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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/14/2025 has been entered.
Status of the Claims
Claims 1-5, 7-9, and 18-20 are pending.
Claims 1 and 18 are newly amended.
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/27/2022.
Claims 1-5 and 7-9 have been examined on their merits.
Withdrawn Objections & Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in the application. Any objections or rejections not specifically reiterated are hereby withdrawn. The rejections, have been maintained but modified to address the new limitations. Prior objections have been addressed by amendment.
The rejection of the pending claims under 35 USC 112(a) as discussed in the Office Action on 05/15/2025 is withdrawn due to amendment of the claims.
Claim Objections
Claim 5 is objected to for the following informalities: claim 5 recites “claim 4 , wherein” and therefore has redundant extra spaces around the comma.
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 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.
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.
Claims 1 and 7-8 are rejected under 35 U.S.C. 103 as unpatentable over Tong et al. (Biomaterials, 2018, previously cited) in view of Halloin et al. (Stem Cell Reports, 2019) as evidenced by Tamminen et al. (PLOS ONE, 2015, previously cited), Miquel et al. (Stem Cell Rev and Rep, 2010, previously cited), and Yin et al. (Nature Methods, 2014).
In regards to claims 1 and 7-8, Tong teaches methods for expanding and differentiating (preparing) monolayers of Lgr5+ intestinal stem cells (Abstract, p60; Fig. 1, p63) (intestinal epithelial cell progenitors (see instant specification, p15, lines 7-16).
Tong teaches that this method comprises culturing cells in ENR media, which as evidenced by Tamminen comprises EGF (Formation of organoids from hindgut cells is independent of R-spondin 1, p9). Continuing, Tong teaches that the media can be supplemented with a Wnt inhibitor and valproic acid (VPA, a Notch activator) (p67, column 2, last paragraph; Figure 5, p69).
While Tong uses Wnt inhibitor IWP-2 specifically (p67, column 2, last paragraph; Figure 5, p69), as taught by Halloin, IWP-2 and Wnt-C59 are both known in the art to be suitable for inhibiting Wnt signaling in vitro (Introduction, p366), and are therefore, art recognized equivalents for the same purpose. According to MPEP 2144.06, it is prima facie obvious to substitute equivalents known for the same purpose. Moreover, a person of ordinary skill in the art would have been motivated to choose Wnt-C59 because Halloin teaches that it has greater differentiation efficiency compared to IWP-2 (p371, left column; Fig. 4, p371). Additionally, because Halloin teaches that cells can be cultured alike with IWP-2 and Wnt-C59 (p371, left column; Fig. 4, p371), it could have been done with predictable results and a reasonable expectation of success.
In regards to the types of cells used, the Lgr5+ cells as taught by Tong are derived from gut biopsies of either mouse or human intestinal crypts (Materials and Methods, p61-62).
As evidenced by Miquel, pluripotency is defined as the potential of a cell to differentiate into cells of the three germ layers: endoderm, mesoderm, and ectoderm, and that these cells give rise to any fetal or adult cell type (Mammalian Early Development, p633). Therefore, all cells ultimately derived from pluripotent stem cells, and as a result, even though the cells of Tong are obtained from gut biopsy, they are still “derived” from pluripotent stem cells, which reads on the limitation.
In regards to the specific animal, Tong teaches that both human and mouse intestinal epithelial cells were used in their experiments (Abstract, p60; Figure 1, p63). While it is unclear if human or mouse cells were specifically used in the experiments, in the event that Tong does not teach that the cells used the experiments were human cells specifically, a person of ordinary skill in the arts would have been motivated to choose human intestinal epithelial cells because it would be most relevant to studying or treating human disease. Furthermore, because Tong teaches that their experiments could employ both human and mouse cells (Abstract, p60; Figure 1, p63), it could have been done with predictable results and a reasonable expectation of success.
In regards to the cell types obtained, Tong also teaches that the media can be supplemented with a Wnt inhibitor (IWP-2) and a Notch inhibitor (valproic acid, VPA) for the differentiation of enterocytes, that the intestinal epithelial cell population can differentiate into goblet cells, enteroendocrine cells and Paneth cells, and that ENR media alone is known to drive simultaneous differentiation of intestinal stem cells into multiple lineages (citing Yin who evidenced that ENR conditions grow organoids with all intestinal epithelial cell types, p108).
Therefore, the teachings of Tong and Halloin render obvious the invention as claimed.
Claims 2-4 are rejected under 35 U.S.C. 103 as unpatentable over Tong et al. (Biomaterials, 2018, previously cited) in view of Halloin et al. (Stem Cell Reports, 2019) as evidenced by Tamminen et al. (PLOS ONE, 2015, previously cited), Miquel et al. (Stem Cell Rev and Rep, 2010, previously cited), and Yin et al. (Nature Methods, 2014), as applied to claim 1 above, and further in view of Vallier et al. (US 20160237401 A1, 2016, previously cited) as evidenced by Thermo Fisher RPMI 1640 (Retrieved from internet 03/15/2023, previously cited).
In regards to claims 2-4, as discussed above, while Tong teaches that the intestinal epithelial cell progenitors are derived from biopsies, these cells are still derived from pluripotent stem cells as discussed above.
However, in as much as Applicant intends to imply an induced pluripotent stem cell (as suggested in claims 2-4 which are methods for inducing pluripotent stem cells), a person of ordinary skill in the arts would have been motivated to modify the method of Tong and derive human pluripotent intestinal epithelial cells from induced hPSCs because, as taught by Vallier, numerous cultured hESCs lines are publicly available from repositories (paragraph [0033]), and using cell lines would eliminate the need to invasively take biopsy samples from humans. Furthermore, because Vallier teaches that stem cell lines are readily available, and teaches methods for inducing human pluripotent intestinal epithelial cells from hESCs or hiPSCs to form endoderm (Fig. 4; paragraph [0025]) discussed in depth below), it could have been done with predictable results and a reasonable expectation of success.
Additionally, methodologically, for derivation of intestinal epithelial progenitors, Vallier teaches that this method comprises culturing hPSCs through definitive endoderm to hindgut endoderm that can further differentiate into intestinal epithelium which can be patterned to hindgut endoderm that can differentiate into intestinal epithelium (paragraph [0025]; Fig. 4).
In regard to claims 2-3, Vallier also teaches that the method comprises culturing endoderm in media comprising R-spondin and EGF supplemented with B27 (which itself comprises insulin) (paragraph [0222]).
Additionally, Vallier teaches that definitive endoderm can be induced by culturing cells in RMPI medium supplemented with Activin A (paragraph [0066]). As evidenced by Thermo Fisher RPMI 1640, RPMI medium requires supplementation, and usually with 10% FBS (Using RPMI, second page). Therefore, Vallier suggests that media conditions comprise FBS.
Furthermore, Vallier teaches that the hPSCs can be either hESCs and hiPSCs (paragraph [0219]).
A person of ordinary skill in the art would have been motivated to utilize the method of Vallier for derivation of human pluripotent stem cells because Vallier indicates that the method is useful for the in vitro production of endoderm cells for research and therapeutic applications and can establish heterogeneous populations of cells (paragraph [0011]), which addresses the issue of inconsistencies in cell populations by other methods (paragraph [0002]). Furthermore, because Vallier teaches methods for differentiation of endoderm cells from human pluripotent stem cells, as discussed above, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Tong, Halloin, and Vallier renders obvious the invention as claimed.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Tong et al. (Biomaterials, 2018, previously cited) in view of Halloin et al. (Stem Cell Reports, 2019) and of Vallier et al. (US 20160237401 A1, 2016, previously cited), as evidenced by Tamminen et al. (PLOS ONE, 2015, previously cited), Miquel et al. (Stem Cell Rev and Rep, 2010, previously cited), Yin et al. (Nature Methods, 2014), and Thermo Fisher RPMI 1640 (Retrieved from internet 03/15/2023, previously cited), as applied to claims 1 and 4 above, and further in view of Higuchi et al. (PLOS ONE, 2015, previously cited).
In regards to claim 5, as discussed above, Tong teaches that the human pluripotent intestinal epithelial cells were obtained from gut biopsy (Figure 1, p63). As above, Vallier teaches that human pluripotent intestinal epithelial may be derived from hESCs or iPSCs (paragraph [0219]). While Vallier also teaches that hESCs or iPSCs may derive from fibroblasts (paragraph [0034]), Vallier does not explicitly teach where the fibroblasts may be derived.
However, Higuchi teaches that fibroblasts are the principal stromal cells that exist in whole organs (Background, p1). Higuchi also teaches that compared to fibroblasts from other parts of the body, gastrointestinal fibroblasts are distinguished by their gene expression patterns (Introduction, p1; Figure 2, p8). A person of ordinary skill in the arts would have been motivated to modify the method of Tong, as suggested by Vallier, and use fibroblasts derived from intestinal tissues specifically because their gene expression profiles suggest that they are especially suited for an intestinal niche and would therefore be more ideal for differentiation into intestinal cell types. Furthermore, because Higuchi indicates that human fibroblasts can readily be obtained from intestinal tissue (Isolation and primary culture of fibroblasts, p3) and because as taught by Vallier, it is known in the art that iPSCs can be derived from fibroblasts, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Tong, Halloin, Vallier, and Higuchi renders the invention unpatentable as claimed.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Tong et al. (Biomaterials, 2018, previously cited) in view of Halloin et al. (Stem Cell Reports, 2019) as evidenced by Tamminen et al. (PLOS ONE, 2015, previously cited), Miquel et al. (Stem Cell Rev and Rep, 2010, previously cited), and Yin et al. (Nature Methods, 2014), as applied to claim 1 above, and further in view of Nossol et al. (Histochem Cell Biol, 2011, previously cited).
In regards to claim 9, Tong teaches the cells cultured in a transwell system (see Fig. 1), and does not explicitly teach that the human pluripotent intestinal epithelial cells were exposed to air.
However, Nossol teaches that the specific function of the epithelium, as a critical barrier between the intestinal lumen and the organism’s internal microenvironment, is reflected by permanent maintenance of intercellular junctions and cellular polarity (Abstract, p103). Nossol continues that the intestinal epithelial cells are responsible for absorption of nutritional components, facing mechanical stress and changing oxygen supplementation via blood stream, and that oxygen itself can regulate the barrier and the absorptive function of the epithelium (Abstract, p103). To more accurately recapitulate the in vivo environment, Nossol devised a method that exposes intestinal epithelial cells to an oxygen enriched air-liquid interface, in vitro (ALI culture) (Abstract, p103). Compared to other methods, Nossol teaches that the ALI culture resulted in a significant increase in cell number, epithelial cell layer thickness, and expression and apical localization of the microvilli-associated protein villin (Abstract, p103). Nossol also teaches that functional analysis of protein uptake and degradation by epithelial cells cultured by this method demonstrates that the ALI system provides the necessary oxygen supply needed by cells (Abstract, p103). Moreover. Nossol teaches that the ALI system directly affects morphological differentiation and functional properties of intestinal cells in vitro (Abstract, p103).
Therefore, a person of ordinary skill in the arts would have been motivated to modify the method of Tong and add a step of exposing the human pluripotent intestinal epithelial cells because it would improve cell numbers, differentiation, and provide the oxygen needed to most accurately recapitulate an in vivo setting. Furthermore, because Nossol provides specific methods for culturing intestinal epithelial cells in air-liquid interface culture (Materials and methods, p104) and Tong and Nossol are in the same technical field of culturing intestinal epithelial cells, it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Tong, Halloin, and Nossol renders the invention unpatentable as claimed.
Response to Arguments
Applicant argues that claim 1 has been amended to use the open-ended term “comprising” to address enablement (Remarks, p5).
Applicant’s arguments filed 11/14/2025 with respect to the rejection under 35 USC 112(a) has been fully considered and is persuasive. The rejection of the instant claims under 35 USC 112(a) has been withdrawn.
Applicant argues that Tong discloses the WNT inhibitor IWP-2 specifically, and therefore, fails to disclose the Wnt inhibitors, including Wnt C-59, etc., as in claim 1 as amended.
Applicant’s arguments filed 11/14/2025 have been fully considered but are not found persuasive.
As discussed above, while Tong uses, the Wnt inhibitor IWP-2 (p67, column 2, last paragraph; Figure 5, p69), as taught by Halloin, IWP-2 and Wnt-C59 are both known in the art to be suitable for inhibiting Wnt signaling in vitro (Introduction, p366), and are therefore, art recognized equivalents for the same purpose. According to MPEP 2144.06, it is prima facie obvious to substitute equivalents known for the same purpose. Moreover, a person of ordinary skill in the art would have been motivated to choose Wnt-C59 because Halloin teaches that it has greater differentiation efficiency compared to IWP-2 (p371, left column; Fig. 4, p371). Additionally, because Halloin teaches that cells can be cultured alike with IWP-2 and Wnt-C59 (p371, left column; Fig. 4, p371), it could have been done with predictable results and a reasonable expectation of success.
Applicant requests rejoinder of claims 18-20 since they are similar to the currently examined claims which should be allowed (Remarks, p6).
Applicant’s arguments have been fully considered but are not persuasive. The instantly examined claims are not allowable, as discussed above, and therefore, consideration of rejoinder is premature at this time.
Conclusion
Nio claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631