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
Amended claims 1-7, 9-17 are pending.
Newly amended claim 9-17 are directed to an invention that is not linked to form a single general inventive concept: since the composition of the processes of cl. 9-17 lacks the same or corresponding special technical feature since the composition has been rejected in prior action; thus, invention of claims 9-17 lack unity.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 9-17 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are to a single general inventive concept, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Since the examiner has withdrawn the process claims 9-17, if all the product claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product claims will be considered for rejoinder.
Claims 1-7 are examined here.
Priority
The benefit to 63/178,229 and 63/330,092 filed on 04/22/2021 and 04/12/2022, respectively, via its PCT filing CL/CL2022/050039, filed on 10/20/2023 is recognized. However the provisional applications have submitted specification without claims for each application in Spanish. Similarly, the PCT filing document is also in Spanish. Thus, for search purposes the filing date of instant filing will be used, 10/20/2023.
Claim Rejections - 35 USC § 112
Rejection of claims 1, 6, and 7 under 112(b) is withdrawn, the claims correct the inconsistency by reciting “osmolarity between 250 and 310 mOsmol/L.”
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.
Claim 1 and dependent claims 2-7 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.
Amended claim 1 recites “inflammatory and immunological pathways associated with osteoarticular and autoimmune disease” The limitation is not definite since the term “associated” is a relative term and thus the scope of inflammatory and immunological pathways is unclear. A skilled artisan understands existence of numerous inflammatory and immunological pathways associated with osteoarticular and autoimmune disease and, further, the limitation encompasses any cellular molecule involved in inflammatory and immunological pathways and thus it is unclear what is excluded.
Claims 2-7 are rejected since they do not overcome the indefiniteness of claim 1.
Claim Rejections - 35 USC § 101
Rejection of amended claims 1-5 under 101 is maintained but edited to address the Remarks of 07/02/2026 and it is understood that the claimed product is composition of enriched EVs.
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon or a law of nature without significantly more. The claims are directed to a “composition comprising an enriched population of extracellular vesicles (EV) derived from a culture of umbilical cord mesenchymal cells, and a medium or vehicle free of animal components and proteins, the medium or vehicle having an osmolarity between 250 and 310 mOsmol/L and a pH between 6.0 and 8.0, the EVs comprise” claimed miRNAs along with specific surface markers and claimed functional limitation and particular size/concentration. The claims do not provide EVs that are markedly different from their naturally occurring counterpart, and this judicial exception is not integrated into a practical application. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
Prong 1 - Statutory category: Here, the claimed invention is either a composition of matter or a manufacture. Under 35 USC 101, the claimed invention must be “any new and useful process, machine, manufacture, or composition of matter.” The composition of EVs can be considered a composition of matter or a manufactured product, thus, falls under one of the statutory category identified in 35 U.S.C 101.
Step 2A-Prong One– Judicial exception: Here, the claimed invention is a composition or a manufactured product but is directed to the judicial exception: a law of nature or a natural phenomenon (product of nature). Even composition or a manufacture may not be patent eligible if it falls under a judicial exception. The three judicial exception categories are enumerated abstract idea, a law of nature, or a natural phenomenon (product of nature). Nature based products include both naturally occurring or not naturally occurring but have characteristics that are not markedly different from a natural occurring counterpart fall within the judicial exception.
The claims are directed to enriched EVs derived from a culture of umbilical cord mesenchymal cells. Here, there is no difference between claimed EVs derived from MSCs and natural EVs produced by natural MSCs, which would comprise the claimed miRNAs and surface markers, and thus would not be markedly different from a natural occurring EVs from umbilical cord mesenchymal cells.
Step 2A-Prong Two: Practical Application: This part of the eligibility analysis evaluates whether the claim as a whole integrates the recited judicial exception into a practical application of the exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application.
Here the claim only requires that the composition with enriched EVs of umbilical mesenchymal cells consisting of claimed miRNAs and surface markers be in a medium free of animal components and proteins, with claimed osmolarity and pH. The additional elements are the medium with certain osmolarity and pH. The additional element is a generic medium to maintain the ionic equilibrium with the composition with EVs. The medium does not meaningfully limit the claim. Saline water or even purified plasma, both natural products are not markedly different from natural product, would have required osmolarity.
Step 2B: Judicial Exception/Significantly More: This part of the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements, adds an inventive concept to the claim. MPEP 2106.05. Step 2B analysis also assesses whether the additional elements represent well-understood, routine, conventional activity.
Claim 1 does not add any particular additional element that amounts to significantly more; alternatively, even if it is argued that the claimed medium is man-made, the suspension of the EVs in the medium can be considered a well-understood, routine, conventional activity, since suspending the EVs in a medium compatible for administration either in vivo or in vitro or for storage is required.
Claim 2 only requires additional claimed miRNAs within the EVs, and the natural EVs from claimed mesenchymal cells would naturally comprise the claimed miRNAs. Thus, the EV of claim 2 is not markedly different from the natural product of EVs produced by the claimed mesenchymal cells and do not include additional elements that integrate the judicial exception into a practical application.
Claim 3 requires the EVs to have additional surface markers, which is still not markedly different from the natural product and these EVs would still fall under the judicial exception and do not have additional elements that integrate the judicial exception into a practical application.
Claims 4 and 5 only require that the EVs are concentrated and limited to particular size (30-300 nm). Step 2B analysis also assesses whether the additional elements represent well-understood, routine, conventional activity. Here, concentrating the EVs (i.e. enriching) and limiting them to a particular size is well-understood, routine, conventional activity. Prior art cited below, including, e.g., Hu et al. (2020, Theranostics, 10, 2293-2308) and Wright (4/20/2021, Kansas State Uni., Thesis Dissertation, pg. 1-303), Correia et al. (US Pub. 20210369789, pub. 12/2/21), note identifying the size of EVs and/or their concentration (vesicles/mL).
Therefore, claims 1-5 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon or a laws of nature without significantly more.
Response to Arguments
Applicant's arguments filed 07/02/2026 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks urge the following:
The claims are directed to “non-naturally occurring manufactured composition comprising an enriched population of extracellular vesicles derived from a culture of umbilical cord mesenchymal cells an formulated in a defined pharmaceutical vehicle free of animal components and proteins” (pg. 6). Further, the claimed composition has a specific molecular profile (i.e. claimed miRNAs and specific surface markers).
The arguments are not persuasive.
Enrichment does not make the EVs markedly different from their natural counterpart. As noted in prior action that saline or purified plasma, which can be the vehicle/medium that meet the claimed limitation of pharmaceutical vehicle free of animal components and proteins, is either not markedly different from natural products or suspending the EVs in such vehicle/medium is considered a well-understood, routine, conventional activity for administration (pg. 5). The inherent molecular profile is not markedly different between the natural and the enriched EVs.
Thus, the claims are rejected under 101.
Claim Rejections - 35 USC § 102
Rejection of cl. 1, 2, 3, 5, 6, 7 under 102 is withdrawn due to claim amendment. However, upon identifying appropriate reference, claims 1, 2, 3, 6, and 7 are rejected under 102 as noted below.
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.
Claim(s) 1, 2,are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu et al. (2020, Theranostics, 10, 2293-2308, “Hu”, of record) as evidenced by Molekula Phosphate-Buffered Saline (PBS) Product page (https://molekula.com/glossary/phosphate-buffered-saline-pbs, accessed 09/01/2026) and Ginaldi et al. (2005, Immun. Ageing, 4, pg. 1-5, “Ginaldi”).
Regarding instant cl. 1, 2, Hu discloses isolating human umbilical cord mesenchymal stromal cell (MSC)-derived extracellular vesicles (hucMSC-EVs) for therapeutic use (abstract). The cells were cultured, and the conditioned medium was collected, centrifuged to remove dead cells and debris, and ultra-filtered and processed for hucMSC-EVs, which were stored in PBS (pg. 2295). The EVs expressed CD9, CD63, CD81 (see Fig. 1F, p. 2299). As evidenced by Molekula PBS product site, the osmolarity of PBS is around 300 mOsmol/L and pH of approximately 7.4.
Although Hu does not disclose the miRNA content of the EVs, based on similar processing of the UC-MSCs and disclosing the same surface markers of the EVs as directed by EVs of claim 1, Hu’s enriched hucMSC-EVs would comprise the same claimed miRNAs. Here, the identification of the miRNAs within the EVs is a further characterization of a known material (hucMSC-EVs), which does not make it novel (MPEP 2112(I)).
Further, since Hu meets the structural limitation it would necessarily perform the claimed intended use of the product, i.e. “modulate inflammatory and immunological pathways associated with osteoarticular and autoimmune disease.” Regardless, Hu discloses that “MSC-derived EVs have therapeutic effects in variety of diseases including bone defect repair and fracture healing, due to their specific advantages of high stability, low immunogenicity” and demonstrate improved bone properties in mice model of osteoporosis (pg. 2304), as evidenced by Ginaldi et al. “inflammation also exerts significant influence on bone turnover, inducing osteoporosis;” thus inflammation is associated with osteoporosis (abstract).
Claim 3 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu et al. (2020, Theranostics, 10, 2293-2308, “Hu”) and as evidenced by Abels and Breakerfield (2016, Cell. Mol. Neurobiol., 36, 301-312, “Abels”, of record)
Regarding instant cl. 3, Hu discloses the flow cytometric analysis of hucMSCs positively expressed CD90 and CD44, and it is known that extracellular vesicles occur through outward budding of the plasma membrane or through the inward budding of the endosomal membrane, resulting in the formation of multivesicular bodies, which release vesicles upon fusion with the plasma membrane, as evidenced by Abels (abstract). Thus, although Hu does not specifically test for the expression of CD90 and CD44 on EVs using western blot, the flow cytometric analysis of the cells expressed CD90 and CD44 and since it is known that EVs use the plasma membrane of cell origin, the EVs would inherently express CD90 and CD44.
Further Abels also discloses that EVs contain miRNAs (pg. 306-309).
Claims 6, 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hu et al. (2020, Theranostics, 10, 2293-2308, “Hu”) as evidenced by Wright (4/20/2021, Kansas State Uni., Thesis Dissertation, pg. 1-303, of record).
Regarding instant cl. 6, Hu discloses a method of obtaining composition of EVs, wherein primarily EVs within the size range of 60-150 nm were isolated from the supernatant of the culture of UC-MSCs expanded in vitro, and the cells express various surface markers, including CD44 and CD90 and are resuspended in PBS (pg. 2295), which is animal and protein free composition with the osmolarity around 300 mOsmol/L and pH of approximately 7.4.
As evidenced by Wright, who demonstrates that MSCs isolated are positive for CD90, CD105 and CD44 (Fig. 47 of human UC-MSCs flow cytometry data, pg. 259).
Regarding instant cl. 7, Hu discloses EVs are isolated by ultrafiltration and centrifugation, washed, at least 2X (“The ultrafiltration supernatant was washed with PBS for twice and re-ultrafiltrated to 1 mL” (pg. 2295)) and “hucMSC-EVs pellets were resuspended in a right amount of PBS” (pg. 2295), as noted above PBS is within the range of claimed mOsmol/L and pH.
As noted above, Hu discloses the expression of various surface markers on the hucMSC-EVs and as evidenced by Wright, hucMSC-EVs also express CD105 (pg. 63) and, as demonstrated in Hu, also expressed CD63, CD81 and CD9 (see pg. 86).
Response to Arguments
Applicant's arguments filed 07/02/2026 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue the following:
The amended limitations are not disclosed by the cited art (pg. 8).
Details the teaching of Hu reference and indicates that a) “the present application describes different culture conditions and a different purification process” and the differences “demonstrate that the Office has not established that Hu necessarily produces extracellular vesicles having the specific quantitative miRNA profile recited in amended claim 1” (pg. 8).
The action’s inherency is misguided since “the missing limitation necessarily be present in the prior art reference” and Hu and additional cited references do not disclose the “specific quantitative miRNA profile” (pg. 8-9).
The argument is not persuasive.
First, Hu meets all the structural limitations required by the amended claims and therefore inherently possesses the characteristics of the claimed product, including the claimed miRNAs even though Hu does not disclose them (see MPEP 2112(V)). Here, the burden is on the Applicant to show that Hu’s product is different from instant product and would not necessarily possess the claimed features/characteristics (addressing argument 1, 3).
Second, the “different culture conditions and a different purification process” are not claimed and the prior art meets the process elements required by the claims. Further, the conditions and processes used to enrich the EVs would amount to a product-by-process claims (i.e. cl. 6 and 7). MPEP 2113 indicates that determination of patentability is based on the product itself and not by its method of production but process needs to be considered if it “impart[s] distinctive structural characteristics to the final product.” Here, the prior art discloses same claimed processes and same claimed structural features of the product (i.e. size, surface markers, cells from which EV are derived, enrichment process), thus the claimed product is anticipated by the prior art cited (addressing argument 2).
Claim Rejections - 35 USC § 103
Rejection of claim 4 is maintained under 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 4, 5 are rejected under 35 U.S.C. 103 as being unpatentable over Hu et al. (2020, Theranostics, 10, 2293-2308, “Hu”) and as evidenced by Molekula Phosphate-Buffered Saline (PBS) Product page (https://molekula.com/glossary/phosphate-buffered-saline-pbs, accessed 09/01/2026) and Ginaldi et al. (2005, Immun. Ageing, 4, pg. 1-5, “Ginaldi”) as applied to claims 1-3, 6-7 above, and further in view of Correia et al. (US Pub. 20210369789, pub. 12/2/21).
Regarding instant cl. 1, Hu discloses isolating human umbilical cord mesenchymal stromal cell (MSC)-derived extracellular vesicles (hucMSC-EVs) for therapeutic use (abstract). The cells were cultured, and the conditioned medium was collected, centrifuged to remove dead cells and debris, and ultra-filtered and processed for hucMSC-EVs, which were stored in PBS (pg. 2295). The EVs expressed CD9, CD63, CD81 (see Fig. 1F, p. 2299). As evidenced by Molekula PBS product site, the osmolarity of PBS is around 300 mOsmol/L and pH of approximately 7.4.
Although, Hu does not disclose the miRNA content of the EVs, based on similar processing of the UC-MSCs and noting the same surface markers to the EVs as instant specification, Hu’s enriched hucMSC-EVs would consist of the same claimed miRNAs. Here, the identification of the miRNAs within the EVs is further characterization of a known material (hucMSC-EVs), which does not make it novel (MPEP 2112(I)).
Hu does not disclose the concentration of cells.
Correia discloses administering a concentration of 2.5X10^8 small extracellular vesicles (SEVs) from umbilical cord blood mononuclear cells in solution applied topically to wound area (par. 351) and can also be stored in lyophilized SEVs composition having 1X10^9 to 1X10^11 particles/mL (par. 150, relevant to instant cl. 4). Correia discloses using Nanoparticle Tracking Analysis (NTA) to determine the yield of SEVs following purification steps (par. 39, Fig. 3).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is 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. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified concentration of particles of Hu in view of Correia and arrive at the claimed invention with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to apply a consistent and known concentration of particles per volume of Hu’s hUCSMC-EVs based on the use of NTA and administration of particles/mL of Correia to administer similar range of particles/mL of EVs across studies or for treatment. Thus, cl. 4 is obvious.
Regarding instant cl. 5, Hu discloses that the EVs diameters “primarily ranged from 60 nm to 150 nm” (pg. 2299, Fig. 1D, E).
Response to Arguments
Applicant's arguments filed 07/02/2026 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue that since Hu fails to disclose the specific quantitative miRNA profile of amended claim 1, Correia does not remedy the deficiency.
The issue regarding Hu is addressed in above response to the Remarks of 35 USC 102.
Claim 4 remains rejected and claim 5 is rejected under 35 USC 103.
Allowable Subject Matter
No claim allowed.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KEYUR A. VYAS whose telephone number is (571)272-0924. The examiner can normally be reached M-F 9am - 4 pm (EST).
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/KEYUR A VYAS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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