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 .
Applicant's amendment and response received on 03/20/2026 has been entered. Claims 1-20 are currently pending.
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 Claim 1-18 have been withdrawn from consideration.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. Applicant is reminded of the right to petition under 37 CFR 1.144, if applicant disagrees with the requirements for restriction filed on 08/22/2025.
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.
Response to Arguments
Withdrawn Rejections in response to Applicants’ arguments
35 USC § 112(b)
The rejection of claims 19 is withdrawn in view of applicant’s claim which now recite that the centrifuged medium produces a supernatant, filtering of the supernatant produces a filtrate, and ultracentrifuging the filtrate produces and ultrafiltered liquid wherein the ultrafiltered liquid is precipitated to obtain the exosome composition. Applicant’s argument with regard to a withdrawn rejection are moot.
The rejection of claims 20 is withdrawn in view of applicant’s claim which is now dependent on claim 19 and recites the characteristics of the population of enriched exosomes (concentration and particle size). Applicant’s argument with regard to a withdrawn rejection are moot.
Claim Rejections - 35 USC § 102
The rejection of claim 20 under 35 U.S.C. 102(a)(2) as being anticipated by Lobb et al. (Journal of Extracellular Vesicles. 2015; page 1-12; as cited in IDS) is withdrawn in view of applicant’s claim which is now a dependent on claim 19 and recites the characteristics of the population of enriched exosomes (concentration and particle size). Applicant’s argument with regard to a withdrawn rejection are moot.
Claim Rejections - 35 USC § 103
The rejection of Claim 19 under 35 U.S.C. 103 as being unpatentable over Lobb et al (Journal of Extracellular Vesicles. 2015; page 1-12; as cited in IDS) further in view of ExoQuick Manual (2016; page 1-12) has been withdrawn.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’ Amendments
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 19 and 20 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 applicant regards as the invention.
Claim 19 and 20 are indefinite in the recitation of “greater than about” for the following reason. “About” encompasses values above and below a reference point whereas “greater than” encompasses only values above the reference point. Therefore, the combination of both terms (greater than about) is confusing because one term is including values below the reference point whereas the other term is excluding values below the reference point.
Claim 20 is indefinite in the recitation of “less than about” in lines 5 and 6 for the following reason. “About” encompasses values above and below a reference point whereas “less than” encompasses only values below the reference point. Therefore, the combination of both terms (less than about) is confusing because one term is including values above the reference point whereas the other term is excluding values above the reference point.
Claim Rejections - 35 USC § 101
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.
Claim 20 is newly rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. This is a new rejection necessitated by amendment of the claims in the response filed 03/20/2026. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claim is drawn to a method, however no method steps are recited and rather, the claim is further drawn to a natural product (exosome composition). The claim recites a method for producing exosome composition of claim 19 wherein the population of exosomes has characteristics including a certain concentration and proportion of certain particle sizes. The claim is directed to a natural product (exosome composition) which is derived from mesenchymal stem cells in media. While it appears that the inventors have isolated the exosome population that was not previously recognized by the art in its claimed format, the isolation does not distinguish the exosome composition from its naturally occurring form. As explained by Klymiuk et al (BMC Veterinary Research, 2019), microvesicles (i.e. exosomes) are generated and secreted naturally by MSCs and can be isolated (Background, left col, page 2).
Even though the exosome composition as recited in the claim recites specific concentrations and mean sizes that, it is not enough to distinguish the claimed exosome composition from its naturally occurring counterpart. Rather, the exosome composition is simply a collection of exosomes that would be naturally occurring. Indeed, naturally occurring exosomes have a size range of ~40 to 160 nm (average ~100 nm), as evidenced by Kalluri et al (Science, 2020; abstract, background, page 1, para 1), falling within the claimed range of 138 nm to 148 nm. This is analogous to the contention rejected by the Supreme Court in Funk Bros. Seed Co. V. Kalo Inoculant Co.. 333 U.S. 127, 131 (1948), where the court held that even though the combination of bacteria did not occur in nature, the combination [of bacteria] did not provide a different structural or functional characteristic than each bacteria possessed on its own.
"It is no more than the discovery of some of the handiwork of nature and hence is not patentable. The aggregation of select strains of the several species into one product is an application of that newly-discovered natural principle Each species has the same effect it always had. The bacteria perform in their natural way." Id.). In the instant situation if "bacteria" is replaced with "exosome," the same reasoning applies. In selecting a subpopulation from an exosome population, applicants have selected a subpopulation of exosomes within a naturally occurring population of exosomes. While this subpopulation of exosomes may work as a product, it does not overcome the assertion that the claimed product is not markedly different from what is found in nature.
In the exosome composition, the exosomes function the same as it would when not enriched - each exosomes’ function (and structure) is the same when enriched as it is singly. As such, the enrichment is analogous to the naturally-occurring bacterial group in Funk Bros., which the Supreme Court found to be patent ineligible subject matter.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because only the characteristics of a "population of enriched exosomes" is claimed.
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.
Claim 19 and 20 are newly rejected under 35 U.S.C. 103 as being unpatentable over Lobb et al. (Journal of Extracellular Vesicles. 2015; page 1-12; as cited in IDS) and further in view of ExoQuick Manual (2016; page 1-12) and Klymiuk et al (BMC Veterinary Research. 2019; page 1-9). This is a new rejection necessitated by amendment of the claims in the response filed 03/20/2026.
Regarding claim 19, Lobb teaches "comprehensively characterizing a variety of exosome isolation protocols for their efficiency, yield and purity of isolated exosomes" and "using ultrafiltration devices results in increased vesicle isolation when compared to traditional ultracentrifugation protocols" (Page 1, abstract) and the population of enriched exosomes from ultrafiltration results in a concentration of exosomes between 5.0 x 1011 and 2.0 x 1012/mL (Figure 1b, page 4), rendering obvious a method for producing an exosome composition comprising a population of enriched exosomes in a concentration greater than about 1x109 exosomes/mL, wherein the exosome composition is directly obtained by ultrafiltration rather than by formulation.
Lobb further teaches the following steps:
Culturing the SK-MES-1 cell to isolate exosomes and collecting cell culture conditioned media (CCM) (page 2, col. 1, para 1) and centrifuging conditioned medium to remove detached cells (page 2, col 2, para 2), falling within the scope of providing a
desired amount of cells in a medium and centrifuging the medium to remove cell debris and produce a supernatant,
Supernatant was collected and filtered through 0.22 mm filters (Merck Millipore)
to remove contaminating apoptotic bodies, microvesicles and cell debris (page 2, col. 2,
para. 2), falling within the scope of "filtrating the supernatant to remove
cell apoptotic bodies and microvesicles and produce a filtrate", and
Media can be concentrated with the Centricon Plus-70 Centrifugal Filter
(Ultracel-PL Membrane, 100 kDa) device" (Page 3, Ultrafiltration) and high particle/low
protein fractions from CCM were pooled and concentrated in Amicont Ultra-4 10 kDa
nominal molecular weight centrifugal filter units (page 3, col. 2, para. 3) and that the ultrafiltration process takes only 20 minutes (page 5, col 2, para 2), falling within the scope of ultrafiltering with a membrane having a molecular weight cutoff of 10 kDa for less than 60 minutes to produce an ultrafiltrated liquid, and
ExoQuick precipitation can be carried out to purify exosomes, wherein ExoQuickTM uses a polymer-based system (Datasheet of ExoQuick Manual: Page 5, Product Description) to precipitate exosomes through centrifugation (page 3, col 1, para 2, ExoQuickTM precipitation), falling within the scope of precipitating exosomes with polymer-based precipitation through centrifuging the ultrafiltrated liquid to obtain the exosome composition comprising enriched exosomes.
Lobb does not teach that the cells in a medium are mesenchymal stem cells (MSCs).
Klymiuk teaches that MSCs have multipotent differentiation capacity, have been thoroughly investigated for their therapeutic potential for various diseases (Page 1, right col, para 1), and their therapeutic action can most likely be attributed to the release of cytokines into the culture medium which are in vesicular structures (i.e. exosomes) (page 2, left col, para 1). Furthermore, Klymiuk teaches exosome isolation from equine MSCs using ultrafiltration (Page 2, right col, para 3)
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 Lobb for exosome isolation using the claimed method with the teachings of using MSCs as a cell source for conditioned media as taught by Klymiuk to ultimately isolate exosomes from MSCs. One would be motivated to do so to isolate exosomes secreted from a cell type (MSCs) that are known to provide therapeutic potential and one would have a reasonable expectation of success since exosome isolation from MSC conditioned media is known in the art.
Regarding claim 20, the teachings of Lobb, ExoQuick Manual, and Klymiuk, render obvious claim 19. Moreover, Lobb teaches that the exosome isolated from the ultrafiltration process are in a concentration of between 5.0 x 1011 and 2.0 x 1012/mL (Figure 1b, page 4), the particle size is between 50-250 nm (Figure 3a, page 6), and a majority of the particle sizes are less than about 200 nm (Figure 3a, page 6).
The teachings of Lobb, ExoQuick Manual, and Klymiuk do not explicitly teach 14% to 18% of the exosomes have a particle size from -less than about 100 nm.
However, it is noted that the claim is directed to an inherent result based on the methodology of the isolation of the exosomes. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). It is noted that, if the prior art discloses identical chemical structure, the properties applicant discloses and/or claims are necessarily present, In re Spada,911 F.2d 705, 709, 15 USPQ2d. As such the functional limitations would be present in the identical methods taught by Lobb, ExoQuick Manual, and Klymiuk and would therefore elicit these characteristics whenever the isolation process is carried out.
Response to Applicants’ Arguments as they apply to rejection of claims 19 and 20 under 35 USC § 103 as they applied to Lobb and ExoQuick Manual
Applicant's amendments to the claims and arguments filed 03/20/2026 have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
At page 2-3 of the Remarks filed 03/20/2026, the applicant submits that the amended claims recite that the specific combination of the 10 kDa MWCO membrane and shortened processing time yields unexpected technical effects. More specifically, the applicant argues that 1) the selection of a 10kDa membrane for MSC-derived exosome enrichment leads to change in production efficiency and product quality as seen by shortened processing time of ultrafiltration with 10 kDa versus 3 kDa, 2) there was an unexpected higher concentration of exosomes when using a 10 kDa versus 3, 50, and 100 kDa membrane pore size, and 3) that the prior art does not provide any motivation to select a 10 kDa MWCO membrane specifically for MSCs to achieve the precise “mass division diameter” profile claimed in claim 20. The applicant argues that the 90% - 93% of exosomes being below 200 nm with high concentration and through rapid ultrafiltration step is a critical range discovery with advantage in large-scale production.
Regarding argument 1), the selection of different pore size membranes to decrease processing time is a matter of routine optimization. "[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) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.") See MPEP 2144.05 II. A. Moreover, the prior art of Lobb teaches the use of 10 kDa and 100 kDa membranes for ultrafiltration and the desire to decrease the process time of exosome isolation while increasing concentration to ultimately increase efficiency of sample output (page 9, left col, para 1), hence one would be motivated to perform routine optimization to test a range of pore size membranes including such that correctly sized exosomes are isolated and the process occurs in the minimal amount of time. Thus, these remarks do not comply with MPEP 2144.05II. A and are not persuasive.
Regarding argument 2), it is noted that differences between the claimed invention and the prior art may be expected to result in some differences in properties. “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)”. See MPEP § 716.02. The applicant recites data presented in Table 2 of the specification showing increase in concentration of exosomes in 10 kDa versus 3 kDa, however the data shows no statistically significant difference between the exosome concentrations of 10 kDa and 3KDa, therefore it is inconclusive that 10 kDa would always lead to a greater concentration of exosomes compared to 3 kDa. “Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) MPEP § 716.02 (a)I. Thus, these remarks do not comply with MPEP 716.02. A and are not persuasive.
Regarding argument 3), the examiner reiterates the argument presented against argument 1 above. More specifically, the selection of different pore sizes to achieve the correct exosome size profile and concentration which leads to the minimal amount of processing time would provide motivation to try the 10 kDa membrane for exosome isolation by ultrafiltration. Moreover, the selection of membrane size is not specific to certain cell types as the prior art Lobb, for example, indicates a range of membrane sizes from 10 kDa – 100,000 kDa for conditioned media of SK-MES-1 cells being ultrafiltered and the newly presented prior art of Klymiuk used a 3 K(da) for conditioned media of MSCs being ultrafiltered. Thus, these remarks do not comply with MPEP 2144.05II. A and are not persuasive.
Conclusion
Claims 19 and 20 are rejected.
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 Juliana Candelaria whose telephone number is (571)272-5488. The examiner can normally be reached Monday - Friday 8am - 5pm.
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/JULIANA IRENE CANDELARIA/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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