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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/20/2026 has been entered.
Claims 1-20 are currently pending as per claims filed on 07/20/2026. Applicant's election with traverse of Group II, claim 19 and 20 in the reply filed on 10/22/2025 was previously acknowledged. Claim 1-18 have been withdrawn from consideration. Claims 19 and 20 have been amended per claims filed 07/20/2026.
Therefore, claims 19 and 20 are under examination in the instant application. An action on the merits follows.
Priority
The instant application claims domestic benefit to US provisional patent application number 63/203,662 filed on 07/27/2021. Thus, the earliest possible priority for the instant application is 07/27/2021.
Withdrawn Rejections in response to Applicants’ arguments
Claim Rejections - 35 USC § 101
The amendments of claim 20 to a method of producing an exosome composition combined with applicants’ arguments are sufficient to
overcome the rejection, therefore the rejection has been withdrawn. The applicant’s
amendments and arguments further clarify the claimed method is directed to producing an exosome composition comprising a population of enriched exosomes and not directed to the exosomes themselves. Applicants’ arguments are moot in view of the withdrawn rejection.
Claim Rejections - 35 USC § 112(b)
In view of applicant’s amendments to claims 19 and 20 removing the word “about”, the rejection has been withdrawn. Applicants’ arguments are moot in view of the withdrawn rejection.
Claim Rejections - 35 USC § 103
In view of applicants’ arguments and amendments to claim 19 adding the characteristics of the enriched exosome composition and amendments to claim 20 removing its dependency from claim 19 (now an independent claim) and adding active steps, the rejection has been withdrawn.
A response to Applicant’s arguments with regard to a withdrawn rejection is
moot. A response to any argument pertaining to a new or maintained rejection can be
found below.
New rejections in response to Applicants’ arguments or
Amendment
Claim Rejections - 35 USC § 102
It is noted that claim 20 recites “the method comprising the steps of:”, hence the instant method is interpreted to include additional steps not recited in the claim. Moreover, in view of the comprising language, the steps may be performed in any order, including the order in which step of “filtrating the resulting supernatant to remove cell apoptotic bodies” is performed prior to “centrifuging the medium to remove cell debris and produce a supernatant”.
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 20 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Klymiuk et al (BMC Veterinary Research. 2019; page 1-9; as cited in office action filed 04/21/2026). This is a new rejection necessitated by amendment of the claims in the response filed 07/20/2026.
Regarding claim 20, Klymiuk teaches methods of isolating exosomes from equine adipose tissue derived mesenchymal stem cells (MSCs) wherein the method comprises the following steps:
Supernatant from MSCs is collected and centrifuged (which removes cell debris)
Resulting Supernatant is filtered through a 0.2 μm filter (which removes cell apoptotic bodies and microvesicles)
The resulting filtrate is centrifuged for 10 min at 2,000 g, followed by a centrifugation at 10,000 g for 30 min and then further centrifuged by ultracentrifugation at 100,000 g (50.2 Ti Rotor Beckmann) for 70min followed by another ultracentrifugation step of the in PBS resuspended pellet at 100,000 g for additional 70 min (page 6, Isolation of exosomes by ultracentrifugation)
Furthermore, claim 20 recites “wherein the population of enriched exosomes has a concentration greater than 1 x 109 exosomes/mL, a particle size less than 200 nm for 90% to 93% of the exosomes, a particle size less than 100 nm for 14% to 18% of the exosomes, and a mean particle size from 138 nm to 160nm”, therefore the claim is directed to an inherent result based on the methodology of producing an exosome composition. Because Klymuit discloses the methodology as claimed, the effect of the methodology is rendered obvious by the combination of references, absent evidence to the contrary.
Claim Rejections - 35 USC § 103
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Klymiuk et al (BMC Veterinary Research. 2019; page 1-9; as cited in office action filed 04/21/2026) and further in view of Sidhom et al (Int. J. of Molecular Sciences, 2020, pages 1-19) and Vergauwen et al (Scientific Reports, 2017, pages 1-12). This is a new rejection necessitated by amendment of the claims in the response filed 07/20/2026.
Regarding claim 19, Klymiuk teaches methods of isolating exosomes from equine adipose tissue derived mesenchymal stem cells (MSCs) wherein the methods comprise either ultrafiltration or precipitation. For the methods using ultrafiltration, the steps comprise:
MSCs are centrifuged and the supernatant is filtered through a 0.2 μm filter to remove cell debris
The filtrate is then subjected to ultrafiltration using a 3K Ultra Filter (page 6, Isolation of exosomes by ultrafiltration)
For the methods using precipitation, the steps comprise:
MSCs are centrifuged twice to remove cell debris and other contaminants
The supernatants are filtered through a 0.2 μm filter
The resultant sample is mixed with 15 μl 2% protaminesulfate (PS) and 300 μl 50% polyethylene glycol (PEG 35.000) were added
After incubation for 1 h at 4 °C the mixture was centrifuged at 12.000 g for 10min at 4 °C and the supernatant was discarded, resulting in isolated exosomes (i.e. through a polymer-based precipitation method; page 6-7 Isolation of exosomes by precipitation).
Klymiuk does not teach the combined chronological steps of ultrafiltering the filtrate with a membrane having a molecular weight cutoff of 10 kDa for 60 minutes or less to obtain an ultrafiltered liquid and precipitating exosomes from the ultrafiltered liquid with polymer-based precipitation through centrifuging the ultrafiltered liquid to obtain the exosome composition after filtrating the resulting supernatant to remove cell apoptotic bodies and microvesicles to obtain a filtrate.
However, one of ordinary skill in the art would have considered the teachings of Sidhom and Vergauwen as these references are analogous prior art pertaining to the benefits and drawbacks of ultrafiltration and precipitation for exosome isolation and reasons to combine the two methods.
Sidhom teaches “the recovery of exosomes is dependent on the type of filter, as different membrane types and pore sizes exist: cellulose membranes with a pore size of 10 kDa have the most efficient recovery. Used on its own, the exosomal preparations from ultrafiltration are significantly contaminated with non-exosomal free-floating humoral peptide” and there is reduced efficiency when using the ultrafiltration method, decreasing both purity and yield of isolated exosomes.” In regard to using poly-ethylene glycol (PEG)-based precipitation (i.e. a type of polymer-based precipitation), Sidhom teaches there are drawbacks to using PEG-based precipitation for exosome isolation, including contamination, thus “combining PEG-based isolation with other techniques of exosomal enrichment is a viable strategy to avoid the drawbacks associated with use of PEG alone.” (page 8, 2.3. Poly-Ethylene Glycol (PEG)-Based Precipitation). Indeed, a study by Vergauwen (cited by Sidhom), which found that 10 kDa cellulose membrane was superior in isolating exosomes, further teaches using the Amicon Ultra-2 10k membrane by centrifuging for 10-20 minutes (page 3, Ultrafiltration).
It would have been prima facie obvious to one of ordinary skill, in the art at the time of the effective filing date, to modify the teachings of ultrafiltration and polymer-based precipitation for exosome isolation by Klymiuk such that the two methods were combined where the filtrate from ultrafiltration was further purified by using polymer-based precipitation since Sidhom teaches that only using a PEG (i.e. polymer)-based preciptitation method or only ultrafiltration with 10 kDa membrane leads to contamination and the combination of exosomal enrichment methods would be a viable solution. One would be motivated to do so to generate a method of producing an exosome composition that has greater purity and since each method has been used for the purpose of exosome isolation, one would have a reasonable expectation of success.
Furthermore, claim 19 recites “the population of enriched exosomes has a concentration greater than 1 x 109 exosomes/mL, a particle size less than 200 nm for 90% to 93% of the exosomes, a particle size less than 100 nm for 14% to 18% of the exosomes, and a mean particle size from 138 nm to 160 nm”, therefore the claim is directed to an inherent result based on the methodology of producing an exosome composition rendered obvious by the combined teachings Klymiuk ,Sidhom and Vergauwen, absent evidence to the contrary.
Response to Applicant’s arguments as they apply to rejection of claims 19 and 20 under 35 USC § 103
Applicant’s arguments filed 07/20/2026 have been fully considered but not persuasive.
Applicant asserts that 1) there is a fundamental difference in the experimental purpose and technical field between the art of Lobb and the instant application; 2) the conditioned medium derived from MSCs has an entirely different biomolecular profile compared to cancer cell lines or human plasma which is used in Lobb; 3) The present invention relies on a highly specific, synergistic combination of operative parameters including the 10 kDa membrane, operational duration of 60 minutes or less, and tailored sequence of low-speed pre-clearing steps which led to unexpected results; 4) There was an unpredictable result of an 8 fold reduction in processing time; and 5) the centrifugation parameters recited in claim 20 is defined and specific to MSC exosomes, and Lobb’s disclosure does not render obvious this specific parameters.
Regarding arguments 1, 2, and 5, the withdrawn 103 rejection and withdrawn Lobb art renders these arguments moot.
Regarding argument 3, the applicant asserts that the highly specific synergistic combination of operational parameters (the 10 kDa membrane, operational duration of 60 minutes or less, and tailored sequence of low-speed pre-clearing steps) led to an unexpected result of producing an exceptionally high concentration AND highly stable, narrow particle size distribution profile, however the applicant has not described or disclosed how the combination of these parameters indeed are a “synergistic” combination and furthermore it is unclear what the “tailored sequence of low-speed pre-clearing steps” specifically pertains to, as for example, claim 19 does not recite any speed and indicate what steps are “pre-clearing” steps. Moreover, Vergauwen teaches that a 10 kDa cellulose membrane indeed leads to a high extracellular vesicle (i.e. exosome) recovery, thus demonstrating that the 10 kDa cellulose membrane had an expected result of high exosome recovery (Figure 1A).
Regarding argument 4, based on the specification Example 1 which discloses conditioned medium is centrifuged to remove dead cells and debris (routine step and shown in prior art cited above), filtered to remove apoptotic bodies and microvesicles (routine step and shown in prior art cited above) and simply added to a spin column of a designated membrane pore size, does not demonstrate an unpredictable result. Vergauwen discloses that 10 kDa cellulose membrane is superior in isolating exosomes and when using the Amicon Ultra-2 10k membrane, centrifugation of 2 ml can occur in as little as 10 mins. The claims, as written, do not indicate a required volume to achieve the ultrafiltering rate of being 60 mins or less, thus the teachings of Vergauwen indeed provide the expected results of the exosome composition and ultrafiltration timing.
Conclusion
No claims are allowed.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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