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 .
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 6/26/2026 has been entered.
Claims status
Claims 1-3, 5, 7-16 is/are currently pending with claims 7-14 is/are withdrawn.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.
Withdrawn Objections
The objections presented herein represent the full set of objections currently pending in this application. Any objections not specifically reiterated are hereby withdrawn.
Claim Interpretation – Updated due to claim amendments
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 Melton, US 2014/0329704 A1; ref of record). 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.
These are now combined with the newly added claim limitation regarding “population of endocrine progenitors” and “insulin-producing cells”.
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.
The claim is amended to recite that the endocrine progenitor cell population comprises less than 5% insulin-producing cells, further reciting that insulin-producing cells express NKX6.1 and one other marker for these cells. The claims do not recite any additional markers.
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 and also includes other less-differentiated cells such as Ki67-positive cells, pancreatic progenitors and more differentiated cells such as insulin-producing cells, as long as the insulin-producing cells are less than 5%. 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 comprising cells at various stages of differentiation such as Ki67-positive cells, pancreatic progenitors, at least 30% endocrine progenitors and less than 5% insulin-producing cells. For example, a pancreatic progenitor population that is in the earlier stages in the process of differentiating into an endocrine progenitor population such that about 30% of the cells are differentiated into an endocrine progenitors but very few, such as 0-5%, of these endocrine progenitors have further differentiated into “insulin-producing cells”.
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].
The claim is amended to recite that the insulin-producing cells express at least two markers, one is NKX6.1 and any additional marker.
Regarding “a marker of insulin”, the specification does not provide any specific definition or a specific list of markers. It states “Insulin-producing cells" are cells that may express a marker of NKX6.1 and preferably express both markers of insulin and NKX6.1” [0054].
Taken together, an insulin-producing cell population is a cell population that comprises at least 5% cells that express two markers of insulin, NKX6.1 and any other marker of insulin, 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 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”.
Therefore, the insulin-producing cell population as claimed is not necessarily a uniformly mature beta-cell-like population but a population in the process of differentiating into a mature beta-cell-like 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 two insulin markers 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
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.
Rejection of Claim(s) 1, 3, 5 and 15 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) is withdrawn in light of claim amendments.
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.
Rejection of Claim(s) 2 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) is withdrawn due to withdrawal of rejection it relied upon.
Rejection of Claim(s) 16 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) is withdrawn due to withdrawal of rejection it relied upon.
Claim(s) 1, 3, 5, 15, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Yamashita-Sugahara et al (Sci. Rep. 6, 35908, October 2016; ref of record; hereinafter Yamashita) in view of Maury et al (Nature biotechnology VOLUME 33 NUMBER 1 JANUARY 2015; ref of record) as evidenced by Melton et al (US 2014/0329704 A1; Nov. 6, 2014; 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 and function in a glucose responsive manner; Figure 5A, 5B) 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 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). Additionally, Yamashita shows that exposure to the FGFR1 inhibitor early in the differentiation process is detrimental to the final product, inhibiting production of insulin producing cells (Figure S3). Yamashita note that it was known in the art that FGFR1 signaling is vital for the differentiation into pancreatic progenitors (page 7, para 2) such that inhibiting FGFR1 too early would inhibit this early stage of differentiation.
Yamashita does not explicitly identify if their pancreatic progenitors are same as the claimed “population of endocrine progenitor cells” and comprise less than 5% cells that express NKX6.1 and another marker of insulin, nor do they identify if their endocrine progenitors are same as the “insulin-producing cell population” and comprise at least 5% cells that express NKX6.1 and another marker of insulin (as recited in claim 1).
However, Yamashita’s “endocrine progenitors” at day 10, when FGFR1 inhibitor is added, comprise at least 5% cells that express NKX6.1 (see evidence provided in Declaration filed 11/14/2025: Figure 1). Further, Yamashita shows that at day 10 cells express PDX1, another marker for insulin producing cells known in the art, as evidenced by Melton ([0238] identifying both NKX6.1 and PDX1 as markers). See claim interpretation above regarding “insulin-producing cell population” and “insulin-producing cells” and markers identified for “insulin-producing cells”.
Further, since cells before day 10 are expected to be less differentiated than the cells at day 10, Yamashita’s pancreatic progenitors are expected to comprise fewer cells in the advanced stage of differentiation, such as the claimed “insulin-producing cells”. See claim interpretation above regarding “population of endocrine progenitors cells” above and its relation to the “insulin-producing cell population”.
As detailed in the claim interpretation section above, based on the amendments, definitions and examples provided in the specification, both the population of insulin-producing cells and the population of endocrine progenitor cells 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, comprising greater i.e. at least 5% cells that are more differentiated i.e. the “insulin-producing cells” than the population of endocrine progenitor cells that comprise less than 5% of these more differentiated 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 does not teach the recited intended results in the claimed method i.e. percentage of cells that express Ki67, INS and NKX6.1 in comparison to cells not treated with FGFR1, produced by their method (as recited by claims 1, 15, 16).
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 while exposure to FGFR1 inhibitor too early is detrimental because it would inhibit the production of pancreatic progenitors, a required intermediary for the production of insulin-producing cells (Figure 5, S3). An ordinary artisan is normally motivated to increase the proportion of desired cells, such as insulin producing cells or INS and NKX6.1 positive cells, in a method for producing said cells while reducing the proportion of undesired cells, such as Ki67 which is a well-known marker of proliferating cells (as evidenced by Ki67 antibodies from Thermo Fisher scientific).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, as taught by Maury.
Therefore, in providing a critical teaching regarding the role of FGFR1 inhibition, Yamashita renders the instant claim – which the recites the intended results of a maintained percentage of cells that express INS and NKX6.1 in comparison to cells not treated with FGFR1 while reducing the proportion of undifferentiated Ki67 positive cells- prima facie obvious. An ordinary artisan would use routine optimization to identify the optimal timing of exposure to the FGFR1 inhibitor such as to at least maintain the cells that express INS and NKX6.1 while reducing the cells that express Ki67.
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) 2 is rejected under 35 U.S.C. 103 as being unpatentable over Yamashita in view of Maury et al (Nature biotechnology VOLUME 33 NUMBER 1 JANUARY 2015; ref of record) as evidenced by Melton et al (US 2014/0329704 A1; Nov. 6, 2014; ref of record), and Ki67 antibodies from Thermo Fisher scientific (ref of record) as applied to claim 1, further in view of Kroon et al (NATURE BIOTECHNOLOGY, VOLUME 26 ,NUMBER 4, APRIL 2008; ref of record).
As noted above, Yamashita, in view of Maury, 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.
Response to Arguments
Applicant's arguments filed 6/4/2026 regarding the U.S.C. 102/103 rejection of claims 1, 3, 5, 15 have been fully considered but are moot because of new grounds of rejection necessitated by claim amendments.
Arguments pertinent to instant rejection are addressed below.
First, Applicant allege that “Under the Examiner's interpretation, the endocrine progenitor cell population could already contain significant numbers of insulin-producing cells at the outset, thereby collapsing the distinction between the starting material of step (i) and the output of step (i).” and the newly added wherein clauses “forecloses this interpretation”. (page 7)
To clarify, based on the claim interpretation presented in the last OA and the instant OA, the endocrine progenitor cell population was not interpreted to contain “significant” number of insulin-producing cells and a clear distinction between the starting population of step (i) and output of step (i) was identified. Although it was noted that the claimed endocrine cell population was not uniform such that it comprised at least 30% endocrine progenitor cells but also some insulin-producing cells, this did not lead to an interpretation that this population comprised “significant” number of insulin-producing cells (page 4, para 3). Specifically, it was noted that the output of step (i) i.e. the insulin-producing cell population was required to comprise at least 5% or more insulin-producing cells (page 4, para 4). Most importantly, it was clearly identified that the starting population of step (i) i.e. the endocrine progenitor cell population was at an earlier stage of differentiation in comparison to the output of step (i) i.e. the insulin producing cell population.
Regarding Yamashita, Applicant allege that “Yamashita's Figure 2D demonstrates that at day 10, the cells do not express insulin. This means that Yamashita begins FGFR1 inhibitor treatment when the cell population does not yet comprise insulin producing cells, let alone an "insulin-producing cell population" within the meaning of the claims.” and thus “Yamashita's method […] cannot anticipate or render obvious a method that expressly requires the FGFR1 inhibitor treatment to begin only after differentiation has produced a population comprising 5% or more insulin-producing cells.” (page 8, para 3). Similarly, Applicant argue that “There is no evidence in Yamashita that the cells at day 10 -when FGFR1 inhibitor treatment begins - express any marker of insulin in addition to NKX6.1.” (page 9-10, bridging para) and “Yamashita's pancreatic progenitors express NGN3, they cannot be equated with the claimed endocrine progenitor cell population unless it is also established that they comprise less than 5% insulin-producing cells” (page 9, para 2). Finally, Applicant argue that Yamashita does not provide “any motivation to modify the method in a manner required to arrive at the claimed invention.” (page 10, para 1)
In response, the claims do not require the insulin-producing cells to express insulin. Even the most recent amendment only requires expression of NKX6.1 and any other marker of insulin-producing cells, not insulin itself. Melton provides markers of insulin-producing cells, identifying PDX1. Yamashita shows PDX1 expression at day 10 (Figure 2D). Evidence provided in Declaration filed 11/14/2025 (Figure 1) showed that Yamashita’s cells express NKX6.1 at day 10. Thus, amendment does not clearly distinguish Yamashita’s day 10 population from the claimed starting population of step (ii) that is exposed to FGFR1 inhibitor.
Regarding the Yamashita's pancreatic progenitors, this population of cells is less differentiated than the subsequent population i.e. that of endocrine progenitors. Thus, although Yamashita does not explicitly show if their pancreatic progenitors comprise less than 5% insulin-producing cells, the expectation is that the less differentiated cell population would comprise less cells in the advanced stage of differentiation.
Of note, this argument regarding pancreatic progenitors is unclear because, on the one hand, Applicants appear to be arguing that Yamashita’s endocrine progenitors are not differentiated enough in comparison to the claimed insulin-producing cell population but also that Yamashita’s pancreatic progenitors may be too differentiated thus potentially comprising more than 5% insulin-producing cells.
Finally regarding motivation to modify, 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. “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 “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.")”
Finally, Applicant argue unexpected results pointing to table 3 of example 2 where “treatment from the start reduced these cells of interest to only 45 ± 15% of the untreated control, whereas treatment for the last 7 or 4 days maintained them at 88 ± 13% and 91 ± 16%, respectively” (page 10, para 2). Applicant allege that “Yamashita's teaching - that FGFR1 inhibition "robustly improves pancreatic endocrine differentiation" - gives no indication that the timing of FGFR1 inhibitor treatment within the insulin-producing cell production step would dramatically alter the retention of insulin-producing cells. To the contrary, Yamashita' s teaching that FGFR1 inhibition promotes beta cell differentiation would lead a person of ordinary skill to expect that earlier treatment would yield equivalent or even superior results, not the marked decrease in insulin-positive and NKX6.1-positive cells observed in the "Present (1 μM) From start" group in Example 2.”
In response, 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 (MPEP 716.02). Further, Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. (MPEP 716.02(c).
As noted above, optimizing the timing of inclusion of known factors, such as FGFR1 inhibitor, to achieve a higher percentage of the desired cells is routine. No evidence is provided that the expectation in the art was that when changing the timing of exposure to an active agent, the resultant cell population would remain unchanged. On the contrary, the art taught that timing of exposure to an active agent should be optimized to change the proportions of the resultant cell population (see Maury). Yamashita also changed the timing of exposure to FGFR1 and showed that early exposure is detrimental (Figure S3).
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. Based on Yamashita’s teachings, contrary to Applicant’s allegation, a person of ordinary skill would expect that earlier treatment would not yield equivalent let alone superior results. This is because earlier treatment would inhibit generation of pancreatic progenitors. On the other hand, an ordinary artisan would delay the FGFR1 introduction so as to generate as many pancreatic progenitors as possible before starting the next phase of the differentiation. This is because pancreatic progenitors are the cells that differentiate into endocrine progenitors and finally into cells that produce insulin. Promoting complete generation of pancreatic progenitors from hiPSC would increase this population and thus further increase the subsequent populations that derive from it. Identifying optimal time point when sufficient pancreatic progenitors are generated such that the finally desired population is increased would require routine experimentation, such as taught by Maury.
Regarding Kroon and Maury, Applicant argue that these “fails to remedy Yamashita's deficiencies.” (page 11, para 2).
In response, since arguments pertaining to Yamashita were unpersuasive, this argument is found to be unpersuasive.
Conclusion
No claim is allowed.
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/MATASHA DHAR/Examiner, Art Unit 1632
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