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 .
Claims 1, 3-12 and 14-24 are pending in this application and were examined on their merits.
The rejection of Claim 8 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or 35 U.S.C. § 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claim 8 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to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 6, 7, 8 and 10 under 35 U.S.C. § 102(a)(1) as being
anticipated by Fortunato et al. (2021), cited in the IDS, has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 6, 7, 8 and 10 are rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 4, 5, 6, 7, 8 and 10 under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, and further in view of Gibbings (US 2021/0163550 A1), has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 6, 7, 8, 9 and 10 under 35 U.S.C. § 103 as being
unpatentable over Fortunato et al. (2021), cited in the IDS, and further in view of Doherty et al. (WO 2021/092193 A1), has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 6, 7, 8, 10 and 11 under 35 U.S.C. § 103 as being
unpatentable over Fortunato et al. (2021), cited in the IDS, and further in view of Larocca et al. (WO 2021/151029 A1), has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19 and 22 under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited
in the IDS, and further in view of Gibbings (US 2021/0163550 A1) and Doherty et al. (WO 2021/092193 A1), has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20 and 22 under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Gibbings (US 2021/0163550 A1) and Doherty et al. (WO 2021/092193 A1), and further in view of Anderson et al. (US 2020/0113943 A1), has been withdrawn due to the amendments to the claim filed 01/16/2026.
The rejection of Claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 21 and 22 under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Gibbings (US 2021/0163550 A1) and Doherty et al. (WO 2021/092193 A1), and further in view of Larocca et al. (WO 2021/151029 A1), has been withdrawn due to the amendments to the claim filed 01/16/2026.
The provisional rejection of Claims 1-19 and 21 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2-15, 18-20 and 22 of copending
Application No. 17/936,020 (reference application), has been withdrawn due to the amendments to the claim filed 01/16/2026 and the amendments to the copending ‘020 application specifying that extracellular vesicles are not purified by column chromatography or other filtration media that separates unwanted components from the extracellular vesicles, resulting in purified extracellular vesicles prior to the contacting in step c. which contradicts instant step (a).
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.
Claims 1, 3, 6, 7, 8, 10 and 23 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
Fortunato et al. teaches a method comprising:
concentrating cell-derived, secreted extracellular vesicles (sEV/CDVs) in a biological fluid (HT29 cell conditioned medium/CCM) by centrifugal ultrafiltration (Pg. 15, Paragraph 4.1);
determining a concentration of the sEVs to be 1x10⁷ to 1x10⁸ particles/µl (or
1x10¹⁰ to 1x10¹¹ particles/ml) (Pg. 15, Paragraph 4.1);
incubating the sEVs with various stains including CFSE or anti-CD9, anti-CD63
and anti-CD81 antibodies to generate a labeled sEV population (Pgs. 15-16, Paragraph
4.2.1 and Pg. 16, Paragraph 4.2.2.);
passing the stained sEVs though an ultrafiltration centrifugal device (NANOSEP®
300K, having a molecular weight cutoff of 300 Kda polyethersulfone filter media (see the
Specification as published at Pg. 4, Paragraph [0036]);
and analyzing/recovering the labeled sEVs (Pgs. 15-16, Paragraph 4.2.1 and Pg.
4, Fig. 1), and reading on Claims 1, 6, 7, 8 and 10.
The teachings of Fortunato et al. were discussed above.
Fortunato et al. did not teach a method comprising preparing a suspension of nucleated mammalian cells and conducting a serial extrusion of the nucleated cells by sequentially passing them through filters with diminishing micro-size pores to produce a biological fluid comprising CDVs retaining the same membrane topology as that of the nucleated mammalian cells, as now required by Claim 1;
wherein the serial extrusion comprises serially passing the nucleated
mammalian cells through membrane filters with a pore size of about 10 µm, about 3 µm,
and about 0.4 µm, as required by Claim 3;
or wherein the CDVs comprise a therapeutic agent, as now required by Claim 23.
Jang et al. teaches a method wherein human umbilical vein cells (HUVECs) are suspended in chemotherapeutics and then sequentially extruded three times through 10, 5 and 1 µm polycarbonate membrane filters to produce a biological fluid comprising chemotherapeutic loaded nanovesicles (CDVs), which is then ultracentrifuged to obtain the chemotherapeutic loaded nanovesicles (Pg. 7707, Column 1, Lines 1-3 and 18-28 and Pg. 7699, Fig. 1A).
The reference further teaches that by subjecting cells of different origin to serial extrusion through filters with diminishing pore sizes after the cells had been loaded
with chemotherapeutic agents, “…we generated high quantities of exosome-mimetic nanovesicles (CDVs) carrying sheltered drugs.” (Pg. 7699, Column 2, Lines 21-26).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Fortunato et al. of isolating labeled sEV (CDVs) with the method of Jang et al. of producing isolated chemotherapeutic loaded nanovesicles (CDVs) because this would produce isolated, labeled, chemotherapeutically loaded CDVs.
Those of ordinary skill in the art would have been motivated to make this modification because Jang et al. teaches the method generates high quantities of exosome-mimetic nanovesicles (CDVs) carrying sheltered drugs. There would have been a reasonable expectation of success in making this modification because both references are reasonably drawn to the same field of endeavor, that is, the isolation of useful cell derived vesicles.
With regard to the limitation of Claim 1, that the “CDVs retaining the same membrane topology as that of the nucleated mammalian cells”, this is an inherent feature of the serial extrusion of nucleated cells through filters with diminishing micro-size pores. As Jang et al. teaches the same process using the same cells as claimed, the same characteristics and properties of the obtained CDVs would be expected.
With regard to Claim 3, the claimed membrane filters with a pore size of about 10 µm, about 3 µm, and about 0.4 µm are made prima facie obvious by the similar sized 10, 5 and 1 µm polycarbonate membrane filters of the prior art such that those of skill in the art would expect them to have the same properties, particularly as the Specification as published at Pg. 1, Paragraph [0011] states that the term “about” can encompass up to an approximately 20% difference. See the MPEP at 2144.05, I.
Claims 1, 3, 4, 5, 6, 7, 8, 10 and 23 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), as applied to Claims 1, 3, 6, 7, 8, 10 and 23 above, and further in view of Gibbings (US 2021/0163550 A1), of record, as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
The teachings of Fortunato et al. and Jang et al. were discussed above.
Fortunato et al. did not teach a method wherein the concentrating comprises
passing the biological fluid through a tangential flow filter (TFF), as required by Claim 4;
or wherein the TFF has a molecular weight cutoff of about 300-750 kD, as required by Claim 5.
Gibbings teaches that CDV/exosomes can be enriched (e.g. concentrated) using
size-based filtration using tangential flow filtration or centrifugal filtration (Pg. 20,
Paragraph [0185]).
It would have been obvious to those of ordinary skill in the art to modify the
method of Fortunato et al. and Jang et al. comprising concentrating labeled, secreted extracellular vesicles (sEV/CDVs) comprising therapeutic agents in a biological fluid by centrifugal ultrafiltration with an ultrafiltration centrifugal device (NANOSEP® 300K, having a molecular weight cutoff of 300 Kda polyethersulfone filter media (see the Specification as published at Pg. 4, Paragraph [0036]) to use TFF with the same molecular weight cutoff as the concentration method because Gibbings teaches that TFF and the centrifugal ultrafiltration method of Fortunato are art-recognized equivalent techniques for concentration exosomes from a sample and Fortunato teaches a particular desired molecular weight cutoff value. See the MPEP at 2144.06, II. Those of ordinary skill in the art would have been motivated to make this modification based on the availability of filters and artisan preference. There would have been a reasonable expectation of success in making this modification because the art recognizes both filtering techniques as being suitable for the same purpose and Fortunato already teaches a 300 kDa molecular weight cutoff.
Claims 1, 3, 6, 7, 8, 9, 10 and 23 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), as applied to Claims 1, 3, 6, 7, 8, 10 and 23 above, and further in view of Doherty et al. (US 2021/092193 A1), of record, as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
The teachings of Fortunato et al. and Jang et al. were discussed above.
Neither reference taught a method wherein the concentration of CDVs in the
biological fluid is determined using a flow cytometer, as required by Claim 9.
Doherty et al. teaches determining the concentration of exosomes by counting
the number of complexes in a population by microscopy, flow cytometry or
hemacytometry (Pgs. 43-44, Paragraph [0149]).
It would have been obvious to those of ordinary skill in the art at the time of the
instant invention to modify the method of Fortunato et al. and Jang et al. whom teach determining the concentration of exosomes by an unspecified method to use the flow cytometry method of Doherty et al. because the reference teaches flow cytometry as a suitable method for determining exosome concentration. Those of ordinary skill in the art would have been motivated to make this modification because Fortunato is silent with regard to the method used to determine exosome concentration and Doherty et al. teaches specific methods for doing so. There would have been a reasonable expectation of success because all of the references are reasonably drawn to the same field of endeavor, that is, exosomes/extracellular vesicles.
Claims 1, 3, 6, 7, 8, 10, 11 and 23 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), as applied to Claims 1, 3, 6, 7, 8, 10 and 23 above, and further in view of Larocca et al. (WO 2021/151029), of record, as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
The teachings of Fortunato et al. and Jang et al. were discussed above.
Neither reference taught a method wherein the labeled CDVs are passed
though the centrifugal filter for at least 10 minutes at a centrifugal force of at least
10,000 g, as required by Claim 11.
Larocca et al. teaches a method wherein exosomes are isolated using a
centrifugal filter at a centrifugal force of 10,000 g for 15 minutes (Pg. 23, Paragraph
[0140]).
It would have been obvious to those of ordinary skill in the art at the time of the
instant invention to modify the method of Fortunato et al. and Jang et al. whom teaches isolating labeled, chemotherapeutic loaded CDVs with centrifugal ultrafiltration for an unspecified time and force to use the particular operating parameters for centrifugal filtration taught by Larocca et al. because Larocca teaches a particular force and time as a suitable for exosome isolation/recovery. Those of ordinary skill in the art would have been motivated to make this modification because Fortunato is silent with regard to the time and force used to recover/isolate exosomes by centrifugal filtration and Larocca et al. teaches specific operating parameters for doing so. There would have been a reasonable expectation of success because all of the references are reasonably drawn to the same field of endeavor, that is, exosomes/extracellular vesicles.
Claims 1, 3, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 22, 23 and 24 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), as applied to Claims 1, 3, 6, 7, 8, 10 and 23 above, and further in view of Gibbings (US 2021/0163550 A1) and Doherty et al. (WO 2021/092192), both of record, as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
The teachings of Fortunato et al. and Jang et al. were discussed above. The Examiner notes that the rationale for a finding of obviousness for the new limitations of Claim 1, the limitations of Claim 3 and the new limitations of Claim 23 are applicable to the new limitations of Claim 12, the limitations of Claim 14 and the new limitations of Claim 24.
Neither reference taught a method wherein the CDVs are concentrated with
a tangential flow filter and analyzing the recovered, labeled CDV population using a flow
cytometer, as required by Claim 12;
or wherein the concentration of CDVs in the sample is determined using a flow
cytometer, as required by Claim 18.
Gibbings teaches that CDV/exosomes can be enriched (e.g. concentrated) using
size-based filtration using tangential flow filtration or centrifugal filtration (Pg. 20,
Paragraph [0185]).
Doherty et al. teaches determining the concentration of exosomes by counting
the number of complexes in a population by microscopy, flow cytometry or
hemacytometry (Pgs. 43-44, Paragraph [0149]).
It would have been obvious to those of ordinary skill in the art to modify the
method of Fortunato et al. and Jang et al. comprising concentrating secreted extracellular vesicles (sEV) comprising chemotherapeutic agents in a biological fluid by centrifugal ultrafiltration with an ultrafiltration centrifugal device (NANOSEP® 300K, having a molecular weight cutoff of 300 Kda polyethersulfone filter media (see the Specification as published at Pg. 4, Paragraph [0036]) to use TFF as the concentration method because Gibbings teaches that TFF and the centrifugal ultrafiltration method of
Fortunato and Jang are art-recognized equivalent techniques for concentration exosomes from a sample. See the MPEP at 2144.06, II. Those of ordinary skill in the art would have been motivated to make this modification based on the availability of filters and artisan preference. There would have been a reasonable expectation of success in making this modification because the art recognizes both filtering techniques as being suitable for the same purpose.
It would have been further obvious to those of ordinary skill in the art at the time of the instant invention to modify the method of Fortunato et al., Jang et al. and Gibbings whom teach determining the concentration of exosomes by an unspecified method to use the flow cytometry method of Doherty et al. because the reference teaches flow cytometry as a suitable method for determining exosome concentration. Those of ordinary skill in the art would have been motivated to make this modification because Fortunato and Gibbings are silent with regard to the method used to determine exosome concentration and Doherty et al. teaches specific methods for doing so. There would have been a reasonable expectation of success because all of the references are reasonably drawn to the same field of endeavor, that is, exosomes/extracellular vesicles.
With regard to Claims 15 and 16, Fortunato teaches incubating the sEVs with
various stains including CFSE or anti-CD9, anti-CD63 and anti-CD81 antibodies to
generate a labeled sEV population (Pgs. 15-16, Paragraph 4.2.1 and Pg. 16, Paragraph
4.2.2.).
With regard to Claim 17, Fortunato teaches concentrating secreted extracellular
vesicles (sEV) in a biological fluid (HT29 cell conditioned medium/CCM) by centrifugal
ultrafiltration (Pg. 15, Paragraph 4.1).
With regard to Claim 19, Fortunato teaches determining a concentration of the
sEVs to be 1x10⁷ to 1x10⁸ particles/µl (or 1x10¹⁰ to 1x10¹¹ particles/ml) (Pg. 15,
Paragraph 4.1).
With regard to Claim 22, Fortunato teaches analyzing the recovered, labeled
exosomes for labeling percentage (efficiency) (Pg. 4, Fig. 1A).
Claims 1, 3, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23 and 24 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), Gibbings (US 2021/0163550 A1) and Doherty et al. (WO 2021/092192), both of record, as applied to Claims 1, 3, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 22 and 23 above, and further in view of Anderson et al. (US 2020/0113943 A1), as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
The teachings of Fortunato et al., Jang et al., Gibbings and Doherty et al. were discussed above.
None of the above references taught a method wherein the CDVs are
concentrated using a 750 kDa molecular weight cutoff tangential flow filter, as required
by Claim 20.
Anderson et al. teaches the isolation and/or purification of a population of cell-
derived vesicles by applying tangential flow filtration (TFF) to a conditioned medium and
concentrating the cell-derived vesicle fraction (Pg. 1, Paragraph [0011]) and wherein the
tangential flow filter has a molecular weight cutoff between about 50-750 kDa (thereby
encompassing the claimed value) (Pg. 6, Paragraph [0039]).
It would have been obvious to those of ordinary skill in the art at the time of the
instant invention to modify the method of Fortunato et al., Jang et al., Gibbings and Doherty et al. whom teach isolating labeled, chemotherapeutic loaded extracellular vesicles with tangential flow filtration to use a tangential flow filter with a molecular weight cutoff of 750 kDa as taught by Anderson et al. because Anderson et al. teaches a particular molecular weight cutoff range as a suitable for exosome isolation/recovery. Those of ordinary skill in the art would have been motivated to make this modification because while Fortunato teaches ultrafiltration with a molecular weight cutoff of 300 kDa and Gibbings teaches exosome isolation/recovery using TFF, only Anderson et al. teaches that exosomes can be isolated/purified using TFF with about a 750 kDa molecular weight cutoff. There would have been a reasonable expectation of success because all of the references are reasonably drawn to the same field of endeavor, that is, exosomes/extracellular vesicles.
Claims 1, 3, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23 and 24 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013), Gibbings (US 2021/0163550 A1) and Doherty et al. (WO 2021/092192), both of record, as applied to Claims 1, 3, 6, 7, 8, 10, 12, 13, 14, 15, 16, 17, 18, 19, 22 and 23 above, and further in view of Larocca et al. (WO 2021/151029 A1), of record, as necessitated by Applicant’s amendments to the claims filed 01/16/2026.
The teachings of Fortunato et al., Jang et al., Gibbings and Doherty et al. were discussed above.
None of the above references taught a method wherein the labeled CDVs are
passed though the centrifugal filter for at least 10 minutes at a centrifugal force of at
least 10,000 g, as required by Claim 21.
Larocca et al. teaches a method wherein exosomes are isolated using a
centrifugal filter at a centrifugal force of 10,000g for 15 minutes (Pg. 23, Paragraph
[0140]).
It would have been obvious to those of ordinary skill in the art at the time of the
instant invention to modify the method of Fortunato et al., Jang et al., Gibbings and Doherty et al. whom teach isolating labeled, chemotherapeutic loaded extracellular vesicles with centrifugal ultrafiltration for an unspecified time and force to use the particular operating parameters for centrifugal filtration taught by Larocca et al. because Larocca teaches a particular force and time as a suitable for exosome isolation/recovery. Those of ordinary skill in the art would have been motivated to make this modification because Fortunato is silent with regard to the time and force used to recover/isolate exosomes by centrifugal filtration and Larocca et al. teaches specific operating parameters for doing so. There would have been a reasonable expectation of success because all of the references are reasonably drawn to the same field of endeavor, that is, exosomes/extracellular vesicles.
Response to Arguments
Regarding Applicant’s arguments, see Remarks, filed 01/16/2026, with respect to the rejection(s) of claim(s) 1, 3-12 and 14-24 under 35 U.S.C. § 103 have been fully considered and are persuasive. Therefore, the rejections have been withdrawn. However, new ground(s) of rejection in view of Fortunato et al. (2021), cited in the IDS, in view of Jang et al. (2013) are set forth above, as necessitated by amendment..
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653