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 .
Status of the Claims
Claims 1-17, 20, 22-23, and 29-32 are currently pending.
Claims 8-11 are amended.
Claims 20 and 22 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, there being no allowable generic or linking claim.
Claims 18-19, 21, and 24-28 remain cancelled.
Claims 1-17, 23, and 29-32 have been considered on the merits.
Withdrawn Objections/Rejections
The rejections made under 112(b) onto claims 8-11 are withdrawn in light of the amendments submitted on 01/20/2026.
New and Maintained Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-17, 23, and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al (US20150104430A1) in view of Karp et al (US20170349884A1) as evidenced by Haikarainen et al (PLoS One, 2013).
With regards to claim 1, Keller teaches a method of producing PDX1 ([0074]) and NKX6-1 ([0003]) positive pancreatic progenitor cells ([0003]) from a PDX1 positive endodermal cell population ([0204]). Keller teaches that the starting population of PDX1 positive endodermal cells are also NKX6-1 negative as required by claim 1 ([0064]). The method comprises contacting the population with EGF ([0003]/[0204]).
Regarding claims 6-7, Keller teaches that the method further comprises contacting the population of cells with a BMP inhibitor which can be Noggin, dorsomorphin, LND, CHORDIN, BMPR1A, or BMPR1B ([0078]).
Regarding claims 10-11, Keller teaches that the method comprises contacting the population of cells with Noggin ([0078]). The method comprises contacting the population with EGF ([0003]/[0204]).
Regarding claims 12-13 and 29, Keller discloses that the endodermal cell population is differentiated from embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) ([0102]/[0103]).
Regarding claim 14, Keller discloses first producing the PDX1 positive cell population ([0204]).
Regarding claim 15, Keller teaches that the method of producing the PDX1 positive endodermal cell population comprises contacting a pluripotent stem cell population with any one of:
ActA (a nodal agonist) and Wnt3a (a wnt signaling agonist) ([0105]),
ActA (a nodal agonist), bFGF (an FGF agonist), and optionally a Wnt3a (a wnt signaling agonist) ([0105]), and
ActA (a nodal agonist) and bFGF (an FGF agonist) ([0105]).
Keller teaches that this produces stage 1 differentiated cells which are then contacted with a FGF agonist, FGF10, to produce stage 2 differentiated cells ([0105]).
Regarding claim 16, Keller teaches the production of insulin producing cells from the PDX1 and NKX6-1 positive pancreatic progenitor cells ([0028].
Regarding claim 17, Keller discloses that the insulin producing population comprises from 10-95% insulin producing cells ([0140]). Additionally, Keller teaches the enriching and/or isolation of PDX1/NKX6-1 positive pancreatic progenitor cells ([0139]/[0142]).
Regarding claim 30, Keller teaches that the nodal agonist is ActA, that the wnt signalling agonist is Wnt3a, that the FGF agonist is bFGF, and that the Extendin-4 component is Extendin-4 ([0105]).
Regarding claim 31, Keller teaches that step a) II) is additionally contacted with a wnt signaling agonist ([0105]).
Regarding claim 32, Finally, the stage 2 differentiated cells are contacted with Noggin, cyclopamine-KAAD, FGF10 (FGF agonist), and Extendin-4 ([0105]).
Keller does not teach that the method comprises contacting the endodermal cell population with a tankyrase inhibitor as required by claim 1. Further, Keller does not teach that the tankyrase inhibitor is WIKI4, G007-LK, JW74, JW55, CMP24, CMP40, and CMP4 as required by claims 8-11.
However, Karp teaches a method of producing a population of enteroendocrine cells, defined as specialized endocrine cells of the gastrointestinal tract and pancreas (abstract and [0086]). Karp teaches the use of small molecules such as a Wnt inhibitor, which is taught to be a tankyrase inhibitor ([0135]), in the differentiation process (abstract). The tankyrase inhibitor is taught to be WIKI4 as required by claims 8-11. Further, Karp teaches that the small molecule treatment (i.e. WIKI4) increases the insulin expression of the cells (abstract).
One of ordinary skill in the art would find it obvious at the effective filling date of the instant invention to combine the method of producing pancreatic progenitors taught by Keller with the tankyrase small molecule inhibitor taught by Karp to arrive at the instant invention. One of ordinary skill in the art would be motivated to make this combination because Karp teaches that the small molecule treatment (i.e. WIKI4) increases the insulin expression of the cells (abstract). Further, it would be obvious to apply the Wnt inhibitor prior to NKX6.1 expression as required by the newly amended claim 1 because Karp teaches Fig. 61 where it is seen that the Wnt inhibitor is applied starting from day 1 and after the beginning of day 2 NKX6.1 expression is seen in the cells, which also supports the motivation to apply a Wnt inhibitor prior to NKX6.1 expression is seen in the cells. One of ordinary skill in the art would have a reasonable expectation of success when combining Keller with Karp because both teach a method of producing pancreatic cells which express insulin.
Keller and Karp meet the limitations of the tankyrase inhibitor binding to an adenosine subsite of the tankyrase enzyme as required by claim 1 as evidenced by Haikarainen et al. Keller and Karp meet the limitation of the enzyme being TNK1 or TNK2 as required by claim 2. Keller and Karp meet the limitation that the tankyrase inhibitor has a higher affinity to the adenosine subsite than nicotinamide as required by claim 3. Keller and Karp meet the limitation of wherein the tankyrase inhibitor selectively binds the adenosine subsite as required by claim 4. Finally, Keller and Karp meet the limitation that the tankyrase inhibitor does not bind the nicotinamide site. These limitations are all supported by the evidentiary art, Haikarainen et al.
Haikarainen teaches about the WIKI4 tankyrase inhibitor. Haikarainen teaches that WIKI4 mainly binds to the adenosine subsite as required by 1, 3, and 4 (Fig. 4A, and pg. 5, column 1, para 1). WIKI4 is taught to bind both TNK1 and TNK2 as required by claim 2 (pg. 2, column 1, para 4). Further, WIKI4 does not contain a nicotinamide motif, i.e. unable to bind nicotinamide, as required by claim 5 (pg. 2, column 1, para 3).
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 of Dr. Maria Cristina Nostro under 37 C.F.R 1.132
At points 5-9, Dr. Nostro provides information regarding the understanding of the skilled artisan prior to the present application and concludes that “NKX6-1 was therefore understood as a required marker for [multipotent pancreatic progenitors] and it was demonstrated that progenitors lacking NKX6-1 could not generate proper endocrine progenitors that had potential to form beta cells” (point 9).
In response to point 5-9, These arguments are not found persuasive. It appears that the conclusion that prior to the time of filling of the instant application progenitors lacking NKX6-1 could not generate proper endocrine progenitors that had potential to form beta cells is directly refuted by the main art relied upon in the rejection, Keller. Keller teaches a population of cells which is NKX6-1 negative up until day 9 of the differentiation protocol (see data of Fig. 2 of Keller). Additionally, Keller teaches that these cells begin to express NKX6-1 at day 10 and these now NKX6-1 cells are capable of the potential to form beta cells (see [01223] of Keller). Therefore, the argument that prior to the instant application, a skilled artisan would not have the ability to make beta cells from progenitors lacking NKX6-1 appears to be directly refuted by Keller.
At point 11, Dr. Nostro provides an interpretation of the disclosure of Karp that Karp’s “protocol generates insulin+ cells from NGN3+ endocrine progenitors, which are already known to express NKX6- 1” (point 11). Dr. Nostro states at point 12 that “critically, Karp does not attribute NKX6-1 induction to Wnt inhibition” and provides information from Karp regarding NGN3 expression and Wnt inhibition/activation. Dr. Nostro states “Fig. 33 explicitly shows that the Wnt inhibition is applied after NGN3 expression begins. This directly contradicts the notion that Wnt inhibition is responsible for NKX6-1 induction” (point 12). Dr. Nostro states that “Karps’ own data confirms that Wnt-C59 anole does not induce endocrine or B-cell markers… because NKX6-1 is characteristic of B-lineage endocrine progenitors and B-cells, any condition that does not produce insulin+ cells would not be expected to induce NKX6-1 cells” (point 13). Dr. Nostro concludes at point 14 that “turning specifically to Fig. 61 in Karp, there is notation of Nkx6.1 above the timeline seemingly after the addition of WntC59. I am unsure whether they simply did not test for Nkx6.1 expression until that moment in time, but it would be clear to anyone skilled in this area as demonstrated above, that Nkx 6.1 expression would not have only begun at that time” (point 14). Finally, Dr. Nostro states “nothing in Karp indicates or hints that Wnt inhibition induces NKX6-1, or that NKX6-1 expression depends on Wnt inhibition. Instead, Karp’s experimental; logic and textual teaching state the opposite: NKX6-1-positive endocrine progenitors arise under Wnt-activated conditions (NGN3 induction), and only afterward are Wnt inhibitors applied to promote hormone expression” (point 15).
In response to points 11-15, these arguments are not found persuasive.
An underlying assumption that the arguments of points 11-15 make is that progenitors lacking NKX6-1 could not generate proper endocrine progenitors that had potential to form beta cells, which has been addressed above at point 12 of this Action. Dr. Nostro extends this logic to Karp, making the assumption that the cells of Karp must express NKX6-1 even though Karp specifically provides Fig. 61 which shows NKX6-1 expression after day 2 of the protocol. Dr. Nostro dismisses this by stating “turning specifically to Fig. 61 in Karp, there is notation of Nkx6.1 above the timeline seemingly after the addition of WntC59. I am unsure whether they simply did not test for Nkx6.1 expression until that moment in time, but it would be clear to anyone skilled in this area as demonstrated above, that Nkx 6.1 expression would not have only begun at that time” (point 14). Based on the fact that Keller specifically demonstrates NKX6-1 expression begins at day 10 of their differentiation protocol, a skilled artisan could not confidently conclude that the cells of Karp must have expressed NKX6-1 prior to when Karp describes the cells as NKX6-1+. A skilled artisan would not inherently read Fig. 61 of Karp which shows NKX6-1 expression on day 2 to mean Karp must have not tested the cells for NKX6-1 expression until that point, as Dr. Nostro implies. Thus, the Fig. 61 of Karp must be interpreted to demonstrate what it specifically describes, which is:
i) NKX6-1 expression on day 2 of the protocol
ii) Wnt inhibitor is applied prior to the KNX6-1 expression
Additionally, Dr. Nostro makes multiple statements regarding Wnt inhibition not directly inducing NKX6-1. The rejections presented in previous office actions and above do not state that Wnt inhibition directly induces NKX6-1 at any point, thus these arguments are interpreted as arguments against the combination of Keller and Karp based on not having a motivation to combine. However, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would be motivated to make this combination because Karp teaches that the small molecule treatment (i.e. WIKI4) increases the insulin expression of the cells (abstract). Further, it would be obvious to apply the Wnt inhibitor prior to NKX6.1 expression as required by the newly amended claim 1 because Karp teaches Fig. 61 where it is seen that the Wnt inhibitor is applied starting from day 1 and after the beginning of day 2 NKX6.1 expression is seen in the cells, which also supports the motivation to apply a Wnt inhibitor prior to NKX6.1 expression is seen in the cells. One of ordinary skill in the art would have a reasonable expectation of success when combining Keller with Karp because both teach a method of producing pancreatic cells which express insulin.
Therefore, the arguments are not considered persuasive.
Response to Arguments
Applicant's arguments filed 01/20/2026 have been fully considered but they are not persuasive.
Applicant argues (Remarks, pg. 5-6) that a 2017 review demonstrates that NKX6-1 is expressed across all stages from multipotent pancreatic progenitors through bipotent endocrine/ductal progenitors and that before the filling of the instant application the skilled person understood that multipotent pancreatic progenitors express NKX6-1 and that it is understood as a required marker for multipotent pancreatic progenitors. References are made to the identical argument presented in the Declaration submitted by Dr. Nostro which are addressed in the Response to Declaration section above.
In response these arguments are not found persuasive. It appears that the conclusion that prior to the time of filling of the instant application progenitors lacking NKX6-1 could not generate proper endocrine progenitors that had potential to form beta cells is directly refuted by the main art relied upon in the rejection, Keller. Keller teaches a population of cells which is NKX6-1 negative up until day 9 of the differentiation protocol (see data of Fig. 2 of Keller). Additionally, Keller teaches that these cells begin to express NKX6-1 at day 10 and these now NKX6-1 cells are capable of the potential to form beta cells (see [01223] of Keller). Therefore, the argument that prior to the instant application, a skilled artisan would not have the ability to make beta cells from progenitors lacking NKX6-1 appears to be directly refuted by Keller.
Applicant argues (Remarks, pg. 7-8) that Dr. Nostros Declaration establishes that Karp only uses a Wnt inhibitor after NKX6-1 expression and not before and thus there is not reasonable expectation of success in combining the references as suggested by the examiner.
In response, an underlying assumption that the argument makes is that progenitors lacking NKX6-1 could not generate proper endocrine progenitors that had potential to form beta cells, which has been addressed above at points 12 and 15 of this Action. Applicant and Dr. Nostro extends this logic to Karp, making the assumption that the cells of Karp must express NKX6-1 even though Karp specifically provides Fig. 61 which shows NKX6-1 expression after day 2 of the protocol. Based on the fact that Keller specifically demonstrates NKX6-1 expression begins at day 10 of their differentiation protocol, a skilled artisan could not confidently conclude that the cells of Karp must have expressed NKX6-1 prior to when Karp describes the cells as NKX6-1+. A skilled artisan would not inherently read Fig. 61 of Karp which shows NKX6-1 expression on day 2 to mean Karp must have not tested the cells for NKX6-1 expression until that point, as Applicant and Dr. Nostro imply. Thus, the Fig. 61 of Karp must be interpreted to demonstrate what it specifically describes, which is:
i) NKX6-1 expression on day 2 of the protocol
ii) Wnt inhibitor is applied prior to the KNX6-1 expression
Additionally, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would be motivated to make this combination because Karp teaches that the small molecule treatment (i.e. WIKI4) increases the insulin expression of the cells (abstract). Further, it would be obvious to apply the Wnt inhibitor prior to NKX6.1 expression as required by the newly amended claim 1 because Karp teaches Fig. 61 where it is seen that the Wnt inhibitor is applied starting from day 1 and after the beginning of day 2 NKX6.1 expression is seen in the cells, which also supports the motivation to apply a Wnt inhibitor prior to NKX6.1 expression is seen in the cells. One of ordinary skill in the art would have a reasonable expectation of success when combining Keller with Karp because both teach a method of producing pancreatic cells which express insulin.
Therefore, the argument is not found persuasive.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONSTANTINA E STAVROU whose telephone number is (571)272-9899. The examiner can normally be reached M-F 8:00-5:00.
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CONSTANTINA E. STAVROU
Examiner
Art Unit 1632
/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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