (see 0045) and teaches ““an individual suffering from or at risk of suffering from an aging-associated cognitive impairment” it is meant to include an individual that is about 50 years old or older, e.g., 60 years old or older, 70 years old or older, 80 years old or older, and usually no older than 100 years old, such as 90 years old, i.e., between the ages of about 50 and 100, e.g., 50, 55, 60, 65, 70, 75, 80, 85 or about 90 years old, and suffers from an aging associated condition, e.g.” (see 0046).
Regarding claim 54, Wyss-Coray teaches intravenous administration see (see figure 3).
Therefore it would have been obvious to persons having ordinary skill in the art to use young individual’s plasma that is at most half of the young animals expected life span.
It would have also been obvious to create an RNA-enriched, purified, plasma composition by combining a purified plasma fraction which comprises of exosomes or extracellular vesicles with a purified RNA-enriched fraction which is substantially free from iummunogenic components because Hamdan teaches that these nanoparticles can be found in plasma and these vesicles are known to carry varying RNA species which can alter phenotypes/genotypes of other cells which take them up. The applicant recites wherein the second composition can comprise of plasma and platelets (see instant 0016) and Yousra teaches that these RNA species are found in exosomes which can come from plasma. Additionally, Wyss-Coray teaches administering purified plasma from young patients to old in order to treat age-related disease. Hamdan teaches successful transfer or exogenous and xenogenic transfer from different species has low immunogenic effects.
Claims 55-56 are rejected under 35 U.S.C. 103 as being unpatentable over Yousra Hamdan et. al. (Exosomes and Micro-RNAs in Aging Process, biomedicines 2021, 9, 968) and Steven Braithwaite (from IDS, WO2018200560) as applied to claims 43-44, 50-52, 57-59 above, and further in view of Cody J. Schmidlin et. al. (Redox Regulation by NRF2 in Aging and Disease, Free Radic Biol Med. 2019 April; 134: 702–707.).
Hamdan and Braithwaite teach the instant invention however are silent on wherein one or more of the beneficial cellular response factors comprises Nrf2.
Schmidlin teaches that “NRF2, a transcription factor that has been deemed the master regulator of cellular redox homeostasis, declines with age. NRF2 transcriptionally upregulates genes that combat oxidative stress; therefore, loss of NRF2 allows oxidative stress to go unmitigated and drive the aging phenotype. Oxidative stress is a common theme among the key features associated with the aging process, collectively referred to as the “Hallmarks of Aging”, as it disrupts proteostasis, alters genomic stability, and leads to cell death” (see abstract).
“Interestingly, microRNAs have also been shown to play a role in the epigenetic regulation of genes, as they control the expression of key DNA methyltransferases and histone deacetylases [24]. Along these lines, NRF2 expression is also decreased by microRNAs (i.e. miRNA-144), leading to increased hydrogen peroxide levels” (see page 4, last para.).
Therefore it would have been obvious to persons having ordinary skill in the art to target Nrf2 as a beneficial cellular response factor to be increased upon administration of the invention taught by Hamdan and Braithwaite because Schmidlin teaches that NRF2 transcriptionally upregulates genes that combat oxidative stress; therefore, loss of NRF2 allows oxidative stress to go unmitigated and drive the aging phenotype. Additionally, the administration of the same components to the same patient population would render the same results as being claimed because the activity would be inherent. There was nothing done by the applicant that would allow for any additional activities.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. (from IDS, WO2015088915), US2021/315932, (from IDS, US10905779) and CN114748504A.
Currently no claims are allowed.
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JACOB A BOECKELMANExaminer, Art Unit 1655
/ANAND U DESAI/Supervisory Patent Examiner, Art Unit 1655