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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/28/2026 has been entered.
Claim Status
1. The amendment filed 01/28/2026 has been entered. Claims 1 – 15, 51, 55, and 57 remain pending.
Election/Restrictions
2. Applicant’s election without traverse of Group I (claims 1 and 3 – 14) in the reply filed on 12/01/2023 is acknowledged.
3. Claims 2, 15, 51, 55, and 57 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/01/2023.
4. Claims 1 and 3 – 14 are under consideration.
Priority
5. This application is a national stage application, filed under 35 U.S.C. § 371, of International Patent Application No. PCT/CA2019/050705, filed on May 24, 2019, which claims priority from U.S. provisional application serial number 62/676,582 filed on May 25, 2018.
6. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/676,582, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. In the instant application, claim 12 recites EOMES and claim 14 recites AFP and albumin. The disclosure of the prior filed application does not support EOMES recited in claim 12 or AFP and albumin recited in claim 14 of the instant application. Claim 13 of the instant application is not recited in the claims or described in the specification of Application No. 62/676,582. The disclosure of the prior filed application does not support claim 13 of the instant application. Accordingly, claim 13, EOMES recited in claim 12, and AFP and albumin recited in claim 14 are not entitled to the benefit of the prior application.
Withdrawn Claim Rejections
7. The rejection of claims 1, 4 – 12, and 14 under 35 U.S.C. 103 is withdrawn in view of Applicant’s arguments that Ang teaches Wnt inhibition promotes expression of foregut markers but only in zebrafish embryos and not human cells and Ang teaches away from Wnt inhibition in human endodermal cells.
8. The rejection of claim 3 under 35 U.S.C. 103 in view of Applicant’s arguments that Ang teaches Wnt inhibition promotes expression of foregut markers but only in zebrafish embryos and not human cells and Ang teaches away from Wnt inhibition in human endodermal cells.
9. The rejection of claim 13 under 35 U.S.C. 103 in view of Applicant’s arguments that Ang teaches Wnt inhibition promotes expression of foregut markers but only in zebrafish embryos and not human cells and Ang teaches away from Wnt inhibition in human endodermal cells.
New Claim Objections
10. Claim 1 is objected to because of the following informalities: the bullets for each of the additives should be removed such that the claim reads “A process of making human posterior foregut cells from human endodermal cells, the process comprising contacting the human endodermal cells with a first culture medium excluding insulin and comprising a first set of additives under conditions allowing the differentiation of the human endodermal cells into the posterior foregut cells, wherein the first set of additives excludes insulin and comprises: an activator of a bone morphogenetic protein (BMP) signaling pathway; an activator of a fibroblast growth factor (FGF) signaling pathway; an inhibitor of a Wnt signaling pathway; and an inhibitor of a transforming growth factor 13 (TGFl3) signaling pathway~
and wherein the first culture medium remains in contact for 2 or more days with the human endodermal cells. Appropriate correction is required.
Claim Interpretation
11. For the purpose of applying prior art, “basic FGF” of claim 7 is interpreted as FGF2 based on Applicant’s specification at page 13, line 35.
12. For the purpose of applying prior art, “the inhibitor of the Wnt signaling pathway is capable of inhibiting the biological activity of Porcupine” of claim 8 is interpreted as IWP2 based on Applicant’s specification at page 2, line 12 – 13.
13. For the purpose of applying prior art, “the inhibitor of the TGFβ signaling pathway is
capable of inhibiting the biological activity of at least one of ALK4, ALK5 or ALK7” of claim 10 is interpreted as A83-01 based on Applicant’s specification at page 2, lines 13 – 15.
14. For the purpose of applying prior art, “fails to substantially express c-Kit” of claim 13 is interpreted as less than 3% of the cells are positive for the c-Kit marker based on Applicant’s specification at page 2, lines 17 – 19.
New Claim Rejections
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
15. Claim(s) 1, 4 – 12, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Ang (WO-2016056999-A1; previously cited), hereinafter Ang, in view of Loh (Loh, Kyle M., et al. Cell stem cell 14.2 (2014): 237-252; previously cited), hereinafter Loh in view of Touboul (Touboul T, et. al. J Hepatol. 2016 Jun;64(6):1315-26), hereinafter Touboul which is cited on the IDS filed 05/08/2024.
Regarding claim 1, Ang teaches a method of differentiating definitive endoderm (DE) cells into posterior foregut cells comprising contacting cells with an activator of BMP signaling (“activator of BMP signaling pathway”), an activator of FGF signaling (“activator of a FGF signaling pathway”), and a TGFβ signaling inhibitor (“inhibitor of a TGFβ signaling pathway”), and a Wnt inhibitor (“an inhibitor of a Wnt signaling pathway”) in CDM KOSR medium that does not comprise insulin (“first culture medium excluding insulin and comprising a first set of additives”) for 24 hours (page 22, 00102 – 00106; page 23, 00107 – 00110; page 33, 00184; page 38, 00214 step d; page 40, para. 00220; Figure 1A and 8A). Ang teaches in Figure 1A that low WNT (WNTlo) in combination with retinoic acid, FGF, BMP4, and TGFb inhibition forms posterior foregut, while high WNT (WNThi) forms midgut/hindgut (page 10, para. 0054). Ang does not teach “remains in contact for 2 or more days”, but does teach where the differentiation of definitive endoderm to posterior foregut may be about 1 day or may be greater than 1 day (page 23, 00109; Table 1, page 16, 0075).
Regarding claims 4 and 5, Ang teaches BMP4 (page 22, 00106; page 38, 00214 step d).
Regarding claims 6 and 7, Ang teaches FGF2 (page 23, 00107; page 38, 00214 step d).
Regarding claims 8 and 9, Ang teaches IWP2 (page 40, para. 00220; Figure 8A).
Regarding claims 10 and 11, Ang teaches A83-01 (page 22, 00105; page 38, 00214 step d).
Regarding claims 12 and 14, Ang teaches the definitive endoderm cells express SOX 17 (claim 12) and posterior foregut cells express HNF4A (claim 14) (page 18, Table 2; Fig. 2A; page 11, 0055; page 40, 00224).
Ang teaches Wnt inhibition by DKK1, C59, and IWP2 during foregut specification reduces MHG markers and markers for early pancreatic and liver cells were upregulated upon Wnt inhibition (page 40, para. 00220, Figure 8A). Ang teaches it was found that a combination of TGFβ inhibition and treatment with BMP, FGF, and retinoic acid generated posterior foregut cells that are competent to generate hepatic cells (page 40, para. 00221). Ang teaches early Wnt inhibition during early foregut promotes downstream hepatocyte specification (page 46, 00250). Ang teaches end-stage liver failure results in severe clinical symptoms including bleeding, encephalopathy, and eventually death (page 1, 0003). Ang teaches understanding of the processes of liver specification, formation of liver cells and maturation of liver functions remains limited and mechanisms that induce formation of liver stem cells as well as their mature progeny remain unclear (page 1, 0005). Ang teaches although pluripotent stem cells could yield liver cells with some liver function, there remains an apparently un-surmounted barrier for these liver cells to progress into an adult-like state and generating authentic and transplantable hepatocyte-like cells from these pluripotent stem cells that could engraft and robustly repopulate in the adult liver remains challenging (page 2, 0006 – 0007). Ang teaches it is important to understand the signaling logic underlying multiple steps of induction and patterning of the germ layers and differentiation into the various cell lineages and the signaling factors that regulate liver specification and to formulate a signaling paradigm for hepatogenesis using human pluripotent stem cell-based differentiation (page 2, 0008).
Regarding “an inhibitor of a Wnt signaling pathway” of claim 1, Loh teaches treating human definitive endoderm with a Wnt inhibitor including IWP2 to form human posterior foregut (page 250, left col. last para.; Extended Experimental Procedures page 3, para. 3; Figure 4B). Loh teaches the rationale for treatment including a Wnt inhibitor was to suppress mid/hindgut formation and prevent excess posteriorization (Extended Experimental Procedures page 3, para. 3). Loh teaches in Figure S4A that Wnt activation forms mid/hindgut formation from DE (Figure S4 legend at page 4, para. 2 of Supplemental). One would have been motivated to combine the teachings of Ang and Loh to include a WNT signaling inhibitor in the process of making human posterior foregut from human DE of Ang because both teach the use of IWP2 to form human posterior foregut from human DE.
Touboul teaches a method of making human posterior foregut cells from human endodermal cells comprising contacting the DE with a WNT inhibitor for 3 days (Figure 1A; page 1316, right col. para. 4 and 6; Supplementary materials and methods page 2). Touboul teaches the WNT inhibitor IWR-1 significantly improved DE differentiation to posterior foregut as demonstrated by the expression of HNF4, HHEX, and HNF1β (page 1317, left col.; page 1323, left col. para. 2). Touboul teaches that WNT inhibition combined with inhibition of BMP and FGF had a negative effect on HHEX expression and blocked differentiation to posterior foregut (page 1317, right col.; page 1323, left col. para. 2). Touboul teaches inhibition of the WNT pathway was required to specify posterior foregut (Abstract). Touboul teaches repression of WNT signaling results in specification of the posterior foregut (page 1316, left col. para. 1). Touboul teaches the posterior foregut cells could be further differentiated to functional hepatocytes (page 1322, right col., para. 2 – 3). Touboul teaches hepatocytes differentiated from human embryonic stem cells have the potential to overcome the shortage of primary hepatocytes for clinical use and drug development (Abstract). Touboul teaches for many patients with end-stage liver disease liver transplantation is the only effective long-term treatment (page 1315, right col. para. 1). Touboul teaches given that primary hepatocytes are difficult to culture and amplify while preserving their function, there is a need for alternative sources of large numbers of functional hepatocytes to treat liver disease (page 1315, right col. para. 1).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Ang regarding a method of making human posterior foregut cells from human endodermal cells by culturing DE with BMP4, FGF2, and A83-01 and the signaling strategy of making posterior foregut from DE comprising FGF, WNTlo, BMP4, TGFb inhibition with the teachings of Loh regarding a method of making human posterior foregut cells from human endodermal cells comprising culturing human DE with a Wnt inhibitor with the teachings of Touboul regarding treating human DE with a Wnt inhibitor for 3 days to form human posterior foregut to arrive at the claimed process of making human posterior foregut cells from human endodermal cells, the process comprising contacting the human endodermal cells with a first culture medium excluding insulin and comprising a first set of additives under conditions allowing the differentiation of the human endodermal cells into the posterior foregut cells, wherein the first set of additives excludes insulin and comprises: an activator of a bone morphogenetic protein (BMP) signaling pathway; an activator of a fibroblast growth factor (FGF) signaling pathway; an inhibitor of a Wnt signaling pathway; and an inhibitor of a transforming growth factor 13 (TGFβ) signaling pathway; and wherein the first culture medium remains in contact for 2 or more days with the human endodermal cells. One would have been motivated to combine the teachings of Ang, Loh, and Touboul in a method to produce posterior foregut cells to study the process of liver development and as cells to make hepatocytes to treat liver disease as Ang teaches understanding of the processes of liver specification, formation of liver cells and maturation of liver functions remains limited and mechanisms that induce formation of liver stem cells as well as their mature progeny remain unclear and Touboul teaches hepatocytes differentiated from human embryonic stem cells have the potential to overcome the shortage of primary hepatocytes for clinical use and drug development and Touboul teaches given that primary hepatocytes are difficult to culture and amplify while preserving their function, there is a need for alternative sources of large numbers of functional hepatocytes to treat liver disease. One would have a reasonable expectation of success in combining the teachings as Ang teaches Wnt inhibition by IWP2 during foregut specification reduces midgut/hindgut markers and Ang teaches the method generated posterior foregut cells competent to generate hepatic cells and Loh teaches the rationale for treatment of definitive endoderm inhibitors of BMP, FGF/MAPK, and Wnt signaling was to suppress mid/hindgut formation and prevent excess posteriorization and Touboul teaches the posterior foregut cells could be further differentiated to functional hepatocytes.
16. Claim(s) 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ang (WO-2016056999-A1; previously cited), hereinafter Ang, in view of Loh (Loh, Kyle M., et al. Cell stem cell 14.2 (2014): 237-252; previously cited), hereinafter Loh in view of Touboul (Touboul T, et. al. J Hepatol. 2016 Jun;64(6):1315-26), hereinafter Touboul which is cited on the IDS filed 05/08/2024 as applied to claims 1, 4 – 12, and 14 above, and further in view of Pettinato (Pettinato, Giuseppe, et al. Scientific Reports 6.1 (2016): 32888.), hereinafter Pettinato.
Ang in view of Loh and Touboul make obvious the limitations of claim 1 as set forth above. Ang, Loh, and Touboul do not teach “wherein the first culture medium comprises serum” of claim 3. However, Ang teaches the method generated posterior foregut cells competent to generate hepatic cells (page 40, 00221). Ang teaches although pluripotent stem cells could yield liver cells with some liver function, there remains an apparently un-surmounted barrier for these liver cells to progress into an adult-like state and generating authentic and transplantable hepatocyte-like cells from these pluripotent stem cells that could engraft and robustly repopulate in the adult liver remains challenging (page 2, 0006 – 0007). Touboul teaches given that primary hepatocytes are difficult to culture and amplify while preserving their function, there is a need for alternative sources of large numbers of functional hepatocytes to treat liver disease (page 1315, right col. para. 1).
Pettinato teaches a method of making human foregut from DE by culturing DE in serum with BMP4 and FGF4 (Figure 1a; page 11, para. 8). Pettinato teaches the foregut cells could be further differentiated to mature hepatocyte-like cells (HLCs) (Figure 1a). Pettinato teaches treatment of acute liver failure by cell transplantation is hindered by a shortage of human hepatocytes and current protocols for hepatic differentiation of hiPSCs result in low yields, cellular heterogeneity, and limited scalability (Abstract; page 1, para. 1; page 2, para. 1; page 8, para. 1; page 10, last para.). Pettinato teaches the method allows for robust mass production of human HLCs that expressed liver-specific genes and secreted hepatic proteins and displayed cytochrome P450 activities (Abstract; page 5, para. 1). Pettinato teaches transplantation of the HLCs in a rat model of acute liver failure significantly prolonged the mean survival time and resolved the liver injury (Abstract). Pettinato teaches the HLCs may provide viable substitutes for primary human hepatocytes in regenerative medicine and pathophysiological studies, as well as pharmacological screening and drug discovery (page 11, para. 3).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Ang regarding a method of making human posterior foregut cells from human endodermal cells by culturing DE with BMP4, FGF2, and A83-01 with the teachings of Loh regarding a method of making human posterior foregut cells from human endodermal cells comprising culturing with the Wnt inhibitor IWP2 with the teachings of Touboul regarding treating DE with a Wnt inhibitor for 3 days to form posterior foregut with the teachings of Pettinato regarding a method of differentiating DE to foregut in serum to arrive at the claimed method wherein the first culture medium comprises serum. One would have been motivated to combine the teachings of Ang, Loh, Touboul, and Pettinato in a method to produce hepatocytes from posterior foregut cells for regenerative medicine as Ang teaches although pluripotent stem cells could yield liver cells with some liver function, there remains an apparently un-surmounted barrier for these liver cells to progress into an adult-like state and generating authentic and transplantable hepatocyte-like cells from these pluripotent stem cells that could engraft and robustly repopulate in the adult liver remains challenging and Touboul teaches given that primary hepatocytes are difficult to culture and amplify while preserving their function, there is a need for alternative sources of large numbers of functional hepatocytes to treat liver disease. One would have a reasonable expectation of success in combining the teachings as Pettinato teaches the method allowed for robust mass production of human hepatocyte like cells that were able to resolve liver injury when transplanted into a rat model of acute liver failure.
17. Claim(s) 13 is rejected under 35 U.S.C. 103 as being unpatentable over Ang (WO-2016056999-A1; previously cited), hereinafter Ang, in view of Loh (Loh, Kyle M., et al. Cell stem cell 14.2 (2014): 237-252; previously cited), hereinafter Loh in view of Touboul (Touboul T, et. al. J Hepatol. 2016 Jun;64(6):1315-26), hereinafter Touboul which is cited on the IDS filed 05/08/2024 as applied to claims 1, 4 – 12, and 14 above, and further in view of Christodoulou (Christodoulou C, et. al. J Clin Invest. 2011 Jun;121(6):2313-25), hereinafter Christodoulou.
Ang in view of Loh and Touboul make obvious the limitations of claim 1 as set forth above. Ang, Loh, and Touboul do not teach “the human endodermal cells fail to substantially express c-Kit” of claim 13. However, Ang teaches the method generated posterior foregut cells competent to generate hepatic cells (page 40, 00221). Ang teaches understanding of the processes of liver specification, formation of liver cells and maturation of liver functions remains limited and mechanisms that induce formation of liver stem cells as well as their mature progeny remain unclear (page 1, 0005). Ang teaches although pluripotent stem cells could yield liver cells with some liver function, there remains an apparently un-surmounted barrier for these liver cells to progress into an adult-like state and generating authentic and transplantable hepatocyte-like cells from these pluripotent stem cells that could engraft and robustly repopulate in the adult liver remains challenging (page 2, 0006 – 0007).
Christodoulou teaches c-kit- endoderm derived from human induced pluripotent stem cells that when transplanted into mice produces a greater number of endodermal epithelia structures compared to ckit+ endoderm (Figure S4; page 2317, right col. para. 2). Christodoulou teaches the c-kit- endoderm expresses Gata4, Sox17, and Foxa2 in Figure 4. Christodoulou teaches the endoderm could be differentiated to hepatocytes in a culture medium containing BMP4 and FGF2 (page 2324, left col. para. 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to substitute the DE of Ang with the DE that is c-kit- of Christodoulou to arrive at the claimed method wherein the human endodermal cells fail to substantially express c-Kit. One would have been motivated to make such a substitution as Christodoulou teaches the ckit- DE produces a greater number of endodermal epithelia structures and therefore would have a greater capacity to produce human posterior foregut endoderm compared to ckit+ DE. One would have a reasonable expectation of success in making the substitution as Ang teaches the posterior foregut could be further differentiated to hepatocytes and Christodoulou teaches differentiation of the DE to hepatocytes in culture media containing BMP4 and FGF2.
Applicant’s Arguments/ Response to Arguments
18. Applicant Argues: On page 2, last para. and page 3 para. 1, Applicant asserts that the first part of paragraph 00220 of Ang does state that Wnt inhibition promotes expression of foregut markers but only in Zebrafish embryos. Applicant asserts that there is a clear motivation in Ang to avoid the use of a Wnt inhibitor for the differentiation of human endodermal cells into human foregut cells. Applicant asserts that what Ang actually states in paragraph 00220 is that Wnt inhibition promotes foregut markers in Zebrafish embryos and that did not translate in their in vivo model of human cells implanted in a mouse animal model. Applicant asserts that Ang teaches away from Wnt inhibition in human endodermal cells.
Response to Arguments: This is not found persuasive because in the new rejection set forth above, Ang teaches that three different Wnt inhibitors including IWP2 were added to the human definitive endoderm (DE) during human foregut specification and that these inhibitors reduced expression of midgut/hindgut markers as shown in Figure 8A (page 40, para. 00220). Ang teaches in Figure 1A that low WNT (WNTlo) in combination with retinoic acid, FGF, BMP4, and TGFb inhibition forms posterior foregut, while high WNT (WNThi) forms midgut/hindgut (page 10, para. 0054). Therefore, Ang teaches that Wnt inhibition yields posterior foregut instead of midgut/hindgut thus not teaching away from adding a Wnt inhibitor in the process of making human posterior foregut cells from human endoderm. Loh also teaches Wnt inhibition by IWP2 to suppress midgut/hindgut formation to generate human posterior foregut from human DE and Wnt activation forms mid/hindgut from DE (Extended Experimental Procedures page 3, para. 3; Figure S4 legend at page 4, para. 2 of Supplemental). Touboul teaches a method of making human posterior foregut cells from human endodermal cells comprising contacting the human DE with a WNT inhibitor for 3 days (Figure 1A; page 1316, right col. para. 4 and 6; Supplementary materials and methods page 2). Touboul teaches the WNT inhibitor IWR-1 significantly improved DE differentiation to posterior foregut as demonstrated by the expression of HNF4, HHEX, and HNF1β (page 1317, left col.; page 1323, left col. para. 2). Touboul teaches that WNT inhibition combined with inhibition of BMP and FGF had a negative effect on HHEX expression and blocked differentiation to posterior foregut (page 1317, right col.; page 1323, left col. para. 2). Touboul teaches inhibition of the WNT pathway was required to specify posterior foregut (Abstract). Touboul teaches repression of WNT signaling results in specification of the posterior foregut (page 1316, left col. para. 1). Therefore, Touboul provides motivation and a reasonable expectation of success for including a Wnt inhibitor in the process of Ang of making human posterior foregut from human DE with BMP4, FGF2, and A83-01.
Applicant Argues: On page 3, para. 8, Applicant asserts that the Examiner has failed to consider the specific limitation of the cells being human cells in the claimed subject matter and that the teachings of Ang that concern Wnt inhibition are only for zebrafish embryos.
Response to Arguments: This is not found persuasive because Ang teaches treating human DE with a Wnt inhibitor to form human posterior foregut. Further, in the new rejection set forth above, Touboul teaches Wnt inhibition significantly improved human DE differentiation to human posterior foregut as demonstrated by the expression of HNF4, HHEX, and HNF1β (page 1317, left col.; page 1323, left col. para. 2). Solely to rebut Applicant’s argument, Loh teaches that BMP markedly posteriorized DE by inducing mid/hindgut transcription factors congruent with zebrafish data (page 241, right col. para. 4) demonstrating that signaling and patterning in zebrafish is relevant to human differentiation protocols.
Applicant Argues: On page 3, last two paragraphs, Applicant asserts Munera and Suzuki are completely silent regarding a Wnt inhibitor.
Response to Arguments: The claim rejections citing teachings of Munera and Suzuki have been withdrawn and therefore these arguments are moot.
Conclusion
No claims allowed.
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/ZANNA MARIA BEHARRY/Examiner, Art Unit 1632