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 24-28, 30-39, and 41-42, of record 2/25/2026, are pending and subject to prosecution. Claims 24-25, 37, and 41-42 are amended. Claims 29 and 40 are cancelled.
Status of Prior Rejections/Response to Arguments
RE: Objection to the specification:
The amendment to the specification is effective to obviate the objection. The objection is withdrawn.
RE: Rejection of claim 25 under 35 U.S.C. 112(b):
The amendment to claim 25 is effective to obviate the rejection. The rejection is withdrawn.
RE: Rejection of claim 40 under 35 U.S.C. 101:
The cancellation of claim 40 renders the rejection thereto moot.
RE: Rejection of claims 24-25, 28, 32-34, 36-38, and 40 under 35 U.S.C. 102(a)(1) over Zeng et al. (Experimental Cell Research, 2019).
RE: Rejection of claims 24-25, 28, 32-34, 36-38, and 40 under 35 U.S.C. 102(a)(1) over Lucchetti et al. (Journal of Cellular Physiology, 2020):
RE: Rejection of claims 24-28, 30, 32-34, 36-38, and 40 under 35 U.S.C. 103 over Zeng et al. (Experimental Cell Research, 2019):
RE: Rejection of claims 24-25, 28, 31-34, 36-38, and 40 under 35 U.S.C. 103 over Lucchetti et al. (Journal of Cellular Physiology, 2020):
RE: Rejection of claims 24-28, 30, 32-38, and 40 under 35 U.S.C. 103 over Zeng et al. (Experimental Cell Research, 2019) in view of Gutkin et al. (Oncotarget, 2016):
RE: Rejection of claims 24-28, 30, 32-34, 36-38, and 40-42 under 35 U.S.C. 103 over Zeng et al. (Experimental Cell Research, 2019) in view of Yuana et al. (International Journal of Molecular Sciences, 2020):
The amendment of claim 24 is effective to obviate the rejections. The rejections are withdrawn.
RE: Rejection of claims 24-30, 32-34, 36-38, and 40 under 35 U.S.C. 103 over Zeng et al. (Experimental Cell Research, 2019) in view of Stamp et al. (Biomaterials Science, 2016):
The applicant asserts that:
Stamp et al. are silent with respect to the stimulation of EV production with surface acoustic waves and that one of ordinary skill would not have had any expectation of success in combining the teachings of Stamp et al. and Zeng et al. because they are directed to differing subject matter (Applicant Remarks, page 10).
Because Zeng et al. successfully used ultrasound to generate EVs, one would not be motivated to find an alternative approach (Applicant Remarks, page 10).
Heat produced by ultrasound is not an issue in EV production, nor is it taught as a problem by Zeng et al., therefore no motivation to reduce the effects of heat exists (Applicant Remarks, page 10).
The applicant’s arguments have been fully considered but are not found persuasive. The teachings of Zeng et al. and Stamp et al. pertain to the application of acoustic waves—specifically, types of ultrasound—in cell culture. References from the same field of endeavor as the claimed invention, even if they address different problems, represent analogous art. See MPEP 2141.01(a)(I). While there is no requirement that the references be analogous to each other, the teachings of Zeng et al. and Stamp et al. occupy the same field and are therefore appropriate for combination, given sufficient motivation.
Regarding the assertion that Stamp et al. are silent on the subject of EV production via stimulation with surface acoustic waves, a prior art reference, or the combination of references, need not teach or suggest every claim limitation. See MPEP 2141(III). The teachings of Stamp et al. are relied upon in the rejection only for the use of SAWS and the motivation to do so in place of low-intensity pulsed ultrasound.
The applicant argues that, given the successful production of EVs by Zeng et al., one of ordinary skill would not be motivated to find an alternative approach. However, the normal desire of scientists or artisans to improve upon what is generally known provides a basis for modifying prior art conditions toward optimization. See MPEP 2144.05(II)(A). The method of Zeng et al., while successful, would thus be wholly suitable for improvement.
Although the applicant alleges that the heat produced by ultrasound is not an issue for EV secretion, arguments presented by applicant cannot take the place of factually supported objective evidence. See MPEP 2145(I).
The rejection is maintained in modified form to address amended limitations.
New/Maintained Rejections
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.
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 24-28, 30, 32-34, and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al. (Experimental Cell Research, 2019), of record, in view of Stamp et al. (Biomaterials Science, 2016), of record.
Regarding claims 24-25, 28, 32-34, and 36-38: Zeng et al. teach the establishment of lung cancer cell cultures in dishes (which reads on “receptacle that defines a reservoir” and “a receptacle for accommodating a population of cells in a culture media… configured to receive acoustic energy”) with RPMI 1640 (which reads on “a culture media” and “the cells are cultured for at least 12 hours prior to acoustic wave energy”) (See page 2, col. 1, full 2). The culture dishes were placed in a water (which reads on “a coupling material”) tank equipped with an ultrasound transducer (which reads on “an acoustic wave generator configured to generate acoustic energy at a selected power and frequency”) and exposed to pulsed ultrasound waves (which reads on “acoustic wave energy”) for 20 min (which reads on “about 30 sec to about 60 min”) before being returned to an incubator (which reads on “one or more successive periods of acoustic insonation followed by incubation in the absence of acoustic stimulation”) (See page 3, col. 1, 1 and fig. 1). Exosomes (which read on “extracellular vesicles”) were extracted (which reads on “harvested”) 24 h after ultrasound treatment (which reads on “the EVs are harvested after each cycle of acoustic insonation and incubation”) (See page 3, col. 1, 1).
Zeng et al. do not teach the use of a surface acoustic wave.
Stamp et al. teach ultrasonic stimulation of cultured osteosarcoma cells using surface acoustic wave treatment (See Abstract). The treatment increased cell growth and migration (See fig. 2-8). Stamp et al. suggest that surface acoustic wave treatment could be used to avoid the disadvantages of conventional ultrasound, such as harmful thermal effects and the need for special trained attention during treatment (See page 1092, col. 2, ¶1-2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Zeng et al. to comprise use of a surface acoustic wave. One would be motivated to make this modification because Stamp et al. teach that it can provide benefits of conventional ultrasound with fewer disadvantages (See page 1092, col. 1, ¶1 and col. 2, ¶1-2). There would be a reasonable expectation of success in doing so because Stamp et al. teach that a surface acoustic wave can be applied to cultured cells to good effect (See fig. 2-8) and because the experimental system of Zeng et al. could be readily modified to accommodate a piezoelectric substrate and interdigital transducer, such as are taught by Stamp et al.
Regarding claims 26-27: Following the discussion of claims 24-25, 28, 32-34, and 36-38, Zeng et al. teach the stimulation of exosome production using ultrasound but do not expressly teach the percentage of exosomes in the recovered particles.
However, Zeng et al. teach that the vesicles recovered by ultracentrifugation expressed exosome markers, the structure of the particles was consistent with exosomes, and the median size of the particles was approximately 117 nm (which reads on “a hydrodynamic diameter size of 30-150 nm”), with 90% of the particles smaller than approximately 199 nm, which suggests that at least 80% of the recovered particles were exosomes (See fig. 2).
Regarding claim 30: Following the discussion of claims 24-25, 28, 32-34, and 36-38, Stamp et al. teach that the ultrasound waves were produced by a transducer operating at 159 MHz (which reads on “the frequency of the applied acoustic wave energy is about 7 MHz to about 1GHz”) (See page 1093, col. 1, full ¶1).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to further modify the method of Zeng et al., modified by Stamp et al., to use a frequency of 159 MHz. One would be motivated to make this modification because the data obtained by Stamp et al. suggest that is it an appropriate frequency for cell culture, as it did not lead to detrimental effects on treated cells (See Abstract and page 1094, col. 2, full ¶1). There would be a reasonable expectation of success in doing so because such a frequency could be readily used.
Claims 24-28, 30-34, and 36-38 are rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al. (Experimental Cell Research, 2019), of record, in view of Stamp et al. (Biomaterials Science, 2016), of record, further in view of Bok et al. (Biotechnology and Bioengineering, 2009).
The teachings of Zeng et al. and Stamp et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 31: Following the discussion of claims 24-28, 30, 32-34, and 36-38, Zeng et al., modified by Stamp et al., render obvious the stimulation of exosome production using surface acoustic waves but do not teach an input power of about 0.1-10 W.
Bok et al. teach the use of surface acoustic waves to promote cell seeding on scaffolds (See Abstract). Input power applied to the transduced electrode ranged from 260 mW to 440 mW (which reads on “about 0.1 W to about 10 W”) in viability studies on osteoblasts (See page 390, col. 2, full ¶2; page 391, col. 1, ¶1; and fig. 10).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method of Zeng et al., modified by Stamp et al., to comprise using an input power of 260-440 mW. One would be motivated to make this modification because the results of Bok et al. suggest that such an input power for generating surface acoustic waves is biocompatible and does not significantly affect cell viability (See fig. 10). There would be a reasonable expectation of success in doing so because input power could be readily modulated in the method of Zeng et al., modified by Stamp et al.
Claims 24-28, 30, and 32-38 are rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al. (Experimental Cell Research, 2019), of record, in view of Stamp et al. (Biomaterials Science, 2016), of record, further in view of Gutkin et al. (Oncotarget, 2016), of record.
The teachings of Zeng et al. and Stamp et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 35: Following the discussion of claims 24-28, 30, 32-34, and 36-38, Zeng et al., modified by Stamp et al., render obvious the stimulation of exosome production using surface acoustic waves. Zeng et al. teach the production of exosomes expressing ALIX (See fig. 2) but do not expressly teach expression of calnexin. However, Zeng et al. teach that β-actin, which indicates intracellular protein levels, was not detected in exosome samples (See page 3, col. 1, ¶2 and fig. 2).
Gutkin et al. teach that calnexin is present in total cellular lysates of cancer cell lines but not present in the exosomes produced by those cells (See page 59174, col. 2, ¶2 and fig. 2).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention that exosomes produced by the method rendered obvious by Zeng et al., modified by Stamp et al., would be unlikely to express calnexin. Because Gutkin et al. teach calnexin as a cellular, not exosomal, marker (See page 59174, col. 2, ¶2 and fig. 2), and because Zeng et al. teach that the exosomes do not contain cellular proteins, as shown by the absence of β-actin (See page 3, col. 1, ¶2 and fig. 2), one could reasonably expect the exosomes produced by the method rendered obvious by Zeng et al., modified by Stamp et al., to express ALIX but not calnexin.
Claims 24-28, 30, 32-34, 36-38, and 41-42 are rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al. (Experimental Cell Research, 2019), of record, in view of Stamp et al. (Biomaterials Science, 2016), of record, further in view of Yuana et al. (International Journal of Molecular Sciences, 2020), of record.
The teachings of Zeng et al. and Stamp et al. are set forth in the rejections above and are incorporated herein in their entirety.
Regarding claims 41-42: Following the discussion of claims 24-28, 30, 32-34, 36-38, and 40, Zeng et al., modified by Stamp et al., render obvious the stimulation of exosome production using surface acoustic waves but do not teach the generation and use of drug-loaded exosomes.
Yuana et al. teach the loading of cells with model cargoes to simulate therapeutic drugs (See Abstract and page 2, ¶3). Ultrasound-released extracellular vesicles containing the cargoes were collected and analyzed (See page 11, ¶3-5 and fig. 3-8). Yuana et al. suggest that the methods could be used with therapeutic drugs in order to use extracellular vesicles as carriers for drug delivery in subjects (which reads on “a method of treating a subject”) (See page 10, ¶4).
It would have been obvious to one having ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method rendered obvious by Zeng et al., modified by Stamp et al., to comprise loading of the exosome-producing cells with drugs, as taught by Yuana et al. One would be motivated to make this modification because Yuana et al. suggest that extracellular vesicles could be used as drug carriers (See page 10, ¶4). There would be a reasonable expectation of success in doing so because Yuana et al. demonstrate that drug-loaded extracellular vesicles can be released from cells following ultrasound treatment (See fig. 3-8) and because cells in the method of Zeng et al., modified by Stamp et al., could be readily loaded with drug cargoes.
Allowable Subject Matter
Claim 39 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
The prior art does not teach or suggest the use of surface reflected bulk waves for cell culture, much less for the stimulation of extracellular vesicle production.
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 JENNIFER S SPENCE, whose telephone number is 571-272-8590. The examiner can normally be reached M-F 8:30-5:30.
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/J.S.S./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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