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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 05-01-2026 has been entered.
Applicant's arguments and amendments to claims filed on 05-01-2026 have been received and entered. Claim 1 has been amended. Claims 2-3, 6, 11-20 have been canceled. Claims 1, 4-5, 7-10, 21-29 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10) in the reply filed on 03-08-2024 is acknowledged.
Claims 21-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03-08-2024.
Claims 1, 4-5, 7-10 are under consideration.
Priority
This application is a 371 of PCT/JP2019/037725 filed on 09/18/2019 that claims priority from
foreign application JP 2018-175465 filed on 09/19/2018.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Translation of foreign priority document of application number JP 2018-175465 filed on 02-04-2026 is acknowledged.
Withdrawn-Claim Rejections - 35 USC § 112 (d)
Claim 6 was 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. In view of Applicants' cancelation of claim 6, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 101
Claims 1-2, 4-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. In view of Applicants' amendments of base claim 1 and remarks, the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained in modified form -Claim Rejections - 35 USC § 103 - necessitated by amendments
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.
Claims 1, 4-5, 7 are rejected under 35 U.S.C. 103 as being unpatentable over Rezania et al (Nature Biotechnology Volume 32 Number 11, November 2014, doi:10.1038/nbt.3033).
Claim interpretation:
Claim 1 is interpreted as product by process. See MPEP 2113. [E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
Regarding claim 1, Rezania et al teach a seven-stage protocol that efficiently converts hESCs into insulin-producing cells (Abstract). Rezania et al teach generation of Stage 6 immature beta cells (see Figure 1a page 1122) with optimized S6 protocol (Page 1125, left column, 2nd para) with the following teachings:
Rezania et al teach “…analysis of protein expression in single cells revealed that S6 populations derived from hESCs contained ~50% NKX6.1+/insulin+ cells (Figs. 1c and 2
and Supplementary Fig. 9)…..” (see Page 1125, left column, 2nd para. and see Supplementary Figure 9: Co-expression of insulin and NKX6.1 in stage 4 versus stage 6).
Rezania et al teach 14.2% (Supplementary Figure 9) and 27.9% of insulin-positive and NKX6.1-negative cells was obtained from a sixth-stage culture (Supplementary Figure 10). Thus, at least, the Stage 6 immature beta cell population has insulin-positive and NKX6.1-negative cells between 14.2% (Supplementary Figure 9) and 27.9% (Supplementary Figure 10).
Rezania et al teach Ki67-positive cells at a proportion of less than 3% (S6 D14) (Figure 1c, page 1122) and Supplementary Figure 19-B (Page 21).
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Thus, Rezania et al teach differentiation protocol that can convert hESCs into insulin-producing cells with “optimized S6 protocol” (Page 1125, left column, 2nd para) resulting in populations insulin-positive and NKX6. l-positive cells at a proportion of 30-50%; and insulin-positive and NKX6. l-negative cells at a proportion of 15-40%; and Ki67-positive cells at a proportion of less than 3%, thereby indicating that the differentiation protocol as taught by Rezania et al can be optimized to obtain cell population with various proportion of desired cell types. A person of ordinary skill in the art would have been motivated to perform differentiation protocol as taught by Rezania et al a plurality of times out of the course of routine optimization, in order to obtain desired cell population comprising insulin-producing cells by inducing the differentiation of a single population of pluripotent stem cells.
Rezania et al teach chromogranin A-positive cells at a proportion of 90% or more: Rezania et al teach Figure 1d stage 6, day 14 (Page 1122) showing NKX6.1-positive- chromogranin A-positive cells is 78.7% and NKX6.1-negative - chromogranin A-positive cells is 16.9%. Thus, total chromogranin A-positive cells is 78.7% + 16.9% = 95.6 %. It should be noted that claim 1 requires both “NKX6. l-positive cells” and “NKX6. l-negative cells”.
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Rezania et al teach expression level of MafA gene in Stage 6 immature beta cell population is lower than an expression level of a MafA gene in a human pancreatic islet (Figure 1b, page 1122).
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Regarding claim 4, Rezania et al teach glucagon-positive and insulin-negative cells at a proportion of less than 3% (S6 D14) (Figure 1c, page 1122).
Regarding claim 5, Rezania et al stated that “our protocol generated endocrine cells with an insulin content similar to that of human islet cells and capable of glucose-stimulated insulin secretion in vitro and rapid reversal of diabetes in vivo” (Page 1131, right column, 3rd para.)
Regarding to claim 7, Since Rezania et al teach the population of cells in supplementary Figure 9, 10 are sorted by fluorescence-activated cell sorting (FACS) with surface marker insulin and NKX6.1, the population should be free of undifferentiated pluripotent stem cells due to undifferentiated pluripotent stem cells do not express insulin and NKX6.1, and FACS machine only sorts the intended markers.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to optimize cell population of Rezania et al to prepare insulin-producing cells comprising insulin-positive with desired cell type proportion. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Rezania et al teach several optimization strategies to generate cell population comprising insulin-producing cells such as: optimization of S1–4 to generate PDX1+/NKX6.1+ cells (Page 1123, left column, 2nd para.) and with the optimized S5 differentiation protocol, hESC-derived cells maintained robust co-expression of NKX6.1 and PDX1(Page 1123, right column, 3rd para.), and with optimized S6 protocol, Rezania et al consistently generated populations with similar or higher transcript levels of several key transcription factors (NEUROD1, PDX1, NKX6.1, NKX2.2, MAFB) compared with adult human islets (Page 1125). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Rezania et al were successful in generation of highly differentiated cells display certain key characteristics of mature beta cells, including glucose-induced insulin secretion, and rapidly reverse diabetes after transplantation in mice (Page 1123, left column, 1st para.).
Claims 8, 9, 10 are rejected under 35 U.S.C. 103 as being unpatentable over Rezania et al (Nature Biotechnology Volume 32 Number 11, November 2014, doi:10.1038/nbt.3033) in view of Grinstaff et al (Pub. No.: US 2016/0287745 A1, Pub. Date: Oct. 6, 2016).
The teachings of Rezania et al are as described above and are incorporated herein in their entirety.
Rezania et al do not specifically teach the insulin-producing cells are accommodated in a device, and the insulin producing cells are dispersed in a hydrogel. Grinstaff et al cure the deficiency.
Regarding to claim 8, Grinstaff et al teach islets of Langerhans (the insulin producing cells of the pancreas) can be embedded in the dissolvable hydrogel and/or the dissolvable hydrogel composition, which can then be transplanted into a subject to regulate blood sugar level in a diabetic subject ([0156], page 30). Grinstaff et al teach examples of bioactive agents for use in the dissolvable hydrogel and/or compositions described herein include, without limitations, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness ([0246], page 41).
Regarding to claim 9, Grinstaff et al teach hydrogels are one class of biomaterials currently used in medical and clinical applications, and Hydrogels can be used as coatings (e.g., biosensors, catheters, and Sutures), as "homogeneous' materials (e.g., contact lenses, burn dressings, and dentures), and as devices (e.g., artificial organs and drug delivery systems) ([0009], page 1) (For claim 9).
Regarding to claim 10, Grinstaff et al teach dissolvable hydrogel compositions and methods of uses, e.g., but not limited to, in wound management. Accordingly, methods for wound management involving the dissolvable hydrogel compositions are also provided herein (Abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to accommodate and contain cell population of Rezania et al by using hydrogel device as taught by Grinstaff et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Grinstaff et al teach dissolvable hydrogels, dissolvable hydrogel compositions, and/or kits that can be used to improve wound management ([0166], page 31), and dissolvable hydrogel composition comprises an adhesive thioester hydrogel, which can facilitate adherence of the dissolvable hydrogen composition to a wound surface (e.g., a) and can be controllably dissolved later upon addition of a thiolate compound (Abstract). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Grinstaff et al teach that islets of Langerhans (the insulin producing cells of the pancreas) can be embedded in the dissolvable hydrogel and/or the dissolvable hydrogel composition, which can then be transplanted into a subject to regulate blood Sugar level in a diabetic subject ([0156], page 30).
Response to Arguments
Applicant's arguments filed on 05-01-2026 have been fully considered but they are not persuasive.
1. Applicants argue that “as described in the Prior Response, nowhere does Rezania teach or suggest a cell population comprising pluripotent stem cell-derived insulin-producing cells that simultaneously comprises the proportion of subpopulations as recited in the pending claims …..nowhere does Rezania provide any teaching, suggestion, motivation, or reason to "optimize" the protocols of Rezania to produce a cell population as claimed, which comprises insulin-positive and NKX6. l-negative cells at a proportion of 15-40%.” (Remarks, page 9).
Response to Arguments:
It appears applicants focus on the requirement of “NKX6. l-negative cells at a proportion of 15-40%” recited in the claim. It is noted that Rezania et al teach 14.2% (Supplementary Figure 9) and 27.9% of insulin-positive and NKX6.1-negative cells was obtained from a sixth-stage culture (Supplementary Figure 10). Thus, at least, the Stage 6 immature beta cell population has insulin-positive and NKX6.1-negative cells between 14.2% (Supplementary Figure 9) and 27.9% (Supplementary Figure 10). It is noted that the 14.2% insulin-positive and NKX6.1-negative Stage 6 immature beta cells is so close to the requirement of 15% by the instant claim and Rezania et al also teach Stage 6 immature beta cells can be 27.9% of insulin-positive and NKX6.1-negative cells. Since the converts hESCs into insulin-producing cells and the FACS sorting by Flow cytometry are routine technique as evidenced by Rezania et al , a person of ordinary skill in the art before the effective filing date of claimed invention would be able to optimize and arrive at the claimed invention. In absence of any unexpected result or advantage associated with the claimed pluripotent stem cell-derived insulin producing cells population it would be routine variation during conversion of stem cells into insulin-producing cells.
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2. Applicants argue that
“the seven-stage differentiation protocol of Rezania was specifically aimed at producing more mature insulin-producing cells”
“Rezania evaluated a number of reagents to determine which induced MafA expression (as discussed above, a maturation marker) and successfully produced “highly differentiated cells display[ing] certain key characteristics of mature beta cells." Rezania, page 1123, col. I, paragraph 1. Moreover, Rezania reports expression of PCNA, a proliferation marker, in insulin-positive cells (FIG. 5G, lower panel), suggesting that the differentiated cells still retain a degree of proliferative capacity. By contrast, the claimed cell population exhibits a low proportion of Ki67-positive cells, indicating a suppressed proliferative state, which further distinguishes the claimed cells from those of Rezania. See Specification as filed, paragraph [0258] …Importantly, achieving the specified proportion of insulin-positive and NKX6. l negative cells is not the result of simply increasing immature cells. Rather, it is achieved only under conditions that simultaneously ensure high endocrine purity (chromogranin A positivity) and low proliferative activity. Thus, the cell population as claimed cannot be achieved by routine optimization. ”
(Remarks, page 9-10).
Response to Arguments:
It appears applicants argue Rezania et al only aimed at only producing and using only more mature insulin-producing cells such as Stage 7 maturing beta cells. It is noted that Rezania et al also teach generation of Stage 6 immature beta cells (see Figure 1a page 1122) with optimized S6 protocol (Page 1125, left column, 2nd para), and Rezania et al teach the use of Stage 6 immature beta cells in vivo: Figure 3 S6 insulin+ cells develop faster in vivo than S4 pancreatic progenitor cells and Rezania et al stated that “In STZ-induced diabetic mice, S4 cells required ~23 weeks to reverse hyperglycemia (Fig. 3g; blood glucose values at day 160 were not significantly different (P > 0.05) from pre-STZ). In contrast, S6 cells reversed STZ-induced hyperglycemia in ~8–12 weeks in three independent cohorts of diabetic mice (Fig. 3e, P > 0.05 for day 83 versus pre-STZ; Fig. 3g, P > 0.05 for day 62 versus pre-STZ and Supplementary Fig. 14; P > 0.05 for day 60 versus pre-STZ), and survival nephrectomy confirmed that glycemic control was attributed to the engrafted insulin-secreting cells (Fig. 3e and Supplementary Fig. 15a). Diabetic recipients of S6 cells had significantly improved glucose excursions following oral meal (Supplementary Fig. 15b, P < 0.0001) and intraperitoneal (i.p.) glucose challenges (Fig. 3h, P = 0.0008) compared with S4 recipients at 16- and 20-weeks post-transplant, respectively, presumably as a result of higher human C-peptide levels produced by S6 cells (Supplementary Fig. 15c and Fig. 3a,b,i). Moreover, at 20 weeks S6 cells showed statistically significant glucose-induced human C-peptide secretion, whereas S4 cells did not (Fig. 3i).” (Page 1125, right column, 2nd para.). Thus, a person of ordinary skill in the art before the effective filing date of claimed invention would be motivated to use Stage 6 immature beta cells in vivo for treating diabetes.
3. Applicants argue unexpected results: “In addition, and further supporting patentability is the unexpected functional efficacy following transplantation of a cell population as claimed comprising a higher proportion of more immature insulin-producing cells. See Specification as filed, Examples 4 and 5. Nothing in Rezania teaches or suggests such a cell population would result in the demonstrated functional efficacy. Thus, while Applicant is not required to demonstrate unexpected results, where, as here, there is no prima facie case of obviousness, the data of the present specification provide a separate reason for patentability” (Remarks, page10).
Response to Arguments:
As per MPEP 716.02 Allegations of Unexpected Results: Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, there is no evidence of record that specifically implanting immature insulin-producing cells would result unexpected functional efficacy over implanting immature insulin-producing cells as taught by prior art such as in the teachings of Rezania et al. Applicants argue that transplantation of higher proportion of more immature insulin-producing cells would result in unexpected functional efficacy. However, as described above, Rezania et al teach immature beta S6 insulin+ cells develop faster in vivo (see Figure 3, page 1126). Rezania et al teach transplanted S6 cells reversed STZ-induced hyperglycemia in ~8–12 weeks in three independent cohorts of diabetic mice and diabetic recipients of S6 cells had significantly improved glucose excursions following oral meal and intraperitoneal (i.p.) glucose challenges compared with S4 recipients at 16- and 20-weeks post-transplant, respectively and, at 20 weeks S6 cells showed statistically significant glucose-induced human C-peptide secretion, whereas S4 cells did not (Fig. 3i).” (Page 1125, right column, 2nd para.). Thus, a person of ordinary skill in the art before the effective filing date of claimed invention would expect implanting higher proportion of more immature insulin-producing cells in vivo would effectively treat diabetes.
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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