DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims status
Applicants reply and Dr. Yamazoe’s Declaration filed 11/14/2025 is acknowledged.
Claim 16 is/are newly added. Claims 1-3, 5, 7-16 is/are currently pending with claims 7-14 is/are withdrawn. Claims 1-3, 5, 15, 16 is/are under examination.
Claim Objections - New, necessitated by claim amendment
Claim 15 is objected to because of the following informalities: Claim recites “wherein the step of treating a cell population selected from the group consisting of the insulin-producing cell population”. Claim is amended to remove the recitation of “the pancreatic b cell population” such that the group of “a cell population” now includes only one type of cell population i.e. “of the insulin-producing cell population”.
For the sake of conciseness, following language is recommended: “wherein the step of treating
Alternatively, the claim maybe amended to recite “wherein the step (ii) .
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) - Withdrawn
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.
Rejection of Claim 1-3, 5, 15 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of claim amendments.
Claim Interpretation – Updated due to claim amendment and evidence from Declaration filed 11/14/2025
Claim 1 recites cell populations such as “an insulin-producing cell population”, and “a population of endocrine progenitor cells” and also “insulin-producing cells”.
Step-wise processes of differentiation of hPSC into pancreatic progenitors and then into endocrine progenitors and finally into cells that produce insulin i.e. beta cells like cell are known in the art (see Figure 1B in US 2014/0329704 A1). In the prior art, pancreatic progenitors, endocrine progenitors and beta cells like cell are identified by specific combination of markers. However, the specification provides the definitions analyzed below that result in broad interpretation for each of the claimed cell populations and cell types.
Step (i) requires inducing differentiation of “a population of endocrine progenitor cells” into “an insulin-producing cell population” by any means.
The specification defines “"endocrine progenitor cell population" as a cell population characterized by endocrine progenitor cells [0049]. Further indicating that the endocrine progenitor cell population is a cell population comprising endocrine progenitor cells at a proportion of at least 30% or more and may include other cells (for example, pancreatic progenitor cells, insulin-producing cells, and Ki67-positive cells), in addition to the endocrine progenitor cells [0049]. Of note, the specification does not show that the endocrine progenitor cell population used in the examples comprises at least 30% endocrine progenitor cells.
Regarding “endocrine progenitor cells”, the specification defines it as cells characterized by the expression of at least one of the markers Chromogranin A, NeuroD and NGN3 and no expression of a marker of the pancreas-related hormone system (for example, insulin). The endocrine progenitor cells may express a marker such as PAX-4, NKX2-2, Islet- 1, PDX-1, or PTF-1a [0050]. Of note, none of the endocrine progenitor cell markers (Chromogranin A, NeuroD and NGN3) were measured in any of the cell population.
Taken together, the endocrine progenitor cell population is a population of cells that comprises at least 30% cells that have differentiated into endocrine progenitor cells along with other cells including other less-differentiated cells such as Ki67-positive cells, pancreatic progenitors and more differentiated cells such as insulin-producing cells. Therefore, the endocrine progenitor cell population as claimed is not necessarily a uniform endocrine progenitor cell population but a population in the process of differentiating into a endocrine progenitor cell population comprising cells at various stages of differentiation such as Ki67-positive cells, pancreatic progenitors, at least 30% endocrine progenitors and insulin-producing cells. For example, a pancreatic progenitor population that is in the process of differentiating into an endocrine progenitor population such that at least 30% of the cells are differentiated into an endocrine progenitors meets the limitation “the endocrine progenitor cell population”.
The specification defines “Insulin-producing cell population" is a cell population comprising insulin-producing cells at a proportion of 5% or more” [0055].
Regarding insulin-producing cells, the specification defines “As used herein, "insulin-producing cells" means cells characterized in that the expression of a marker of insulin is found and the expression level of NGN3 is at a proportion of less than 1/3 of the maximum expression confirmed in endocrine progenitor cells” [0054].
Regarding “a marker of insulin”, the specification provides “"Insulin-producing cells" are cells that may express a marker of NKX6.1 and preferably express both markers of insulin and NKX6.1” [0054]. The specification does not identify the level of expression of the insulin marker required for the “insulin-producing cells” and thus the “insulin-producing cells” are interpreted to be cells that express a marker of insulin at any level.
Taken together, an insulin-producing cell population is a cell population that comprises at least 5% cells that express an insulin marker, such as NKX6.1, at any level (i.e. not required to reach mature beta-cell levels) and express lower levels of NGN3 (a marker for endocrine progenitor cells, at 1/3 level). Of note, the examples do not measure NGN3 levels in any population including the “insulin-producing cell population”. The Declaration filed 11/14/2025 does not provide the levels of insulin marker such as NKX6.1 or NGN3 in the insulin producing cells either.
The specification further states that the insulin-producing cell population “may include other cells (for example, endocrine progenitor cells; other pancreatic hormone-producing cells expressing at least one of the markers glucagon, somatostatin, and pancreatic polypeptide; and Ki67-positive cells), in addition to the insulin-producing cells” [0055]. The examples do not measure the proportion of these various cell types in the “insulin-producing cell population”.
The Declaration filed 11/14/2025 provides evidence that shows the proportion of at least “insulin-producing cells” in both “a population of endocrine progenitor cells” (=s5d2 in Figure 1 on page 8) and “insulin producing cell population” (=s6d4 or s6d7 in Figure on page 8). This evidence shows that both these populations express NKX6.1, the marker for insulin-producing cells with both comprising greater than 5% NKX6.1 positive cells. See NKX6.1 expression on y-axis – top two quadrants show NKX6.1 +ve cells.
Therefore, the insulin-producing cell population as claimed is not necessarily a uniformly mature beta-cell population but a population in the process of differentiating into a mature beta-cell population comprising cells at various stages of differentiation such as Ki67-positive cells, pancreatic progenitors, endocrine progenitors and, at least 5% insulin-producing cells that express an insulin marker at some level.
Of note, since both the population of endocrine progenitor cells and the population of insulin-producing cells comprise similar cell types (Ki67-positive cells, pancreatic progenitor cells, endocrine progenitor cells and insulin-producing cells) but the population of endocrine progenitor cells is differentiated into the population of insulin-producing cells, it is interpreted that the population of insulin-producing cells is the population at a later differentiation stage than the population of endocrine progenitor cells.
Claim Rejections - 35 USC § 102/103 – Updated due to claim amendments and evidence from Declaration filed 11/14/2025
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.
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.
Claim(s) 1, 3, 5 and 15 remains rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Yamashita-Sugahara et al (Sci. Rep. 6, 35908, October 2016; ref of record; hereinafter Yamashita) as evidenced by Vethe et al (Scientific Reports 7: 4780, July 2017; ref of record) and Ki67 antibodies from Thermo Fisher scientific (ref of record).
Yamashita teaches a method of producing mature insulin-producing cells (express insulin) that comprises exposing pancreatic progenitors to differentiation factors in the absence of FGFR1 to differentiate into endocrine progenitors (day 1-9 of differentiation) followed by exposing endocrine progenitors to 5µM PD166866, an heterocyclic FGFR1 inhibitor, to produce insulin-producing cells (same as the specific FGFR1 inhibitor of claim 5, as required for claim 3, 5) (day 10-21 of differentiation; Figure 7; Supplementary table S2, Results: High-throughput chemical screening, Materials and Methods: Pancreatic β cell differentiation from hiPSCs).
Regarding the role of FGFR1 signaling in generation of insulin-producing cells from hiPSC, Yamashita teaches that although FGFR1 activity is required for the early differentiation of pancreatic progenitors but inhibition of FGFR1 at a later stage “robustly improves pancreatic endocrine differentiation” (page 7, para 3, last sentence; Figure S3A, B; Introduction, para 3 and 4).
Therefore, Yamashita teaches a two-step differentiation method for the production of insulin producing cells wherein the population of differentiating cells at an early stage (i.e. day 1-9 of differentiation comprising pancreatic progenitors) are exposed to differentiation factors in the absence of FGFR1 inhibitor (as required for step(i)) followed by exposing the population of differentiating cells at a later stage (i.e. day 10-21 of differentiation comprising endocrine progenitors) to differentiation factors in the presence of FGFR1 inhibitor (as required for step(ii)). The cells produced by Yamashita’s method are “a population of insulin producing cells” because Yamashita shows that the cells produced by their method express INS (insulin marker) at day 21 and several populations tested showed less than 1/3 NGN3 expression at day 21 vs day 10 (Figure 2D).
Yamashita is silent regarding “a population of endocrine progenitor cells” of step (i) and “insulin producing cell population” of step (ii). The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not Yamashita’s population of differentiating cells at an early stage are same as or different, and if so to what extent, from applicant’s “a population of endocrine progenitor cells”. Similarly, The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not Yamashita’s population of differentiating cells at the later stage are same as or different, and if so to what extent, from applicant’s “insulin producing cell population” of step (ii).
However, Yamashita’s method for producing insulin-producing cells is similar to applicant’s claimed method for these reasons:
As detailed in the claim interpretation section above, based on the definitions and examples provided in the specification, both the population of insulin-producing cells and the population of endocrine progenitor cells are broadly defined and comprise similar cell types with the key distinction being that the population of insulin-producing cells of step (ii) is at a later differentiation stage than the population of endocrine progenitor cells. The claimed method exposes the population at a later differentiation stage to FGFR1 inhibitor while not exposing the population at an earlier differentiation stage to the FGFR1 inhibitor. Yamashita’s method also teaches the same.
Furthermore, Yamashita’s “pancreatic progenitors” appear equivalent to the claimed “population of endocrine progenitor cells” because they express NGN3, a marker for endocrine progenitor cells, but not INS (Figure 2D). See claim interpretation above regarding “population of endocrine progenitor cells” and “endocrine progenitor cells” and markers identified for “endocrine progenitor cells”.
Yamashita’s “endocrine progenitors” appear equivalent to the claimed “insulin-producing cell population” because at least 5% of Yamashita’s endocrine progenitors express NKX6.1 (see evidence provided in Declaration filed 11/14/2025: Figure 1). See claim interpretation above regarding “insulin-producing cell population” and “insulin-producing cells” and markers identified for “insulin-producing cells”.
Taken together, Yamashita teaches a method comprising differentiating cells that appear equivalent to claimed “population of endocrine progenitor cells” into cells that appear equivalent to claimed “insulin-producing cell population” without FGFR1 inhibitor and then exposing cells that appear equivalent to claimed “insulin-producing cell population” to FGFR1 inhibitor.
The instant specification shows that exposing differentiating cells to FGFR1 inhibitor for 11 days (same as Yamashita) reduces Ki67-positive cells to less than 1% (Table 3) and transplant in vivo to produce insulin-producing cells (Table 2). Therefore, Yamashita method inherently achieves the claimed intended result in claim 1 and 15 (to reduce Ki67-positive cells to 2% or 1% as recited in claims 1 and 15).
Where an examiner cannot determine whether or not the reference inherently possesses properties which anticipate, or render obvious, the claimed invention a rejection under §§102/103 is appropriate. See MPEP §§ 2112-2112.02.
The cited art taken as a whole demonstrates a reasonable probability that Yamashita’s cells and method is either identical or sufficiently similar to the claimed cells and method that whatever differences exist, they are not patentably significant. Critically, Yamashita provides motivating guidance regarding the role of FGFR1 signaling in generation of pancreatic endocrine cells from hiPSC, specifically teaching that FGFR1 inhibition is not desirable early on since FGFR1 signaling is required for early differentiation while FGFR1 inhibition is highly desirable later in the differentiation since it promotes b cell differentiation. Therefore, the burden of establishing novelty or non-obviousness by objective evidence is shifted to applicants. See MPEP § 2112(v). Clear evidence that method of the cited prior art does not possess a critical characteristic that is possessed by the claimed method would advance prosecution and might permit allowance of claims to applicant’s method. Applicant is requested to specifically point out the support for any amendments made to the disclosure and arguments in response to this Office Action, including the claims. See MPEP §§ 714.02 and 2163.06. Applicant is also requested to refer to pages and line numbers in the as-filed specification. It is noted that other art may be applicable under 35 U.S.C. § 102 or 35 U.S.C. § 103(a) once the aforementioned issue(s) is/are addressed.
Regarding the intended result of the method to reduce Ki67-positive cells to 2% or 1% as recited in claims 1 and 15, these results are inherent to the method disclosed by Yamashita. Yamashita discloses that their method results in generation of differentiated beta cells that display the hallmark feature of functional beta cells i.e. glucose responsiveness (Figure 5B) while Ki-67 is a well-known marker of proliferating cells (as evidenced by Ki67 antibodies from Thermo Fisher scientific). Furthermore, Vethe teaches that hiPSC-derived insulin producing cells remain functionally immature since they are not glucose responsive (Figure 4f, 4g) and concurrently express higher amount of Ki67 as compared to primary human mature islets (Figure 4h; page 7, para 3). This is distinct from the cells produced by Yamashita’s method that gain functional maturity and thus are inherently similar to the differentiated beta cells present in human mature islets with low Ki67 expression. Therefore, in disclosing a method that comprises treating insulin-producing cells with the FGFR1 inhibitor, Yamashita inherently discloses a method that results in producing a cell population comprising less than 2% or 1% Ki67-positive cells.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this section can be found in the section above.
Claim(s) 2 remains rejected under 35 U.S.C. 103 as being unpatentable over Yamashita in view of Kroon et al (Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. NATURE BIOTECHNOLOGY, VOLUME 26 ,NUMBER 4, APRIL 2008).
As noted above, Yamashita teaches the method of claim 1. Yamashita does not teach a method for transplanting insulin-producing cells in an animal to induce differentiation into a pancreatic beta cell population. However such methods are known in the art. Kroon teaches a method of transplanting human embryonic stem cell derived insulin producing cells in a diabetes mouse model (Methods: Implants). Therefore, it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to transplant the FGR1-treated insulin producing cells of Yamashita using the method of Kroon in an animal. An ordinary artisan would be motivated to transplant Yamashita’s cell in an animal to investigate its efficacy in treating diabetes. This is because Yamashita teaches that transplantation of hiPSC-derived insulin producing functional beta cells represent an important resource for treating diabetes however “pancreatic β -like cells derived from the differentiation of stem cells in vitro exhibit a limited capacity for glucose-stimulated insulin secretion (GSIS), a hallmark of functionally mature β cells” (Introduction: para 1, 3). Yamashita overcome this limitation by disclosing a method of generating hiPSC-derived insulin producing functional beta cells that are glucose-responsive (Figure 5B) and thus better suited for transplantation therapy in a diabetic patient. An ordinary artisan would reasonably expect to transplant Yamashita’s cell in Kroon’s diabetes mouse model because Kroon teaches the method for transplantation of human stem cell-derived insulin producing cells in a mouse. Furthermore, an ordinary artisan would reasonably expect that transplantation of Yamashita’s cells using Kroon’s method would induce differentiation of any immature beta-cell lineage cells into beta-cell population because Kroon shows that transplantation of immature beta-cell lineage cells (endoderm precursors) in an animal induce differentiation of these cells to acquire a mature beta-cell like phenotype (see section: Mature phenotype of hES cell–derived endocrine cells).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yamashita as applied to claim 1 above, and further in view of Maury et al (Nature biotechnology VOLUME 33 NUMBER 1 JANUARY 2015).
Yamashita anticipates and/or renders obvious the method of claim 1.
Yamashita teaches that although methods to generate pancreatic endocrine cells from hPSC were known but the a limitation in these methods were their “a limited capacity for glucose-stimulated insulin secretion (GSIS), a hallmark of functionally mature β cells” (page 2, para 1). They note that “Although the mode of action of FGFs at the early transition from DE to the PDX1+ PP stage is relatively well defined by genetic ablation studies, the regulatory role of FGFR-mediated signaling in the terminal differentiation and maturation processes of hiPSCs-derived β cells and their differentiation instability remains unclear.” (page 2, para 1).
Yamashita provides the critical teaching regarding the role of FGFR1 signaling in generation of insulin-producing cells from hiPSC. They teach that although FGFR1 activity is required for the early differentiation of pancreatic progenitors but inhibition of FGFR1 at a later stage “robustly improves pancreatic endocrine differentiation” (page 7, para 3, last sentence; Figure S3A, B; Introduction, para 3 and 4).
Regarding the intended result of claim 16, Yamashita teaches that their method results in cells with an increased insulin expression and a decreased NKX6.1 expression in comparison to cells in an otherwise identical population not treated with the FGFR1 inhibitor (Figure 5A). Critically, they teach that FGFR1 inhibition in the later stage of differentiation imparts improved glucose sensitivity to the cells generated (Figure 5B)
Yamashita does not teach the percentage of cells that express INS and NKX6.1 in comparison to cells not treated with FGFR1, produced by their method.
However optimizing hPSC differentiation protocols to efficiently derive cells of interest at a desired proportions is routine in the art.
Maury teaches that “Cell fate is controlled not only by the concentration of sig-naling molecules, but also by the time at which differentiating cells are exposed to them.” (page 90, col.2 para 2). They teach that “differentiation studies often explore only a small fraction of the large combinatorial space that should be tested to optimize conversion of hPSCs into cell types of interest” (page 89, col. 1, para 2). Thus Maury teaches that differentiation studies often explore optimization of concentration and/or timing of known molecules to optimize the results of the differentiation protocols.
They teach means to optimize the concentration and timing of extrinsic molecules used in the methods of differentiating hPSCs into desired cell types (Abstract). They exemplify their means by exposing hPSCs to various concentration of the same molecules (RA, SAG, FGF etc.) for various durations resulting in generation of cells of interest at different proportions (Figure 1, 2).
According to MPEP 2144.05 (II), “In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").” See also “Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.")”
In the instant case, Yamashita provided the critical teaching regarding the role of FGFR1 inhibition in improving pancreatic endocrine differentiation showing that exposure to FGFR1 inhibitor at a later stage of differentiation results in more robust insulin expression in the resultant cells and improved glucose sensitivity (Figure 5). An ordinary artisan is normally motivated to increase the proportion of desired cells in a method for producing said cells. Furthermore, an ordinary artisan routinely optimizes differentiation protocols by changing the concentration and/or timing of exposure of known molecules to improve the results of the differentiation protocols, such as to achieve an increased proportion of desired cells.
Therefore, in providing a critical teaching regarding the role of FGFR1 inhibition, Yamashita renders the instant claim – which requires a maintained percentage of cells that express INS and NKX6.1 in comparison to cells not treated with FGFR1- prima facie obvious. An ordinary artisan would use routine optimization to identify the optimal timing of exposure to the FGFR1 inhibitor.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in
the art at the effective time of filing of the invention, especially in the absence of evidence to the
contrary.
Response to Declaration
The Declaration of Dr. Yamazoe under 37 CFR 1.132 filed 11/14/2025 is insufficient to overcome the rejection of claims 1, 3, 5 and 15 based upon Yamashita as set forth in the last Office action.
The Declaration attempts to establish “Differences between Yamashita and the claimed method include the timing of the treatment and the composition of the cell population at the time the treatment is initiated.” (#7).
Dr. Yamazoe argue that “In Yamashita, treatment begins before the cells have differentiated and when they do not yet comprise any insulin-producing cells. In contrast, the claimed method comprises starting treatment of endocrine progenitor cells after the cells have undergone a period of induced differentiation and when they comprise insulin-producing cells.” (#7). Dr. Yamazoe point to Figures 2D in Yamashita that shows that on day 10 of differentiation, Yamashita’s cells do not express insulin (#8). Next, Dr. Yamazoe presents additional data that “measure the percentage of insulin-positive and NKX6.1-positive cells at the start of treatment in groups 1-3, as described in Example 2 of the present application” (#9; Figure 1). The data shows “the endocrine progenitor cell population in group 1 comprised almost no insulin-producing cells, which aligns with Yamashita' s result. In contrast, the endocrine progenitor cell population in group 2 or 3 comprised insulin-producing cells at a proportion of 5% or more, specifically 16.79% and 60.5%, respectively, as shown in FIG.1.” (#10). Dr. Yamazoe concludes “Yamashita does not teach or suggest the claimed method as Yamashita's method and the claimed method differs in both the timing of the treatment and the composition of the cell population at the time the treatment is initiated.” (#11). Dr. Yamazoe further concludes that “Looking at the cited references, those of ordinary skill in the art would not have had motivation to modify Yamashita based on the disclosure in any one of Vethe, Ki67
antibody, and Kroon, as none of the references provide any particular guidance to modify
the method in the manner required to arrive at the claimed method” (#13).
In response, as detailed in the claim interpretation section, the claimed “insulin -producing cells” are not limited to insulin-positive cells. The specification defines the claimed populations and cells using language that is much broader than the relied upon by Dr. Yamazoe. The data presented in Figure 1 clearly shows that group 1 which is identified as same as Yamashita’s endocrine progenitors are a population of cells that comprise at least 5% NKX6.1 positive cells. The specification only requires the "insulin-producing cells" to express a marker of insulin, identifying NKX6.1 as one of the markers [0054, 0055]. Furthermore, the specification broadly defines the population of endocrine progenitors to comprise only 30% endocrine progenitors, NGN3 identified as a marker [0049, 0050]. Yamashita shows that in their method populations of cells start NGN3 expression at day 0 (Figure 2). Thus, owing to the breadth allowed by the specific definitions provided in the instant specification, Yamashita continues to teach a method that appears to anticipate or render obvious the broadly claimed method.
Vethe, Ki67 and Kroon were not relied upon to teach the active steps of the method of claim 1.
Next, Dr. Yamazoe argues that “The Examples of the present application demonstrate the surprising advantageous effect of method as claimed, which produces a final cell population with a maintained number of insulin-producing cells while reducing the number of Ki67-positive cells.” (#15). Pointing to table 3 in the instant specification, Dr. Yamazoe state that “Compared to the control group, Yamashita's method resulted in a markedly decreased number of insulin-producing cells, while both "Present (1 μM) For last 7 days" and "Present (1 μM) For last 4 days" groups maintained the number of insulin-producing cells.” (#17). Dr. Yamazoe alleges that “Yamashita's method reduces the Ki67-positive cells at the expense insulin-producing cell numbers. In contrast, the claimed method effectively reduces the Ki67-positive cells
while maintaining the population of insulin-producing cells” (#19). Dr. Yamazoe believe that “Maintaining the population of insulin-producing cells while reducing Ki67-positive cells
is critical for translating the method into a clinical setting.” because “The human physiological
environment is a less vascularized environment than the mouse model described in Table 2 of the present application, where a relatively large number of cells were transplanted into the highly vascularized renal subcapsular space. In a less vascularized environment, such as in humans, a decrease in insulin-producing cells would adversely impact target cell engraftment and reduce treatment efficacy” (#20).
In response, the intended result argued i.e. maintenance of the insulin-producing cell number in comparison to an non-FGFR1 inhibitor group is presented in the new claim 16 and is addressed above in a U.S.C. 103 rejection over Yamashita in view of Maury. Of note, the instant specification quantifies the number of INS+NKX6.1 positive cell numbers as the resultant measure while Yamashita quantifies the expression level of INS and the glucose-responsivity of the cells produced. Although, it may appear that Yamashita’s method results in fewer INS+NKX6.1 positive cell (per Table 3 in the instant specification), Yamashita clearly shows an increases insulin expression and glucose-responsivity of the cells produced. Critically, as noted in the U.S.C. 103 rejection of claim 16, Yamashita provides the critical teaching regarding the dualistic role of FGFR1 in beta cell differentiation; specifically teaching that FGFR1 activation is required in the early stages while later stages benefit from FGFR1 inhibition. Optimizing the timing of FGFR1 inhibition to achieve a higher percentage of the desired beta cells using routine methods cannot be considered inventive.
Regarding Dr. Yamazoe’s claims regarding the “vascularized environment”, no evidence is provided that human physiological environment is uniformly less vascularized compared to mice such that a sufficiently vascularized site is not available in humans or that vascularization levels are expected to impact target cell engraftment and reduce treatment efficacy.
Response to Arguments
Applicant's arguments filed 11/14/2025 regarding the U.S.C. 102/103 rejection of claims 1, 3, 5, 15 have been fully considered but they are not persuasive.
First Applicant argue that “The Cited References Do Not Teach or Suggest the Claimed Method of Producing an Insulin-Producing Cell Population” (page 8). Applicant point to #7 and #8 in Dr. Yamazoe’s declaration wherein Dr. Yamazoe argues that Yamashita treats cells with FGFR1 inhibitor before “any insulin-producing cells” (page 8, last para; page 9, para 1). Applicant also point to additional data provided in the declaration to show that cells exposed to FGFR1 inhibitor are insulin producing cells and Dr. Yamazoe’s argument in #9 and #10 (page 9, para 2, 3). Finally, pointing #13 in the declaration, Applicant argue that “In view of the teachings of Yamashita, Vethe, Ki67 antibody, and Kroon, Ms. Yamazoe explains why one of ordinary skill in the art would not have been motivated to modify the method disclosed in Yamashita to arrive at the claimed method.”
In response, the #7, #10 and #13 arguments in the declaration were not persuasive and are addressed above. Briefly, the claimed “insulin-producing cells” are not limited to cells that express insulin. The evidence presented in the declaration (Figure 1) support that Yamashita cells express NKX6.1 before FGFR1 inhibition i.e. are equivalent to the claimed “insulin-producing cells” based on the definitions in the specification (see claim interpretation for additional analysis).
Proper recitation of specific markers for each claimed cell population, in line with the prior art, and exact timing of FGFR1 inhibition maybe remedial. However, care must be taken that the written description support is present in the instant specification. Of note, very few markers were measured for each of the cell populations produced. The markers relied upon in the definitions, for example NGN3 etc., were not measured.
Next Applicant argue that “Only the Presently Claimed Invention Successfully Produces an Insulin-Producing Cell Population as Claimed” (page 10). Applicant allege “unexpected advantage” of the claimed method in that it “produces a final cell population with a maintained number of insulin-producing cells while reducing the number of Ki67-positive cells: (page 10, last para). Applicant point #16-18 in the declaration wherein Dr. Yamazoe alleged that “the cells present at the initiation of FGFR1 inhibitor treatment in Yamashita are materially different from those in the present application, due to differences in the timing at which treatment is commenced” pointing to results in Table 3 of the instant specification (page 11). Applicant also point to #20, 21 in the declaration wherein Dr. Yamazoe alleged that “maintaining the population of insulin-producing cells while reducing Ki67-positive cells is critical for translating the method into a clinical setting," and "the present invention was the first study to demonstrate the claimed method, which shows strong potential for clinical relevance and therapeutic efficacy." and such results "could not have been predicted or expected from the cited references." (page 12).
In response, the #16-18, #20-21 arguments in the declaration were not persuasive and are addressed above. Briefly, based on the evidence provided in the declaration, the cells present at the initiation of FGFR1 inhibitor treatment in Yamashita appear equivalent to the claimed “insulin-producing cell population” (see claim interpretation for analysis of the claimed breadth). Furthermore, as detailed in the response to Dr. Yamazoe’s arguments and the U.S.C. 103 rejection of claim 16, Yamashita provides the critical teaching regarding the dualistic role of FGFR1 in beta cell differentiation; specifically teaching that FGFR1 activation is required in the early stages while later stages benefit from FGFR1 inhibition. Optimizing the timing of FGFR1 inhibition to achieve a higher percentage of the desired beta cells using routine methods cannot be considered inventive.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATASHA DHAR whose telephone number is (571)272-1680. The examiner can normally be reached M-F 8am-4pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras Jr. can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MATASHA DHAR/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632