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 .
Applicant's arguments and amendments to claims filed on 07-28-2025 have been received and entered. Claim 1 has been amended. Claim 3, 11-20 have been canceled. Claims 1-2, 4-10, 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Claims 21-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim.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 1-2, 4-10 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.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)- (d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CPR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 04-10-2025 is in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statement has been considered by the examiner
Withdrawn-Double Patenting
Claims 1-2, 4-10 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 15 of copending Application No. 17049218 (reference application). In view of Applicants' amendment of base claim 1, introducing the limitation “chromogranin A-positive cells at a proportion of 90% or more” the previous rejections of claims are hereby withdrawn. Applicants' arguments with respect to the withdrawn rejections are thereby rendered moot.
New-Claim Rejections - 35 USC § 112 (d) - necessitated by amendments
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 6 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 because claim 6, which is depending on claim 1, recites the phrase “comprising chromogranin A-positive cells at a proportion of more than 45%”. However, the base claim 1 recite the phrase “chromogranin A-positive cells at a proportion of 90% or more”. Claim 6 contain a reference to a previous claim 1 but does not specify a further limitation of the subject matter claimed. Thus, claim 6 encompasses embodiments that are outside the scope of claim 1 so that claim 6 does not satisfy the requirements of the 35 U.S.C. 112(d).
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.
Maintained in modified form-Claim Rejections - 35 USC § 101 - necessitated by amendments
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
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.
Claim interpretation:
Claim 1 is directed to a cell population comprising insulin-producing cells obtained by inducing the differentiation of a single population of pluripotent stem cells 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).
Step 1: Is the claim to a process, machine, manufacture or composition of matter?
Claim 1 is directed to a cell population comprising insulin-producing cells, which is obtained by inducing the differentiation of a single population of pluripotent stem cells and comprises: insulin-positive and NKX6.1-positive cells at a proportion of 30% or more; and insulin-positive and NKX6.1-negative cells at a proportion of more than 15%; and Ki67-positive cells at a proportion of less than 3% and chromogranin A-positive cells at a proportion of 90% or more. Claim 2 specifies an expression level of a MafA gene or a gene product thereof is lower than an expression level of a MafA gene or a gene product thereof. Claim 4 specifies the population further comprise glucagon-positive and insulin-negative cells at a proportion of less than 3% in a pancreatic islet. Claim 5 specifies the insulin-producing cells exhibit glucose-stimulated insulin secretion (GSIS) response. Claim 6 specifies the population further comprises chromogranin A-positive cells at a proportion of more than 45%. Claim 7 specifies the population further comprises alkaline phosphatase-positive pluripotent stem cells at a proportion of less than 0.01 %. Claim 8 is directed to a medicament comprising the cell population comprising insulin producing cells according to claim 1. Claim 9 specifies the cell population comprising insulin-producing cells are accommodated in a device. Claim 10 specifies the cell population comprise insulin-producing cells are dispersed in a hydrogel.
Under the broadest reasonable interpretation, the terms of the claim are presumed to
have their plain meaning consistent with the specification as it would be interpreted by one of
ordinary skill in the art. See MPEP 2111. Broadest reasonable interpretation of the claims encompasses a cell population comprising insulin-producing cells that comprise insulin-positive and NKX6.1-positive cells at a proportion of 30% or more; and insulin-positive and NKX6.1-negative cells at a proportion of more than 15%; and Ki67-positive cells at a proportion of less than 3% and chromogranin A-positive cells at a proportion of 90% or more. Thus, insulin-positive and NKX6.1-positive cells can be interpreted at a proportion of 30% to 100%, insulin-positive and NKX6.1-negative cells can be interpreted at a proportion of 15%-100%, and Ki67-positive cells can be interpreted at a proportion of 0 - 3%, and chromogranin A-positive cells at a proportion of 90% - 100%. Because insulin-positive and NKX6.1-positive cells, insulin-positive and NKX6.1-negative cells and Ki67-positive cells are composed of matter. The claims are to at least one statutory category of invention (Step 1: YES).
Step 2(A), Prong 1: Does the claim recite an abstract idea, law of nature or natural phenomenon?
Claims 1-2, 4-10 are then analyzed to determine whether the therapeutic composition is directed to a judicial exception. In the instant case, Claims 1-2, 4-7 are directed to a cell population comprising insulin-producing cells. Claim 8 recites a medicament comprising the cell population comprising insulin producing cells so that claim 8 is directed to a cell population comprising insulin producing cells as cells alone could be used as medicament. Claim 9 specifies a device to accommodate the cell population. Claim 10 specifies the cell population are dispersed in a hydrogel. Thus, the claims recite nature-based product limitations of cell population comprising insulin-producing cells. The claims also recite a device and a hydrogel which are a generic container to maintain and deliver said nature-based product limitations; however, the device and hydrogel would not be subject to the markedly different characteristics analysis as they are not nature-based products, but would be evaluated as additional elements in Prong Two (and Step 2B). See, e.g., Funk Bros. Seed Co. v. Kala Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280,281 (1948).
The markedly different characteristics analysis is performed by comparing the nature-based product limitation of cell population comprising insulin-producing cells in the claim to its naturally occurring counterpart of stem cell differentiated population comprising insulin-producing cells to determine if it has markedly different characteristics from the counterpart. MPEP 2106.04(c) (II). Rezania et al (Nature Biotechnology Volume 32 Number 11, November 2014, doi:10.1038/nbt.3033) teach differentiation of stem cell into insulin-producing cells (Abstract): Regarding claim 1, Rezania et al teach 51.4% of insulin-positive and NKX6.1-positive cells in Supplementary Figure 9 and 27.9% of insulin-positive and NKX6.1-negative cells was obtained from a sixth-stage culture in Supplementary Figure 10. Rezania et al teach Ki67-positive cells at a proportion of less than 3% (S6 D14) (Figure 1c, page 1122). It is noted that claim 1 recites Ki67-positive cells at a proportion of less than 3%, thus under the broadest reasonable interpretation Ki67-positive cells proportion in the claim can be interpreted to be zero to satisfy the claim.
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Furthermore, 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 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 the instant claim 1 requires both “NKX6. l-positive cells” and “NKX6. l-negative cells”.
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Regarding claim 2, Rezania et al teach expression level of MafA gene is lower than an expression level of a MafA gene in a pancreatic islet (Figure 1b, page 1122). 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), and under the broadest reasonable interpretation glucagon-positive and insulin-negative cells proportion in the claim can be interpreted to be zero to satisfy the claim. Regarding claim 5, Rezania et al teach Stage (S) 7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro (Abstract). Regarding claim 6, Rezania et al teach chromogranin A-positive cells at a proportion of more than 45%. Regarding to claim 7, Rezania et al teach the population of cells in supplementary Figure 9, 10 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 under the broadest reasonable interpretation, alkaline phosphatase-positive pluripotent stem cells proportion in the claim can be interpreted to be zero to satisfy the claim. Thus, the claimed cell population comprising insulin-producing cells are genetically, chemically and structurally similar to natural occurring stem cells derived cell population comprising insulin-producing cells.
Taken together, since there is no limitation to set apart the claimed cell population comprising insulin-producing cells, it appears that the claimed therapeutic composition comprising growth factor concentrates, peripheral blood stem cells, and additional therapeutic agent are identical to what exists in nature (e.g., same structure, same chemical composition and phenotype).
Step 2(A), Prong 2: Do the claims recite additional elements that integrate the judicial exception into a practical application?
In view of foregoing analysis, it is apparent that claim recites a judicial exception of cell population comprising insulin-producing cells, they would still be patent-eligible if the claim as a whole integrates the recited judicial exception into a practical application of the exception. Here, Claims 1-7 are directed to cell population comprising insulin-producing cells without limitation to set them apart from natural occurring stem cells derived cell population comprising insulin-producing cells, and there is no limitation to integrates the recited judicial exception into a practical application. Claim 8 recites “a medicament”. However, the term “medicament” in claim 8 is interpreted as intended use of the cell population comprising insulin producing cells. The claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claims patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430,433 (CCPA 1977). Claim 9 specifies the cell population comprising insulin-producing cells are accommodated in a device, and claim 10 specifies the cell population comprising insulin-producing cells are dispersed in a hydrogel. However, holding natural occurring products together with a device or a hydrogel does not integrate the judicial exception into a practical application because keeping natural occurring products together with a device or a hydrogel is a generic concept of containing/delivering cell population: Wang et al (Current Opinion in Colloid & Interface Science 2018, 38:135–157, doi:10.1016/j.cocis.2018.10.010) teach some hydrogel based encapsulation systems that harbor porcine or human islets and embryonic stem cell-derived islet cells have been applied to clinical trials to treat T1D. Alginate-based microcapsules were used to encapsulate porcine islets and successfully reduced the insulin injection in T1D patients (Page 147, left column, 2nd para). A hydrogel-based encapsulation device should create an environment that features 1) an adequate blood supply and 2) physiological insulin secretion in response to blood glucose levels in a sensitive manner (Page 145, right column, 1st para.). Thus, keeping natural occurring products together with a device or a hydrogel does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claims are more than a drafting effort designed to monopolize the judicial exception.
In summary, there are no additional elements recited in the claims, considered individually or in combination, that integrate the recited cell population comprising insulin-producing cells into a practical application of the judicial exception and the claims are therefore directed to the judicial exception (Step 2A Yes).
Step 2(B): Does the claim recite additional elements that amount to significantly more than the judicial exception?
The claims as a whole do not include additional elements that are sufficient to amount to significantly more than the judicial exception of the recited cell population comprising insulin-producing cells (as recited in claims 1-2, 4-7 ). The use of the recited cell population as medicament in claim 8 well-understood, routine, and conventional activity in the art because insulin-producing cells have been known for its ability to treat diabetes in the art. They do not, individually or in combination, provide sufficient inventive concept to render the claims patent eligible. Further, the element other than the judicial exception includes a device or a hydrogel (claims 9-10). As mentioned above, the cited reference Wang et al hydrogel-based encapsulation systems that harbor porcine or human islets and embryonic stem cell-derived islet cells have been applied to clinical trials to treat T1D (Page 147, left column, 2nd para). Thus, keeping the product of nature together with a device or a hydrogel for delivery is not sufficient to transform a judicial exception into a patent eligible invention. Even when considered in combination with the other additional elements, the use of a device or a hydrogel does not amount to an inventive concept because the act of placing natural products together with a device or a hydrogel describes a well-understood, routine, and conventional activity.
In summary, the additional elements (e.g., a device or a hydrogel) are generic components that do not amount to significantly more than the judicial exception of “product of nature” itself. Thus, the claim does not qualify as patent eligible subject matter. (Step 2B: NO).
Response to Arguments
Applicant's arguments filed on 07-28-2025 have been fully considered but they are not persuasive.
1. Applicant argues that Rezania teach that naturally occurring insulin producing cell populations consist of chromogranin A-positive cells having a proportion that is substantially less than 90%. See Rezania FIG. ID. Accordingly, the claimed population of cells possesses markedly different characteristics from allegedly naturally occurring cell populations - namely chromogranin A-positive cells at a proportion of 90% or more (Remarks, page 6).
Response to Arguments:
As explained above, 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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It should be noted that the specification of the claimed invention teaches similar proportion of chromogranin A-positive cells : Table 7 and Figure 8 show results of measurement of proportions of chromogranin A-positive rates ([0256] page 123) with proportion of chrornogranin A of 96.2 % positive cells (Table 7, [0257] page 123-124). Figure 8 show 96.2 % positive cells : 32.3% + 63.9% = 96.2 %.
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2. Applicant argues that :
The claimed cell population includes a proportion ofNKX6. l, Ki67, and chromogranin A-positive cells that is markedly different than anything found in nature. Moreover, the structural and functional properties of the claimed cell population result in a cell population with higher purity that consumes less nutrients, allowing for therapeutic effects with a smaller number of cells or under low-nutrient conditions.
The markedly different structural and functional properties of the claimed cell population are apparent when analyzing blood glucose normalization following transplantation of the cell population. While the cell population allegedly disclosed in Rezania has demonstrated normalization of blood glucose levels after three months of transplantation under the highly vascularized kidney capsule (see Rezania, at Figure 3g and Figure 7c), the cells of the present invention have achieved blood glucose normalization after three months of subcutaneous transplantation (a site generally considered to have lower vascularity). Applicant's Specification, at Example 4 (Remarks, page 6-7).
Response to Arguments:
Rezania et al reference provide evidence that chromogranin A-positive cells can be obtained by naturally differentiation process. The claimed cell population includes a proportion of NKX6. l, Ki67, and chromogranin A-positive cells that is not markedly different than product of nature. Applicant’s arguments regarding “higher purity that consumes less nutrients” is not persuasive because there is no evidence showing comparison of nutrient consumption resulted from cell purity, and there is no evidence showing how significant/ markedly different it is between the claimed cell population and product of nature.
Also, as applicant admitted, Rezania et al has demonstrated normalization of blood glucose levels after three months of transplantation, and the cells of the present invention have achieved blood glucose normalization after three months of subcutaneous transplantation. Thus, the cell populations are having similar functions, and lower or high vascularity can be variable due to the site of transplantation or route of administration methods. Thus, it is not persuasive that the cells of the present invention are markedly different.
3. Applicant argues that :
The markedly different characteristics of the claimed cell population is further evidenced by Verhoeff et al., 2022, hereby submitted with this response as Exhibit A. As provided in Verhoeff et al., naturally occurring cell populations are of low purity and include exocrine cells (non-chromogranin A-expressing cells). See Exhibit A, at page 99, left column ("Furthermore, islet transplants, although purified, typically still have substantial contamination by pancreatic exocrine tissue components, and even purified islet preparations remain only 30% to 50% pure."). Chromogranin A-expressing cells were found to demonstrate no expression of ABH antigen, which can lead to immune rejection. Id at page 102, right column. However, cells lacking expression chromogranin A continue to express ABH antigens, resulting in cell populations that are likely to encounter immune rejection following transplantation. These cells express ABO antigens, resulting in a higher likelihood of immune rejection. Thus, the present invention provides a higher-purity cell population that is less likely to be rejected, representing a significant advantage over naturally occurring cell populations (remarks, page 7s).
Response to Arguments:
Applicant stated that “islet transplants, although purified, typically still have substantial contamination by pancreatic exocrine tissue components, and even purified islet preparations remain only 30% to 50% pure”; however, the claim 1 recites the term “comprises”, and according to MPEP 2111.03 (I): The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) ("[L]ike the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended."). Further, the claims do not specify any degree of purity, and, as described above, the cell population as taught by Rezania et al which is derived from naturally differentiation process satisfies all required limitations : “insulin-positive and NKX6. l-positive cells at a proportion of 30% or more; and insulin-positive and NKX6. l-negative cells at a proportion of more than 15%; and Ki67-positive cells at a proportion of less than 3%; and chromogranin A-positive cells at a proportion of 90% or more.”. These limitations do not distinguish or show markedly different between the cells of the present invention and product of nature.
Applicant stated that “the present invention provides a higher-purity cell population that is less likely to be rejected, representing a significant advantage over naturally occurring cell populations”; however, it cannot exclude the fact that naturally occurring cell populations can also be used for transplantation. With the claim currently written, there is no markedly different between the claimed population and naturally occurring cells.
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 1-2, 4-7 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 51.4% of insulin-positive and NKX6.1-positive cells in Supplementary Figure 9: Co-expression of insulin and NKX6.1 in stage 4 versus stage 6. Rezania et al teach 27.9% of insulin-positive and NKX6.1-negative cells was obtained from a sixth-stage culture in Supplementary Figure 10: Characterization of iPSC-derived stage 6 cells. 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 resulting in populations with insulin-positive and NKX6.1-positive cells at a proportion of 30% or more; and insulin-positive and NKX6.1-negative cells at a proportion of more than 15%; 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.
Furthermore, 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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Regarding claim 2, Rezania et al teach expression level of MafA gene is lower than an expression level of a MafA gene in a pancreatic islet (Figure 1b, page 1122).
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 teach Stage (S)7 cells expressed key markers of mature pancreatic beta cells, including MAFA, and displayed glucose-stimulated insulin secretion similar to that of human islets during static incubations in vitro (Abstract)
Regarding claim 6, Rezania et al teach chromogranin A-positive cells at a proportion of more than 45%. (Figure 1d, Page 1122).
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 does 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 07-28-2025 have been fully considered but they are not persuasive.
Applicant argues that
Claim 1 is amended to recite wherein the population comprises chromogranin Apositive cells at a proportion of 90% or more. As described above, Rezania does not teach or suggest a cell population having a proportion of cells expressing the claimed percentage of NKX6. l, Ki67, and chromogranin A. Moreover, because of these markedly different structural features, the claimed cell population demonstrates superior therapeutic efficacy with regard to glucose normalization following subcutaneous transplantation. See Rezania, at Figure 3g and Figure 7c; see also Applicant's Specification, at Example 4 (remarks, page 8).
The cited references fail to teach or suggest a cell population having insulinpositive and NKX6. l-positive cells at a proportion of 30% or more, insulin-positive and NKX6. l-negative cells at a proportion of more than 15%, Ki67-positive cells at a proportion of less than 3%, and chromogranin A-positive cells at a proportion of 90% or more. Moreover, one of skill in the art would not have conceived of inducing the differentiation of a single population of pluripotent stem cells in order to produce a cell population having superior purity and functional characteristics with any reasonable expectation of success. Specifically, one of skill in the art could not have expected a cell population produced by inducing the differentiation of a single population of pluripotent stem cells with superior expression of chromogranin A and having reduced potential for rejection based on the cited references (remarks, page 9).
Response to Arguments:
As described above, the cell population as taught by Rezania et al satisfies all required limitations “insulin-positive and NKX6. l-positive cells at a proportion of 30% or more; and insulin-positive and NKX6. l-negative cells at a proportion of more than 15%; and Ki67-positive cells at a proportion of less than 3%; and chromogranin A-positive cells at a proportion of 90% or more.”. Thus, the cell population as taught by Rezania et al is expected to be functionally and structurally similar to the claimed cell population. Further, Rezania et al stated that “Islet cell transplantation can achieve superior glucose homeostasis compared with insulin therapy …… We and others have developed multistep protocols based on developmental paradigms to differentiate hESCs into pancreatic progenitor cells capable of maturation in vivo. Pancreatic progenitor cells can produce glucose-responsive, insulin-secreting cells and prevent or reverse diabetes in mice several months after transplantation” (Page 1121, left column, 1st para.), and “The resulting 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.).
Applicant also cited Rezania et al at Figure 3g and Figure 7c and Applicant's Specification, at Example 4 to state “superior therapeutic efficacy with regard to glucose normalization following subcutaneous transplantation”. In the instant case, Rezania et al stated that “In STZ-induced diabetic mice, ….. S6 cells reversed STZ-induced hyperglycemia in ~8–12 weeks in three independent cohorts of diabetic mice” (page 1125, right column, 2nd para and fig 3g.) and “at 16 d post-transplant into STZ-diabetic mice, blood glucose levels were reduced to levels that were not significantly different (P > 0.05) from pre-STZ levels, and normal fasting blood glucose levels were reached by 40 d post-transplant (Fig. 7c)” (page 1131, left column, last para., and Fig. 7c). Additionally, Applicant's Specification, at Example 4 teaches that “For any animal and transplantation site, human C-peptide was detected in blood 3 to 4 months after transplantation. In the mice, high blood glucose was improved in 3 months after transplantation” ([0248], page 119), and “insulin producing cells transplanted in the living body achieve long-term graft survival and exert physiological insulin regulating action similar to that of the endogenous pancreatic islet in response to the variation of the blood glucose level.” ([0251], page 121). Thus, it appears both populations display therapeutic effects after around 3 months and there is no unexpected/superior over prior arts.
The expression of chromogranin A from population of Rezania et al can be found above, 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 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 %.
Conclusion
No claim is 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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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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