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 .
This action is in response to the papers filed April 29, 2026.
Claims 1-6 and 8-21 are pending in the application.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/12/2025.
Claim 7 has been canceled, claims 1, 6, and 8 have been amended and claim 21 is newly added by applicants’ amendment filed on 04/29/2026.
Therefore, claims 1-6, 8-13 and 21 are examined on the merits.
Priority
This application is a 371 of PCT/US2021/048343 filed 08/31/2021. Applicant’s claim for the benefit of a prior-filed provisional application 63/120,258 filed 12/02/2020and 63/072,282 filed 08/31/2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is August 31, 2020.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Objections
The objection of claim 6 is withdrawn in light of the amendments made to correct the typographical error.
Claim Rejections - 35 USC § 112
The rejection of claims 1-13 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
Applicant’s arguments and amendments filed 04/29/2026 have been considered and are persuasive.
Applicant’s amendments to remove “about” from the claim language have obviated the rejection.
Claim Rejections - 35 USC § 112 (d)
The rejection of claim 8 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form is withdrawn.
Applicant’s arguments and amendments filed 04/29/2026 have been considered and are persuasive. The amendments made to cancel claim 7 and amend claims 1 and 8 correct the dependency.
Claim Rejections - 35 USC § 102
The rejection of Claim(s) 1-5, 7-8 and 12 under 35 U.S.C. 102(a)(1) as being anticipated by Shin et al., (US 20170196818) has been withdrawn.
Applicant’s arguments and amendments filed 04/29/2026 have been considered and are persuasive. Applicant’s amendments to include limitations from claims not previously rejected under 102 have overcome the rejection. However, the claims remain rejected as being obvious.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 1 and 6 remain rejected and claims 2-5, 8 and 12 and claim 21 are newly rejected under 35 U.S.C. 103 as being unpatentable over Shin (US20170196818; Applicant’s own work), and further in view of Chaudhuri ( Nature Mater 15, 326–334 (2016)).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 04/29/2026.
The applied Shin reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(1). The publication dated for Shin is July 13, 2017. The earliest effective filing date of the instant application is August 31, 2020.
Therefor rejection under 35 U.S.C. 103 CANNOT be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02. Because the reference qualifies as prior art under 102(a)(1), the provisions of MPEP 717.02 do not apply.
Regarding claims 1, 6, 8, and 21, Shin teaches a composition of alginate coated cells within alginate capsules which comprise a single cell and wherein the thickness of the alginate is less than 20 microns in thickness (para. 0010, 0038, Claim 1, 63). Shin further specifies that less than 20 microns means for example, less than 19 to less than 1 microns (para. 0038, 0144). This encompasses the less than about 10 microns of the present claim.
Shin additionally teaches the alginate layer is ionically cross-linked and contains a single mesenchymal stromal cell (MSC) (para. 0200, Fig 2A, para. 0046). Shin teaches in order to support cell adhesion to the capsules, they are conjugated with functional ligands such as RGD (para. 0150, 0163, 0366). Shin teaches the alginate has a molecular weight of about 250 kDa or greater (para. 0229, Example 1)
However, Shin does not teach the cross-linked alginate hydrogel layer has a stress relaxation rate of about 4 seconds.
Chaudhuri teaches that alginate hydrogels have tunable stress relaxation rates to regulate stem cell fate and using different molecular weight polymers in combination with different crosslinking densities of calcium, which ionically crosslinks alginate, the stress relaxation properties of the resulting hydrogels could be modulated due to the altered connectivity and chain mobility in the network (Abstract, p. 327, 1st column). Additionally, Chaudhuri teaches that relaxation time is dependent on the concentration of ligands such as RGD (Fig 2a, 2c). Therefore, Chaudhuri teaches that stress relaxation rates are optimizable and would be routine optimization to arrive at 4 seconds (claim 6) or 0.1 seconds to 10 seconds (claim 21).
In view of the benefit of having tunable stress relaxation rates to regulate stem cell fate, it would have been obvious for one of ordinary skill in the art to combine the teachings of Chaudhuri and Shin to measure stress relaxation rate of the cross-linked alginate hydrogel
Layer. Moreover, Chaudhuri above indicates that having a specific concentration of alginate or ligands and specific molecular weight influences the stress relaxation time, therefore, as Shin teaches each and every characteristic of the claimed hydrogel, an artisan would have a reasonable expectation of success in observing a 4 second stress relaxation time or 0.1 seconds to 10 seconds
It is well settled that routine optimization is not patentable, even if it results in significant improvements over the prior art. In support of this position, attention is directed to the decision in In re Aller, Lacey, and Haft, 105 USPQ 233 (CCPA 1955): Normally, it is to be expected that a change in temperature, or in concentration, or in both, would be an unpatentable modification. Under some circumstances, however, changes such as these may impart patentability to a process if the particular ranges claimed produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art. In re Dreyfus, 22 C.C.P.A. (Patents) 830, 73 F.2d 931,24 USPQ 52; In re Waite et al., 35 C.C.P.A. (Patents) 1117, 168 F.2d 104, 77 USPQ 586. Such ranges are termed "critical" ranges, and the applicant has the burden of proving such criticality. In re Swenson et al., 30 C.C.P.A. (Patents) 809, 132 F.2d 1020, 56 USPQ 372; In re Scherl, 33 C.C.P.A. (Patents) 1193, 156 F.2d 72, 70 USPQ 204. However, even though applicant's modification results in great improvement and utility over the prior art, it may still not be patentable if the modification was within the capabilities of one skilled in the art. In re Sola, 22 C.C.P.A. (Patents) 1313, 77 F.2d 627, 25 USPQ 433; In re Normann et al., 32 C.C.P.A. (Patents) 1248, 150 F.2d 708, 66 USPQ 308; In re Irmscher, 32 C.C.P.A. (Patents) 1259, 150 F.2d 705, 66 USPQ 314. More particularly, where 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 Swain et al., 33 C.C.P.A. (Patents) 1250, 156 F.2d 239, 70 USPQ 412; Minnesota Mining and Mfg. Co. v. Coe, 69 App. D.C. 217, 99 F.2d 986, 38 USPQ 213; Allen et al. v. Coe, 77 App. D. C. 324, 135 F.2d 11,57 USPQ 136. (Emphasis added). With regards to determining experimental parameters, such as time in culture, the court has held that "[d]iscovery of optimum value of result effective variable in known process is ordinarily within skill of art (In re Boesch and Slaney, 205 USPQ 215 (CCPA 1980)).
The adjustment of particular conventional working conditions (e.g. molecular weight or concentration to achieve a desired stress relaxation time) is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan having the cited reference before him/her.
Regarding claim 2, Shin teaches the alginate hydrogel is crosslinked ionically (i.e., non-covalently) with a divalent or trivalent cation, such as Ca2+, Mg2+, Sr2+, Ba2+, Be2+ and Al3+ (para. 0216, Example 1, claim 68).
Regarding claims 3 and 4, Shin teaches the cross-linked alginate hydrogel layer has a softness of about 0.1 kPa to about 10 kPa. This encompasses 2kPa. (para 0023).
Regarding claim 5, Shin teaches a crosslinked alginate hydrogel capsules with less than 20 micron thickness and further specifies that less than 20 microns means for example, less than 19 to less than 1 microns (para. 0038, 0144). Moreover, the alginate-coated cells of claim 1, wherein the cross-linked alginate hydrogel layer has a thickness of about 0.5 to about 5 microns.
Regarding claim 12, Shin teaches the alginate-coated cells are in a composition with a pharmaceutically acceptable carrier or aqueous medium as they are described as being administered directly in a cell suspension (para. 0139).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 9 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Shin (US2017196818) in view of Chaudhuri ( Nature Mater 15, 326–334 (2016) as applied to claim 1 above, and further in view of Kong (J Biomed Mater Res A, 2019 Oct;107(10):2282-2295).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 04/29/2026.
The combination of Shin and Chaudhuri makes obvious the alginate coated cells of claim 1, wherein the alginate has a stress relaxation rate of 10 seconds or less, a molecular weight of more than 250 kDa and the hydrogel layer has a thickness of less than 10 microns as discussed in the above 103 rejection and incorporated herein in its entirety.
However, regarding claims 9 and 10, Shin and Chaudhuri do not teach the cross-linked alginate hydrogel layer further comprises one or more growth factors, inflammatory factors or differentiation factors such as BMP-2.
Kong teaches a vehicle system for dual-delivery of encapsulated bone marrow mesenchymal stem cells (BM-MSC) and BMP-2 for the treatment of large bone defects (Abstract). Moreover, Kong teaches dual delivery of encapsulated BM-MSC and BMP-2 shows great advantages for bone repairment and regeneration in a clinical context. When sources of autologous BM-MSCs is limited, allogeneic or xenogeneic BM-MSCs encapsulated in alginate microcapsules could serve as an alternative candidate because they elicit minimal immunological response from the host (p. 2293, 2nd column).
It would have been obvious to one of ordinary skill in the art before the time of the effective filing date to add BMP-2 taught by Kong to the alginate capsules containing MSCs as taught by Shin and Chaudhuri with a reasonable expectation of success. An artisan would be motivated to add BMP-2 because Kong teaches a dual-delivery of encapsulated BM-MSCs and BMP-2 which demonstrates great advantages for bone repair (p. 2293, 2nd column).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Claims 1, 9 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Shin (US2017196818; Applicant’s own work) in view of Chaudhuri ( Nature Mater 15, 326–334 (2016)) as applied to claim 1 above, and further in view of Christian (2012, Immunotherapy, 4:4, 425-441,).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 04/29/2026.
The combination of Shin and Chaudhuri makes obvious the alginate coated cells of claim 1, wherein the alginate has a stress relaxation rate of 10 seconds or less, a molecular weight of more than 250 kDa and the hydrogel layer has a thickness of less than 10 microns as discussed in the above 103 rejection and incorporated herein in its entirety.
However, regarding claims 9 and 11, Shin and Chaudhuri do not teach the alginate capsule further comprising inflammatory factors such as TNFa.
Christian teaches liposomal formulations that comprise TNFa have been developed in cytokine loaded particles (p. 428, 2nd column). Injection of said liposomes were utilized in intravenous injections where they activated macrophages and induced resistance to metastatic tumors (p. 429, 2nd column). Moreover, Christian teaches TNFa imbedded into the membrane of polymer particles were designed to mimic the naturally occurring cell membrane-bound TNFa and are an additional strategy for particle-mediated cytokine delivery (p. 429, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to add TNFa as taught by into the alginate capsules comprising MSCs as taught by Shin and Chaudhuri with a reasonable expectation of success. An artisan would have been motivated to add the TNFa to the capsules because Christian teaches that polymer particles are utilized with TNFa to mimic that of the naturally occurring cell membrane and are a strategy for particle mediated cytokine delivery.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 1, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Shin (US2017196818; Applicant’s own work) in view of Chaudhuri (Nature Mater 15, 326–334 (2016)) as applied to claim 1 above, in view of El-Fattah (Biochimie, Volume 156, January 2019, Pages 59-68).
This rejection has been modified as necessitated by Applicant’s arguments and amendments filed 04/29/2026.
The combination of Shin and Chaudhuri makes obvious the alginate coated cells of claim 1, wherein the alginate has a stress relaxation rate of 10 seconds or less, a molecular weight of more than 250 kDa and the hydrogel layer has a thickness of less than 10 microns as discussed in the above 103 rejection and incorporated herein in its entirety.
Regarding independent claim 12, Shin teaches the alginate-coated cells are in a composition with a pharmaceutically acceptable carrier or aqueous medium as they are described as being administered directly in a cell suspension (para. 0139). In another aspect, Shin’s invention provides a method for treating or preventing a cardiovascular disease in a subject in need thereof utilizing the pharmaceutical composition (para. 0030).
However, regarding claim 13, Shin and Chaudhuri do not teach the cross-linked alginate hydrogel layer further comprising one or more ion channel modulators, one or more cell contractility modulators, or a combination thereof.
El-Fattah teaches the utilization of amlodipine (i.e. ion channel modulator) to improve the therapeutic effects of BM-MSCs through the widening of blood vessels, increasing blood flow, and increasing cellular antioxidant levels which in turn improves the function repair of the cells (p. 67, Abstract).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to additionally administer amlodipine as taught by El-Fattah in the same pharmaceutical composition as the encapsulated BM-MSCs of Shin and Chaudhuri with a reasonable expectation of success. An artisan would be motivated to administer both as El-Fattah teaches amlodipine (i.e. ion channel modulator) improves the therapeutic effects of BM-MSCs.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
In response to Applicant’s arguments against the combination of Shin and Chaudhuri in light of the amendments made,
Applicant’s arguments and amendments filed 04/29/2026 have been considered, however they are not persuasive.
Applicant argues that neither Shin nor Chaudhuri provides for a stress relaxation time of 10 seconds or less and thus fails to teach or suggest every element of the claims. Moreover, Applicants argue that Chaudhuri describes the preparation of high (280 kDa), mid (70 kDa) and low (35 kDa) molecular weight alginate hydrogels and shows that when lowering the molecular weight of the alginate from 280 kDa to 35 kDa, the rate of stress relaxation was markedly enhanced, specifically “the initial stress of the material to be relaxed to half its value during a stress relaxation test (11/2) was decreased from ~1 hour for the hydrogel prepared with 280 kDa alginate to ~1 minute for the hydrogel prepared with 35 kDa alginate”.
In response to applicant's argument that Shin and Chaudhuri do not explicitly state 10 seconds or less as a stress relaxation time, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Chaudhuri is providing motivation to optimize the stress relaxation rate of the alginate.
Moreover, Chaudhuri above indicates that having a specific concentration of alginate or ligands and specific molecular weight influences the stress relaxation time. Therefore, as Shin teaches each and every characteristic of the claimed hydrogel, an artisan would have a reasonable expectation of success in observing a 4 second stress relaxation time or about 0.1 seconds to 10 seconds. Shin does not measure the stress relaxation rate, however as Applicants concede Chaudhuri measures stress relaxation of alginate hydrogels which reads on all other limitations and properties (page 9 of Applicants’ remarks), therefore, Applicant must show evidence of the difference between the alginate of Shin and the alginate of the claimed invention either by concentration or other means in order to distinguish it from the prior art.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Chaudhuri’s experiments further enforce the ability to decrease stress relaxation rates when molecular weight decreases as established in Figure 1b which means the molecular weight can be manipulated to achieve the appropriate result. Chaudhuri’s purpose is not to provide a time of 10 seconds, but demonstrate that it is known in the art to optimize the stress relaxation rate through the manipulation of alginate’s natural properties. Moreover, the exact amount of RGD within the gels as in the present invention, influences the stress relaxation times as seen in Figure 2b-d and the manner in which crosslinking occurs also has influence on the stress relaxation time.
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.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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