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 6/19/2026, are pending and subject to prosecution. Claims 5, 7-8, and 12 are amended.
This is a non-final Office action.
Declaration under 37 CFR 1.130(a)
A declaration under 37 CFR 1.130(a), of record 6/19/2026, was filed by Jae-Won Shin to disqualify the prior art reference Lenzini et al. as being the work of the inventors. Dr. Shin asserts that the non-inventor co-authors did not contribute to the conception of the invention. The declaration is sufficient to overcome the rejections of the pending claims based upon Lenzini et al. as set forth in the last Office action.
Status of Prior Objections/Rejections
RE:
Objection to claims 5, 7-8, and 12:
The amendment to claims 5, 7-8, and 1 is effective to obviate the objection. he objection is withdrawn.
RE: Rejection of claims 1-6 under 35 U.S.C. 102(a)(1) over Lenzini et al. (ACS Nano, 2021):
RE: Rejection of claims 1-7 under 35 U.S.C. 103 over Lenzini et al (ACS Nano, 2021):
RE: Rejection of claims 1-8 under 35 U.S.C. 103 over Lenzini et al (ACS Nano, 2021) in view of Liu et al. (ACS Nano, 2017):
RE: Rejection of claims 1-6 and 9-12 under 35 U.S.C. 103 over Lenzini et al (ACS Nano, 2021) in view of Nath et al. (US 20180066220 A1):
The declaration submitted under 37 CFR 1.130(a) is effective to obviate the rejections. The rejections are withdrawn.
New 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.
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.
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 Shin et al. (US 20170196818 A1), of record.
Regarding claims 1-2 and 4-5: Shin et al. teach methods of using hydrogels comprising encapsulated cells, which can be MSCs (which read on “mesenchymal stromal cells”) (See Abstract and ¶0007). Cells are encapsulated in hydrogel capsules (which reads on “adhering… cells to a cell-adhesive substrate comprising a hydrogel”) of varying stiffness, such as about 0.1-10 kPa (See ¶0023). The encapsulated cells can be cultured (which reads on “incubating”) and any secreted extracellular content collected (See ¶0263 and 0318). The hydrogel comprises at least one polymer such as alginate, gelatin, or collagen (See ¶0013 and 0019). The hydrogel polymer can be functionalized with ligands such as RGD and LDV peptides (which read on “cell-adhesive peptides” and “linear RGD peptides”) (See ¶0150 and 0163). 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). Cells secrete molecules directly into the extracellular space or through extracellular vesicles, and matrix stiffness affects the quantity of vesicles released from MSCs (See ¶0252 and 0258). Shin et al. disclose a method for promoting secretion of a protein factor through release of vesicles by contacting cells with a hydrogel (See ¶0259).
Shin et al. do not expressly teach tuning hydrogel stiffness for increasing extracellular vesicle production, however one of ordinary skill in the art would have found it obvious to obvious to optimize hydrogel stiffness in order to promote the secretion of extracellular vesicles and the proteins they contain, based upon the collective teachings of Shin et al. Such a modification could be readily carried out, as Shin et al. teach that crosslinker and gel concentrations can be varied to achieve optimal mechanical properties (See ¶0262).
Regarding claim 3: Following the discussion of claims 1-2 and 4-5, Shin et al. teach assembly of encapsulated cells within microwells having diameters of 50-221 µm (See ¶0361). The average cell number within each microwell varied between 2.6-37 (See ¶0361), which would yield densities ranging from approximately 68-18870 cells/mm2 and would read on the claimed range of “at least about 25 to about 150 cells per mm2”. See MPEP 2144.05(I).
Regarding claim 6: Following the discussion of claims 1-2 and 4-5, Shin et al. teach embodiments wherein hydrogel-encapsulated MSCs are cultured with blebbistatin (which reads on “one or more inhibitors of cell migration”) or Y-27632 (which reads on “inhibitor of focal adhesion kinase”) (See ¶0334).
Regarding claim 7: Following the discussion of claims 1-2 and 4-5, Shin et al. teach isolation of exosomes from conditioned media (See ¶0329). Shin et al. do not expressly teach multiple isolations within a 24 h period, however, Shin et al. teach that exosomes can be counted at different time points in order to calculate general exosome release kinetics (See ¶0329). One of ordinary skill in the art would have therefore found it obvious to modify the method of Shin et al. to comprise frequent extracellular vesicle collection, such as twice or more in a 24 h period, in order to most accurately model vesicle release.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Shin et al. (US 20170196818 A1), of record, in view of Liu et al. (ACS Nano, 2017), of record.
The teachings of Shin 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, Shin et al. render obvious a method for increasing the production of extracellular vesicles using hydrogel encapsulation 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 Shin 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 Shin et al. could be readily subjected to such processing.
Claims 1-7 and 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Shin et al (US 20170196818 A1), of record, in view of Nath et al. (US 20180066220 A1), of record.
The teachings of Shin 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 1-7, Shin et al. render obvious a method for increasing the production of extracellular vesicles using hydrogel encapsulation but do not expressly teach a microfluidic device for collecting the extracellular vesicles.
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 or encapsulating the cells (See ¶0005-0006, 0009-0012, 0021, 0024, and 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 Shin 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 Nath et al. teach that the device more closely recapitulates the tissue microenvironments needed for mechanistic studies (See ¶0004-0005). 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 an encapsulating hydrogel (See ¶0005-0006, 0009-0012, 0021, 0024, and 0054), and the hydrogel-encapsulated cells taught by Shin et al. could be readily applied to the device.
Regarding claim 10: Following the discussion of claims 1-6, 9, and 11-12, Shin 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, Shin et al. teach that the hydrogel layer has a thickness of less than 20 microns (which reads on “about 5 µm to about 5 mm”) (See ¶0010 and 0033).
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 Shin et al., modified by Nath et al., to comprise a hydrogel coating thickness of no more than 20 µm. One would be motivated to make this modification because the teachings of Shin et al. suggest that it is an appropriate thickness for encapsulating vesicle-releasing cells (See ¶0010, 0033 and 0259), and such a modification could be readily made.
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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/JENNIFER S SPENCE/Examiner, Art Unit 1633
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