-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 November 12, 2025.
Applicant's election with traverse of Group I (Claims 1-13) in the reply filed on 11/12/2025 is acknowledged.
The traversal is on the ground(s) that Ho does not teach all of the limitations of the independent claim in order to show lack of unity and the special technical feature is the thickness of the hydrogel layer.
This is not found persuasive because Ho is no longer utilized to stablish that lack of unity of invention exits. As seen below, Shin (US Pub. 20170196818 ) teaches the hydrogel encapsulating single cells where ligands are conjugated and claimed thickness having less than 10 microns (paragraphs [0008] [0011] [0163] of the published application). Because claim 1 is anticipated by Shin the remaining claims lack the same or corresponding special technical feature and as such, lack unity. The expression “special technical features” means those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art. The requirement of unity of invention shall be fulfilled only when there is a technical relationship among those inventions involving one or more of the same or corresponding special technical features.. Therefore, the technical feature is not special and does not make a contribution over the prior art and lack of Unity of Invention among Groups I-III is maintained.
The requirement is still deemed proper and is therefore made FINAL.
Claims 14-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
No claims have been canceled, amended or newly added by applicants’ amendment filed on 11/12/2025.
Therefore, claims 1-13 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.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
For example, there is no copy or IDS submitted for the multiple references listed in para. 0003 of the instant specification.
Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 6 is objected to because of the following informalities: There is a typographical error in the first word of the claim. The claim should recite “The” instead of “he”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-13 are rejected 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.
Claim 1 is indefinite in the recitation of “less than about” for the following reason. “About” encompasses values above and below a reference point whereas “less than” encompasses only values below the reference point. Therefore, the combination of both terms (less than about) is confusing because one term is including values above the reference point whereas the other term is excluding values above the reference point.
Claim 7 is indefinite in the recitation of “greater than about” for the following reason. “About” encompasses values above and below a reference point whereas “greater than” encompasses only values above the reference point. Therefore, the combination of both terms (greater than about) is confusing because one term is including values above the reference point whereas the other term is excluding values above the reference point.
Claims 2-6 and 8-13 are indefinite insofar as they depend from claim 1.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 8 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 8 recites a molecular weight of about 250kDa to 500 kDa. Claim 8 depends on claim 7 which recites a weight greater than about 250kDa. As Claim 7 can be interpreted as being not inclusive of 250kDa, claim 8 broadens the range of the claim it depends on and does not further limit claim 7.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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.
Claim(s) 1-5, 7-8 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shin et al., (US 20170196818).
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 claim 1, 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).
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). 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 claims 7 and 8, Shin teaches the alginate has a molecular weight of about 250 kDa or greater (para. 0229, Example 1).
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 is anticipated by Shin.
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.
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 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Shin (US20170196818; Applicant’s own work) as applied to claim 1 above, and further in view of Chaudhuri ( Nature Mater 15, 326–334 (2016)).
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.
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).
However, regarding claim 6, 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.
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.
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.
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 10 are rejected under 35 U.S.C. 103 as being unpatentable over Shin (US2017196818) as applied to claim 1 above, and further in view of Kong (J Biomed Mater Res A, 2019 Oct;107(10):2282-2295).
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).
However, regarding claims 9 and 10, Shin does 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 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) as applied to claim 1 above, and further in view of Christian (2012, Immunotherapy, 4:4, 425-441,).
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).
However, regarding claims 9 and 11, Shin does 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 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) as applied to claim 1 above, in view of El-Fattah (Biochimie, Volume 156, January 2019, Pages 59-68).
Regarding independent claim 1, 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).
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 does 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 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
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634