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 1-12, of record 3/6/2023, are pending and subject to prosecution.
Priority
Acknowledgement is made of the applicant’s claim for benefit to provisional application 63/316586, filed 3/4/2022.
Claim Objections
Claims 5, 7-8, and 12 are objected to because of the following informalities:
In claims 5 and 12, the limitation “PHSRN (SEQ ID NO:28) peptides” should be rewritten as “peptides comprising SEQ ID NO: 28”.
In line 1 of claims 7-8, the word “step” should be deleted.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lenzini et al. (ACS Nano, 2021).
Lenzini et al. teach the effects of substrate mechanics on the secretion of extracellular vesicles from MSCs (See Abstract).
Regarding claims 1-6: Lenzini et al. teach an increase in MSC secretion of extracellular vesicles when cultured on relatively soft hydrogel (Young’s modulus of approximately 3 kPa) versus a relatively stiff hydrogel (approximately 20 kPa) or a plastic substrate (See fig. 1-2). Alginate-RGD or RGD-bearing PEG-DA (which read on functionalized with one or more cell-adhesive peptides” and “linear RGD peptides”) hydrogels were generated (See page 17447, col. 1, ¶1). Cells were seeded onto the hydrogels at a density of 25 cells/mm2 (which reads on “at least about 25 to about 150 cells per mm2”) (See page 17447, col. 1, full ¶3). Some cells were treated with cilengitide or CK869 or with siRNA against KAK or TLN1(which read on “inhibitors of cell-cell adhesion, or cell-substrate adhesion” and “an inhibitor of focal adhesion kinase, inhibitor of actin related protein 2/3, inhibitor of actin, inhibitor of a cadherin, or inhibitor of an integrin”) (See fig. 2 and 4-5). Extracellular vesicles were collected after 24 h (See page 17441, col. 1, full ¶1).
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 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Lenzini et al (ACS Nano, 2021).
The teachings of Lenzini et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 7: Following the discussion of claims 1-6, Lenzini et al. teach a method for increasing the production of extracellular vesicles using a relatively elastic hydrogel substrate teach collection of the vesicles only once at 24 h post-seeding of MSCs.
However, one of ordinary skill in the art would have found it obvious to optimize the method of Lenzini et al. by adding one of more intermediate collection time points. Lenzini et al. teach that their results suggest that a fraction of vesicles is released from cells at a given time and that the process is subject to regulation by cell-matrix interactions (See page 17446, col. 1, ¶1), which implies that the process could be further probed by analyzing extracellular vesicles produced at additional, faster times post-seeding.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Lenzini et al (ACS Nano, 2021) in view of Liu et al. (ACS Nano, 2017).
The teachings of Lenzini et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claim 8: Following the discussion of claims 1-7, Lenzini et al. teach a method for increasing the production of extracellular vesicles using a relatively elastic hydrogel substrate but do not teach continuous collection of extracellular vesicles.
Liu et al. teach the continuous collection and size-dependent separation of nanoparticles, including exosomes and extracellular vesicles, from culture medium or serum using a viscoelastic-based microfluidic system (See Abstract and page 6969, col. 1, full ¶1 and fig. 1 and 5).
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 Lenzini et al. to comprise the extracellular vesicle collection and isolation system of Liu et al. One would be motivated to make this modification because Liu et al. teach that their system enables rapid, continuous, label-free, low-cost isolation of nanoparticles while minimizing physical damage (See page 6969, col. 1, full ¶1; page 6971, col. 2, full ¶3; and page 6972, col. 1, ¶1). There would be a reasonable expectation of success in doing so because the culture medium in the method of Lenzini et al. could be readily subjected to such processing.
Claims 1-6 and 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Lenzini et al (ACS Nano, 2021) in view of Nath et al. (US 20180066220 A1).
The teachings of Lenzini et al. are set forth in the rejection above and are incorporated herein in their entirety.
Regarding claims 9 and 11-12: Following the discussion of claims 1-6, Lenzini et al. teach a method for increasing the production of extracellular vesicles using a relatively elastic hydrogel substrate. Lenzini et al. teach that tunable hydrogels could be integrated with microfluidic-based bioreactors (See page 17446, col. 2, full ¶1) but do not expressly teach a microfluidic device for carrying out the method.
Nath et al. teach microfluidic devices for cell culture comprising hollow fibers or channels (See Abstract and ¶0006). The device can include a hydrogel matrix for seeding the cells (See ¶0006, 0009-0012, 0021, 0024, 0054). Exosomes secreted by the cells can be isolated for analysis (See ¶0061 and 0097-0098).
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 Lenzini et al. to comprise use of a device, such as that taught by Nath et al., for culturing extracellular vesicle-producing cells on a hydrogel substrate. One would be motivated to make this modification because Lenzini et al. suggest the possibility of tunable hydrogels being integrated with microfluidic-based bioreactors (See page 17446, col. 2, full ¶1). There would be a reasonable expectation of success in doing so because Nath et al. teach exosome-secreting cells can be cultured and that the microfluidic device can comprise a hydrogel (See ¶0006, 0009-0012, 0021, 0024, and 0054), and the “soft” hydrogel comprising RGD-alginate or RGD-PEG-DA taught by Lenzini et al. could be readily applied to the device.
Regarding claim 10: Following the discussion of claims 1-6, 9, and 11-12, Lenzini et al., modified by Nath et al., render obvious the culture of extracellular vesicle-producing cells in a microfluidic device comprising a hydrogel but do not expressly teach the thickness of the hydrogel inside the device.
However, Lenzini et al. teach the seeding of MSCs on a hydrogel layer approximately 40 µm thick (which reads on about 5 µm to about 5 mm”) (See page 17448, col. 1, full ¶3).
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 device rendered obvious by Lenzini et al., modified by Nath et al., to comprise a hydrogel coating thickness of 40 µm. One would be motivated to make this modification because Lenzini et al. demonstrate that it is an appropriate thickness for seeding cells on a relatively elastic hydrogel (See page 17448, col. 1, full ¶3 and fig. 3-4), and such a modification could be readily made.
Citation of Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The examiner notes that Shin et al. (US 20170196818 A1) teach methods of using hydrogels comprising encapsulated cells (See Abstract). Cells are encapsulated in hydrogel capsules of varying stiffness, such as about 0.1-10 kPa (See ¶0023). Tuning the stiffness of the hydrogels can induce protein release from the cells in the form of extracellular vesicles (See ¶0180, 0182-0183, 0265-0267, and 0329).
Conclusion
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